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WO2025078463A1 - Extended dosing regimens for anti-cd20 antibodies in the treatment of multiple sclerosis - Google Patents

Extended dosing regimens for anti-cd20 antibodies in the treatment of multiple sclerosis Download PDF

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Publication number
WO2025078463A1
WO2025078463A1 PCT/EP2024/078440 EP2024078440W WO2025078463A1 WO 2025078463 A1 WO2025078463 A1 WO 2025078463A1 EP 2024078440 W EP2024078440 W EP 2024078440W WO 2025078463 A1 WO2025078463 A1 WO 2025078463A1
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WIPO (PCT)
Prior art keywords
ofatumumab
antibody
multiple sclerosis
pharmaceutical composition
polysorbate
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French (fr)
Inventor
Gordon Graham
Goeril Karlsson
Martin MERSCHHEMKE
Igor Vostiar
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present disclosure provides regimens in the treatment of multiple sclerosis for (e.g., subcutaneously) administering an anti-CD20 antibody at extended dosing intervals.
  • exemplary extended dosing regimens are provided, including for the monoclonal anti-CD20 antibody ofatumumab.
  • MS Multiple sclerosis
  • RMS Relapsing MS
  • Anti-CD20 monoclonal antibodies target CD20 expressed on B cells, which are thought to play a key role in myelin and axonal damage in MS, thereby suppressing disease inflammatory activity.
  • Exemplary anti-CD20 antibodies used in clinical practice in the treatment of MS include ofatumumab (KESIMPTA®/BONSPRI®), ocrelizumab (OCREVUS®), rituximab (RITUXAN®/MAB THERA®) and ublituximab (BRIUMVI®).
  • Ofatumumab (also known as 0MB 157) is a fully human type 1 immunoglobulin G1 kappa (IgGlx) monoclonal antibody.
  • Subcutaneous (s.c.) administration of ofatumumab leads to a rapid, frequency- and dose-dependent, B cell reduction.
  • Phase III clinical trials COMB157G2301 and COMB157G2302 (Hauser SL, Bar-Or A, Cohen JA, et al (2020) Ofatumumab versus Teriflunomide in Multiple Sclerosis.
  • less frequent subsequent dosing may further improve patient experience and clinical outcomes. For example, less frequent subsequent injections may further reduce the risk of any local injection site reactions, such as bruising, skin irritations, tissue damage or infections, thereby improving patient experience.
  • less frequent subsequent dosing may decrease the treatment burden on patients and their caregivers. This, in turn, may lead to increased compliance with the prescribed treatment regimen and improved clinical outcomes. Less frequent administration may also decrease the cost of distribution and reduce the environmental footprint of the distribution.
  • extended dosing intervals may reduce the ability to tightly control B cell depletion levels and thereby reduce the ability to interrupt MS treatment to enable sufficiently quick B cell repletion when desired, for example in the event of an infection or risk of infection, or emergence of other adverse events/conditions, which may represent a risk to patient safety (e.g. malignancy, pregnancy), or when switching MS therapy.
  • an extended dosing regimen should provide at least non-inferior clinical efficacy and safety to any previously approved regimen.
  • the preferred volume for subcutaneous injections is currently deemed to be around 2 mL or less, with larger volumes typically requiring additional agents that locally degrade the extracellular matrix (e.g., endoglycosidases, such as hyaluronidase). Reformulating antibodies for higher doses in smaller volumes can introduce changes in viscosity and stability, which can lead to aggregation, particle formation, and adverse events (e.g. injection-related reactions).
  • the present disclosure provides a novel and advantageous extended dosing regimen for subcutaneous (s.c.) administration of an anti-CD20 antibody (e.g., ofatumumab) in the treatment of MS.
  • an anti-CD20 antibody e.g., ofatumumab
  • the inventors determined an advantageous combination of anti-CD20 antibody (e.g., ofatumumab) dose and interval of administration which decreases the burden of treatment on patients without compromising the safety and/or efficacy of the treatment.
  • a subsequent (e.g., maintenance) dosing regimen of 135 mg ofatumumab s.c. administered once every two months offers MS patients a less frequent, yet safe and effective, ofatumumab dosing option.
  • the estimated pharmacokinetic and pharmacodynamic profiles for the 135 mg s.c. Q2M regimen show that it provides exposure coverage throughout the entire two-month dosing interval that is at least comparable (e.g., non-inferior) to the approved subsequent (e.g., maintenance) dosing regimen of ofatumumab of 20 mg s.c. once per month (Q1M).
  • a subsequent regimen of ofatumumab 135 mg s.c. once every two months after three s.c. 20 mg initial (e.g., loading) doses for three consecutive weeks is estimated to deplete B cell levels to ⁇ 10 cells/pL and maintain the B cell levels below that threshold during each entire two-month period between injections, and in some patients even below the B cell levels achieved with the Q1M regimen.
  • B cell levels achieved at the end of each 135 mg Q2M interval are similar to the B cell levels achieved at the end of each 20 mg Q1M interval.
  • a method of stabilizing, e.g., maintaining, the B cell count in a subject in need thereof, during dosing intervals comprising dosing the subject with ofatumumab at two-month intervals, to thereby stabilize, e.g., maintain, the B cell count in the subject.
  • the subject is dosed with ofatumumab at 135 mg subcutaneously at two-month intervals, e.g. every two months (Q2M).
  • the method maintains the subject’s B cell count to ⁇ 10 cells/pL.
  • the subject has multiple sclerosis (MS).
  • the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS).
  • SPMS secondary progressive multiple sclerosis
  • PPMS primary progressing multiple sclerosis
  • a method of treating multiple sclerosis (MS) in a subject in need thereof comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject at a dose of about 100-150 mg ((e.g., 100-150) e.g., about 110 mg (e.g., 110 mg) ofatumumab or about 130 mg (e.g., 130 mg) ofatumumab), e.g., about 120-150 mg (e.g., 120-150), e.g., about 130-140 mg ((e.g., 130-140 mg) (e.g., about 135 mg (e.g., 135 mg)) ofatumumab once about every two months (Q2M).
  • an anti-CD20 antibody e.g., ofatumumab
  • the method of treating MS includes (a) subcutaneously administering ofatumumab to the subject during an initial (e.g., loading) dosing regimen of three once-weekly about 19 mg to about 21 mg doses (e.g., about 20 mg doses, e.g., 20 mg) for three consecutive weeks (e.g., at weeks 0, 1 and 2) followed by (b) subcutaneously administering ofatumumab to the subject during a subsequent (e.g., maintenance) dosing regimen of about 130 mg to about 140 mg (e.g., about 135 mg, e.g., 135 mg) two weeks after the final 19-21 mg dose (e.g., at week 4) and once every two months thereafter (or once every eight weeks thereafter; Q2M).
  • an initial dosing regimen of three once-weekly about 19 mg to about 21 mg doses (e.g., about 20 mg doses, e.g., 20 mg) for three consecutive weeks (e.g., at weeks 0, 1 and 2) followed by (
  • the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
  • SPMS secondary progressive multiple sclerosis
  • PPMS primary progressing multiple sclerosis
  • the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
  • RMS relapsing multiple sclerosis
  • CIS clinically isolated syndrome
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS active secondary progressive multiple sclerosis
  • the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
  • the ofatumumab is administered in a pharmaceutical composition having pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0, e.g., pH 5.3 to 5.7, e.g., 5.4 to 5.6, e.g., about pH 5.5, about pH 5.2, about pH 5.3, about pH 5.4, about pH 5.6, about pH 5.7, or about pH 5.8.), e.g., about pH 5.5.
  • pH 5.0 to 7.0 e.g., pH 5.3 to 5.7, e.g., 5.4 to 5.6, e.g., about pH 5.5, about pH 5.2, about pH 5.3, about pH 5.4, about pH 5.6, about pH 5.7, or about pH 5.8.
  • a pH of about 5.5 encompasses, e.g., pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4-5.6), e.g., pH 5.5.
  • a pH of 5.5 ⁇ 0.2 is acceptable.
  • a pH range of 5.3-5.8 or 5.2- 5.8 is acceptable for release of the composition (drug product) for clinical use.
  • the pharmaceutical composition further includes arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), optionally wherein the pharmaceutical composition further comprises EDTA.
  • the pharmaceutical composition comprises about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally wherein the pharmaceutical composition further comprises about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA.
  • the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), optionally wherein the pharmaceutical composition further comprises about 0.05 mM (e.g., 0.05 mM) EDTA.
  • the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), and has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2 cP to about 3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
  • mM e.g., 50 mM
  • 50 mM sodium acetate
  • 51 mM e.g., 51 mM
  • sodium chloride e.g.,
  • the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5).
  • 51 mM e.g., 51 mM
  • sodium chloride e.g., about 1% (w/v) (e.g., 1% (w/v))
  • arginine free base e.g., arginine free base
  • polysorbate e.g., polysorbate 80
  • the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), and has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2 cP to about 3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
  • 51 mM e.g., 51 mM
  • sodium chloride e.g., about 1% (w/v)
  • arginine free base e.g., arginine free base
  • polysorbate e.g., polysorbate 80
  • subsequent (e.g., maintenance) doses of ofatumumab are administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL, e.g., 80-100 mg/mL, e.g., about 90 mg/mL, e.g., 90 mg/mL, wherein the pharmaceutical composition has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
  • the ofatumumab is administered in a pharmaceutical composition that does not comprise an endoglycosidase, e.g., hyaluronidase.
  • the ofatumumab is administered using a pre-filled pen (autoinjector).
  • the pre-filled pen contains a fixed single unit dose of about 135 mg (e.g., 135 mg) ofatumumab.
  • the method results in one or more of (a) reduction in number of Gd+Tl lesions relative to baseline; (b) reduction in number of new or enlarging T2 lesions relative to baseline; and/or (c) reduction in annualized relapse rate (ARR) relative to baseline.
  • the methods provided herein may result in one or more of: a) Gd+ T1 lesion rates of ⁇ 0.03; b) annualized rates of new or enlarging T2 lesions of ⁇ 0.72; and/or c) annualized relapse rates (ARR) of ⁇ 0.11.
  • the IRR number or severity that is non-inferior is an injection-related systemic reaction, which is a reaction or symptom that occurred within 24 hours after injection of ofatumumab.
  • injection-related systemic reactions occur in less than 24.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein. In some embodiments, injection-related systemic reactions occur in less than 16.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein.
  • a solution for injection containing about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) of an anti-CD20 antibody (e.g., ofatumumab), e.g., in a pharmaceutical composition as disclosed herein.
  • the solution for injection is for subcutaneous administration.
  • the solution for injection is pH about 5.0 to about 7.0, e.g. pH 5.0-7.0, e.g., pH about 5.5., e.g., pH 5.5.
  • the solution for injection further includes arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), optionally wherein the solution further comprises EDTA.
  • the solution for injection comprises about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally wherein the solution further comprises about 0.02 to about 0.2 mM (e.g.
  • the solution comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g. pH 5.5), optionally wherein the solution further comprises about 0.05 mM (e.g., 0.05 mM) EDTA.
  • the solution includes ofatumumab at a concentration of about 80-100 mg/mL, e.g., 80-100 mg/mL, e.g., about 90 mg/mL, e.g., 90 mg/mL.
  • the solution for injection described above has a viscosity from no more than about 3 cP (e.g., no more than 3 cP), e.g., about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
  • a pre-filled syringe or pre-filled pen contains the solution as described above, e.g., in a total volume of around 1.5 mL (e.g., 1.5 mL), e.g., formulated for subcutaneous administration.
  • kits comprising an anti-CD20 antibody (e.g., ofatumumab) at one or more fixed single unit doses of about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) each.
  • an anti-CD20 antibody e.g., ofatumumab
  • Figure 1 shows the simulated population B cell profiles of a subsequent dosing regimen (maintenance dose regimen) of 40 mg ofatumumab s.c. once every two months (Q2M) versus 20 mg ofatumumab s.c. once every month (Q1M). Both subsequent dosing regimens start at week 4, following an initial dosing regimen (loading dose regimen) of three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2.
  • Figure 2 shows the simulated population PK profiles for the 40 mg ofatumumab s.c. Q2M subsequent regimen versus the 20 mg ofatumumab s.c. Q1M subsequent regimen. Both subsequent dosing regimens start at week 4, following three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2 (log scale).
  • the arrows point to the 95% percentile (shaded areas) and the median (solid lines).
  • the vertical axis shows the concentration of ofatumumab (mg/mL), while the horizontal axis shows the time since the first dose of ofatumumab was administered.
  • Figure 4 shows the simulated population PK profiles for the 80 mg ofatumumab s.c. Q2M subsequent regimen versus the 20 mg ofatumumab s.c. Q1M subsequent regimen. Both subsequent dosing regimens start at week 4, following three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2 (log scale).
  • the arrows point to the 95% percentile (shaded areas) and the median (solid lines).
  • the vertical axis shows the concentration of ofatumumab (mg/mL), while the horizontal axis shows the time since the first dose of ofatumumab was administered.
  • the anti-CD20 antibody is ofatumumab.
  • Ofatumumab (0MB 157) is a fully human type 1 immunoglobulin G1 kappa (IgGlx) monoclonal antibody (mAb) that targets CD20 expressed on B cells and has been developed for the treatment of MS, particularly relapsing MS (RMS).
  • Ofatumumab specifically recognizes a conformational (i.e., non-continuous) epitope encompassing both the large and small extracellular loops on the human CD20 molecule, which allows ofatumumab to bind very close to the plasma membrane.
  • the binding of ofatumumab to CD20 induces B cell lysis primarily through complement-dependent cytotoxicity (CDC) and, to a lesser extent, by antibody-dependent cell-mediated cytotoxicity (ADCC).
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • PK pharmacokinetics
  • Tl/2 half-life
  • Binding to human B cells has been reported to occur with a concentration of a drug that gives half-maximal response (EC50) of 287 ng/mL.
  • EC50 half-maximal response
  • the theoretical molecular mass is 146 kDa, calculated from the amino acid composition deduced from the DNA sequence.
  • Ofatumumab is typically produced in a murine cell line (NSO).
  • the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the light chain complementarity determining regions of SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, wherein the heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5, and the light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 10.
  • Any one of these anti-CD20 antibodies can be considered similar to ofatumumab, the full sequence of which is defined by SEQ ID NOs 5 and 10.
  • percentage sequence identity refers to the percentage of identical amino acid residues when two sequences are aligned and compared across their full length. Accordingly, the percentage sequence identity can be calculated using global pairwise sequence alignment tools (end-to-end alignment of the sequences to be aligned), such as Needle (EMBOSS), which creates an optimal global alignment of two sequences using the Needleman-Wunsch algorithm.
  • EMBOSS global pairwise sequence alignment tools
  • the default settings are BLOSUM62 matrix, GAP OPEN PENALTY 10, GAP EXTEND PENALTY 0.5, END GAP PENALTY false, END GAP OPEN PENALTY 10, END GAP EXTEND PENALTY 0.5.
  • Ocrelizumab (also known as 2H7) is a humanized monoclonal antibody based on the human immunoglobulin G1 (IgGl) framework that contains heavy chain VHIII and light chain VKI subgroup sequences. Ocrelizumab selectively targets CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis.
  • ADCP antibody-dependent cellular phagocytosis
  • ADCC antibody-dependent cellular cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Ocrelizumab has been reported as having a half-life of around 26 days.
  • the molecular formula of intact ocrelizumab is C6482H9952N1712O2014S46.
  • the calculated molecular mass of intact deglycosylated ocrelizumab is approximately 145,564 Da (peptide chains only, without heavy chain C-terminal lysine residues).
  • Ocrelizumab is typically produced in Chinese Hamster Ovary cells by recombinant DNA technology. Ocrelizumab is defined by SEQ ID NOs 11-20 (Table 9).
  • the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18.
  • the anti-CD20 antibody comprises the variable heavy chain sequence of SEQ ID NO: 14 and the variable light chain sequence of SEQ ID NO: 19, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 14 and/or SEQ ID NO: 19.
  • the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 15 and the light chain sequence of SEQ ID NO: 20, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15 and/or SEQ ID NO: 20.
  • the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the variable heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 14, and the variable light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 19.
  • the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15, and the light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 20.
  • Any one of these anti-CD20 antibodies can be considered similar to ocrelizumab, the full sequence of which is defined by SEQ ID NOs 15 and 20.
  • Ublituximab is a chimeric monoclonal antibody. It is produced in the rat cell line YB2/0. Ublituximab selectively targets CD20-expressing B cells and induces their lysis. Ublituximab depletes B cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Ublituximab has been reported as having an estimated half-life of around 22 days.
  • the molecular formula of intact ublituximab is C6418H9866N1702O2006S48.
  • the calculated molecular mass of ublituximab is 144,504 Da.
  • the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 21 and/or SEQ ID NO: 22.
  • a method of treating multiple sclerosis (MS) in a subject in need thereof comprising subcutaneously administering an anti-CD20 antibody to the subject once every about 2 months, e.g., at a dose of about 100-600 mg (e.g., about 600 mg, about 200 mg or about 135 mg).
  • a method of treating multiple sclerosis in a subject in need thereof comprising subcutaneously administering an anti-CD20 antibody to the subject at a dose of about 100-600 mg once every about 2-6 months.
  • the anti-CD20 antibody is subcutaneously administered to the subject once every 2 months (Q2M).
  • the anti-CD20 antibody is subcutaneously administered to the subject at a dose of about 135 mg.
  • the term “4 weeks” is equivalent to “1 month”
  • the term “12 weeks” is equivalent to “3 months”
  • the term “24 weeks” is equivalent to “6 months”, unless specifically stated otherwise or obvious from context.
  • “about 2 months” can mean between 6 and 10 weeks
  • “2 months” can mean between 7 and 9 weeks, typically 8 weeks.
  • “about 6 months” can mean between 20 and 28 weeks and “6 months” can mean between 22 and 26 weeks, typically 24 weeks.
  • the term “every 2 months” means “once every 2 months”, and “every about 2 months” means “once every about 2 months”, and so on, unless specifically stated otherwise or obvious from the context.
  • the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
  • RMS relapsing multiple sclerosis
  • CIS clinically isolated syndrome
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS active secondary progressive multiple sclerosis
  • the anti-CD20 antibody e.g., ofatumumab
  • the anti-CD20 antibody is administered at a dose of about 130-140 mg once every 6-10 weeks (about 2 months).
  • the anti-CD20 antibody e.g., ofatumumab
  • the anti-CD20 antibody is administered at a dose of about 135 mg once every 6-10 weeks (about 2 months).
  • the pharmaceutical composition comprises (w/v) between about 0.5 and about 5.0% (e.g., 0.5 and 5.0%), about 0.5 to about 2.0% (e.g., 0.5 to 2.0%), about 0.5 to about 2.5% (e.g., 0.5 to 2.5%), about 0.5 to about 3.0% (e.g., 0.5 to 3.0%), about 0.5 to about 3.5% (e.g., 0.5 to 3.5%), about 0.5 to about 4.0% (e.g., 0.5 to 4.0%), or about 0.5 to about 4.5% (e.g., 0.5 to 4.5%) arginine free base (L-arginine).
  • arginine free base L-arginine
  • the pharmaceutical composition comprises about 0.02 mM to about 0.2 mM (e.g., 0.02 to 0.2 mM), about 0.02 mM to about 0.1 mM (e.g., 0.02 mM to 0.1 mM), about 0.02 mM to about 0.15 mM (e.g., 0.02 mM to 0.15 mM), about 0.04 mM to about 0.1 mM (e.g., 0.04 mM to 0.1 mM), about 0.03 mM to about 0.15 mM (e.g., 0.03 mM to 0.15 mM), or about 0.03 mM to about 0.2 mM (e.g., 0.03 mM to 0.2 mM) EDTA.
  • 0.02 mM to about 0.2 mM e.g., 0.02 to 0.2 mM
  • about 0.02 mM to about 0.1 mM e.g., 0.02 mM to 0.1 mM
  • the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM), about 0.03 mM (e.g., 0.03 mM), about 0.04 mM (e.g., 0.04 mM), or about 0.06 mM (e.g., 0.06 mM) EDTA.
  • the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM) EDTA.
  • EDTA can conveniently be incorporated into the composition using disodium edetate dihydrate. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
  • the pH of the pharmaceutical compositions disclosed herein, in particular those comprising ofatumumab can be about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), e.g., about pH 5.5, e.g., pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3- 5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4-5.6), e.g., pH 5.5.
  • the pharmaceutical composition is adjusted to pH 5.0 to 7.0.
  • the pharmaceutical composition is adjusted to pH 5.0, 5.5, 6.0, 6.5 or 7.0. In a preferred embodiment, the pharmaceutical composition is adjusted to pH 5.5. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
  • the pharmaceutical composition may thus comprise about 1 mM (e.g., 1 mM), about 5 mM (e.g., 5 mM), about 10 mM (e.g., 10 mM), about 15 mM (e.g., 15 mM) or about 20 mM (e.g., 20 mM) methionine (e.g., L- methionine).
  • the pharmaceutical composition comprises about 5 mM (e.g., 5 mM) methionine (e.g., L-methionine).
  • the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v) polysorbate (e.g., polysorbate 80), and adjusted to pH about 5.5 (e.g., pH 5.5), and optionally about 0.05 mM (e.g., 0.05 mM) EDTA.
  • the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g. polysorbate 80), and adjusted to pH about 5.5 (e.g., pH 5.5), and optionally about 0.05 mM (e.g., 0.05 mM) EDTA.
  • compositions described herein include low-viscosity formulations of relatively high concentrations of ofatumumab, which can be conducive for subcutaneous administration.
  • pharmaceutical compositions comprising ofatumumab (e.g., about 90 mg/mL ofatumumab, e.g., 90 mg/mL) that have a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., about 2.3 centipoise (cP) (e.g., 2.3 cP).
  • a pharmaceutical composition comprising about 80-100 mg/mL, (e.g., 80-100 mg/mL), e.g., about 90 mg/mL (e.g. 90 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0).
  • This composition can be adjusted to pH about 5.0 to
  • a pharmaceutical composition consisting of about 80- 100 mg/mL (e.g., 80-100 mg/mL), e.g., about 90 mg/mL (e.g. 90 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base (e.g.
  • L-arginine about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) (e.g., with hydrochloric acid).
  • This composition can be used to deliver about 135 mg (e.g., 135 mg) ofatumumab in a volume convenient for s.c. administration.
  • the pharmaceutical composition comprises about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to pH about 5.5 (e.g., pH 5.5).
  • pH about 5.5 e.g., pH 5.5
  • the pharmaceutical composition may consist of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g.
  • L- arginine about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid).
  • About 1.5 mL (e.g., 1.5 mL) of this composition provides about 135 mg (e.g., 135 mg) ofatumumab in a suitably stable formulation acceptable for subcutaneous administration. Indeed, as shown in Example 2, this formulation remains stable for at least 6 months at its intended storage conditions (e.g. 5°C ⁇ 3°C).
  • the anti-CD20 antibody is ofatumumab, and may be present in the compositions at any of the concentrations described above, e.g., about 35-115 mg/mL (e.g., 35-115 mg/mL), such as about 50 mg/mL (e.g., 50 mg/mL) or about 90 mg/mL (e.g., 90 mg/mL).
  • a pharmaceutical composition comprising about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).
  • a solution for injection comprising about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).
  • the anti-CD20 antibody is ocrelizumab.
  • the anti-CD20 antibody is typically administered in a pharmaceutical composition that further comprises an agent that locally degrades the extracellular matrix, to allow the subcutaneous space to receive such larger volume.
  • the anti-CD20 antibody e.g., ocrelizumab
  • An exemplary agent is hyaluronidase, preferably recombinant human hyaluronidase, such as rHuPH20.
  • the enzyme hyaluronidase can be used to induce local and transient modification of the subcutaneous space through degradation of hyaluronan (i.e., hyaluronic acid), which is a naturally occurring glycosaminoglycan found throughout the body that creates resistance to bulk fluid flow in the extracellular matrix and limits large- volume subcutaneous drug delivery.
  • hyaluronan i.e., hyaluronic acid
  • the hyaluronidase enables subcutaneous bulk fluid flow and facilitates the subcutaneous delivery of large volumes.
  • a purified recombinant human form of hyaluronidase (recombinant human hyaluronidase [rHuPH20]) has been commercially available in the US since 2005 (HYLENEX® recombinant) and has been co-formulated with other therapeutic products using the ENHANZE® drug delivery technology.
  • ENHANZE® has been shown to reduce dose administration time and dosing frequency and enable the delivery of large volumes for rapid SC injections (5 to 15 mL).
  • ocrelizumab is administered in a pharmaceutical composition that further comprises recombinant human hyaluronidase (e.g., rHupH20), and optionally sodium acetate, trehalose, polysorbate (e.g., polysorbate 20), typically at pH about 5.0-6.0.
  • the ocrelizumab pharmaceutical composition may further comprise glacial acetic acid.
  • the pharmaceutical composition comprises about 1,000 to about 16,000 U/mL (e.g., 1,000 to 16,000 U/mL) hyaluronidase enzyme (e.g., rHupH20), wherein the said amount corresponds to about 0.01 mg to 0.15 mg hyaluronidase enzyme based on an assumed specific activity of about 100,000 U/mg (e.g., 100,000 U/mg).
  • the pharmaceutical composition comprises about 1,500 to about 12,000 U/ml (e.g., 1,500 to 12,000 U/ml) hyaluronidase (e.g., rHupH20).
  • the pharmaceutical composition comprises about 2,000 to about 12,000 U/mL (e.g., 2,000 to 12,000 U/mL) hyaluronidase (e.g., rHupH20).
  • the pharmaceutical composition comprises about 1 mM mM to about 15 mM (e.g., 1 mM to 15 mM) glacial acetic acid, about 2 mM to about 10 mM (e.g., 2 mM to 10 mM) glacial acetic acid, or about 3 mM to about 5 mM (e.g., 3 mM to 5 mM) glacial acetic acid.
  • the pharmaceutical composition comprises about 4 mM (e.g., 4 mM) glacial acetic acid.
  • the pharmaceutical composition comprises about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g.,
  • the pharmaceutical composition comprises about 40 mg/mL (e.g., 40 mg/mL) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3).
  • This pharmaceutical composition is particularly useful for treating multiple sclerosis in a subject in need thereof.
  • An additional particularly useful pharmaceutical composition comprises about 40 mg/ml ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 12,000 U/ml (e.g., 12,000 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3).
  • hyaluronidase e.g., rhuPH20
  • the anti-CD20 antibody disclosed herein may be administered via any suitable route, but is typically administered subcutaneously (s.c.), typically via injection.
  • a preferred anti-CD20 antibody is ofatumumab.
  • the pre-filled syringe or the pre-filled pen, i.e., autoinjector contains a single unit dose of between about 100-170 mg ofatumumab.
  • the pre-filled syringe or the pre-filled pen, i.e., autoinjector contains a single unit dose of between about 110-170 mg ofatumumab.
  • the pre-filled syringe or the pre-filled pen, i.e., autoinjector contains a single unit dose of between about 120-150 mg ofatumumab.
  • the pharmaceutical composition comprising the anti-CD20 antibody is provided in a pre-filled pen, i.e., autoinjector.
  • a pre-filled pen i.e., autoinjector.
  • an autoinjector suitable for use according to the present disclosure is the Sensoready® pen.
  • the anti-CD20 antibody is ofatumumab.
  • a preferred anti-CD20 antibody is ofatumumab.
  • the solution for injection comprises between about 110 and about 160 mg ofatumumab in a pharmaceutical composition as disclosed herein.
  • the solution for injection comprises between about 120 and about 150 mg ofatumumab in a pharmaceutical composition as disclosed herein.
  • the solution for injection comprises between about 130 and about 140 mg ofatumumab in a pharmaceutical composition as disclosed herein.
  • the solution for injection comprises about 135 mg ofatumumab in a pharmaceutical composition as disclosed herein.
  • the initial doses of the anti-CD20 antibody are administered in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 0.4 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 50 mg/mL.
  • the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises the anti-CD20 antibody in a pharmaceutical composition as disclosed herein.
  • the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 90 mg/mL.
  • the subsequent doses of the anti-CD20 antibody are administered in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 90 mg/mL.
  • a preferred anti-CD20 antibody is ofatumumab. Accordingly, the initial dose of ofatumumab may be administered in a volume of about 0.4 mL; the subsequent dose of ofatumumab may be administered in a volume of about 1.5 mL.
  • ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of between about 80 and about 100 mg/mL.
  • the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of between about 80 and about 100 mg/mL.
  • ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of between about 85 and about 95 mg/mL.
  • the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of between about 85 and about 95 mg/mL.
  • ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of about 90 mg/mL.
  • the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of about 90 mg/mL.
  • MS multiple sclerosis
  • the method comprises subcutaneously administering an anti-CD20 antibody to the subject.
  • the MS is RMS.
  • the MS is RRMS.
  • the MS is PPMS.
  • the MS is SPMS.
  • the MS is CIS.
  • any reference to a method for treatment herein also discloses the anti-CD20 antibody for use in said method for treatment, the use of the anti-CD20 antibody in said method for treatment, and the use of the anti-CD20 antibody in the manufacture of a medicament for said treatment.
  • an anti-CD20 antibody for use in treating multiple sclerosis (MS) in a subject. Also provided herein is the use of an anti-CD20 antibody for treating multiple sclerosis. Additionally, provided herein is the use of an anti-CD20 antibody for the manufacture of a medicament for the treatment of multiple sclerosis.
  • the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
  • RMS relapsing multiple sclerosis
  • CIS clinically isolated syndrome
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS active secondary progressive multiple sclerosis
  • the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
  • the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS).
  • SPMS secondary progressive multiple sclerosis
  • PPMS primary progressing multiple sclerosis
  • a method of treating relapsing multiple sclerosis in a subject in need thereof comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate about 19-21 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering the anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 130-140 mg at week 4 and once every 2 months thereafter.
  • an anti-CD20 antibody e.g., ofatumumab
  • a method of treating multiple sclerosis in a subject in need thereof comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate about 20 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering the anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 135 mg at week 4 and once every 2 months thereafter.
  • an anti-CD20 antibody e.g., ofatumumab
  • the methods disclosed herein further comprise administering a concomitant therapy, for example selected from the group of a corticosteroid, an antihistamine, an acetaminophen.
  • a concomitant therapy for example selected from the group of a corticosteroid, an antihistamine, an acetaminophen.
  • the concomitant therapy is a corticosteroid.
  • the concomitant therapy is an antihistamine.
  • the concomitant therapy is an acetaminophen.
  • the term ‘concomitant therapy’ includes administration of another agent (e.g., selected from the group consisting of a corticosteroid, an antihistamine, and an acetaminophen) before, during, or after administration of the anti-CD20 antibody (e.g., ofatumumab), e.g., before, during, or after administration of the first dose of the anti-CD20 antibody; or before, during, or after administration of one or more subsequent or each dose of the anti-CD20 antibody.
  • another agent e.g., selected from the group consisting of a corticosteroid, an antihistamine, and an acetaminophen
  • the anti-CD20 antibody e.g., ofatumumab
  • the concomitant therapy is administered prior to the administration of the anti-CD20 antibody. In some embodiments, the concomitant therapy is administered 30 to 60 minutes prior to the administrations of the anti-CD20 antibody.
  • the concomitant therapy is administered during the administration of the anti-CD20 antibody. In other embodiments, the concomitant therapy is administered following administration of the anti-CD20 antibody.
  • no premedication is administered prior to administration of the anti-CD20 antibody.
  • a preferred anti-CD20 antibody is ofatumumab.
  • the subject is a mammal. In preferred embodiments, the subject is a human. In some embodiments, the subject is referred to as the patient.
  • the anti-CD20 antibody is administered irrespective of body weight, sex, age, race or baseline B cell count of the subject.
  • the subject is an adult (e.g., a human adult). In some embodiments, the subject is aged 18 to 55 years (inclusive). In some embodiments, the subject is over 55 years old.
  • the subject has been diagnosed with multiple sclerosis according to the 2017 Revised McDonald criteria (see Table 1 of Thompson AJ, Baranzini SE, Geurts J, et al (2016) Multiple sclerosis. Lancet; 391(10130): 1622-36).
  • the subject has a disability status with an (Expanded Disability Status Scale (EDSS) score of 0 to 5.5 (inclusive).
  • EDSS Expanded Disability Status Scale
  • the subject’s B cells have already been depleted by any disease modifying MS therapy prior to initiation of the therapy disclosed herein, e.g., prior to administering ofatumumab Q2M (e.g., at about 135 mg s.c.).
  • an MS subject to be treated by the methods disclosed herein may already have a B cell count ⁇ 10 cells/pL when administering the first dose of the anti-CD20 antibody (e.g., ofatumumab) according to the present disclosure (e.g., at about 135 mg s.c. and once every about two months thereafter).
  • the anti-CD20 antibody e.g., ofatumumab
  • the present disclosure e.g., at about 135 mg s.c. and once every about two months thereafter.
  • the patient is neurologically stable within one month prior to the first administration of the anti-CD20 antibody (e.g. ofatumumab).
  • Neurologically stable refers to a clinical state characterized by lack of change in mental status or level of consciousness. This state may comprise control of seizures; absence of new neurologic defects, e.g. aphasia, ataxia, dysarthria, paresis, paralysis, visual field loss, or blindness, and is defined as neurologically stability.
  • the subject is receiving or has received a disease modifying therapy for multiple sclerosis, such as ofatumumab, glatiramer acetate, ocrelizumab, ublituximab, cladribine, fmgolimod, natalizumab, teriflunomide, mitoxantrone or dimethyl fumarate.
  • a disease modifying therapy for multiple sclerosis such as ofatumumab, glatiramer acetate, ocrelizumab, ublituximab, cladribine, fmgolimod, natalizumab, teriflunomide, mitoxantrone or dimethyl fumarate.
  • the subject is receiving or has received an anti-CD20 antibody therapy.
  • the anti-CD20 antibody is selected from ofatumumab, ocrelizumab, rituximab or ublituximab.
  • the subject has received at least 1 dose of the anti-CD20 antibody.
  • the subject has received at least 12 doses of the anti-CD20 antibody.
  • the subject has received at least between 1-12 doses and the anti-CD20 antibody.
  • the subject is receiving or has received an anti-CD20 antibody (e.g., ofatumumab) once every month.
  • the subject has received an initial dose of an anti-CD20 antibody (e.g., ofatumumab) at weeks 0, 1 and 2, followed by one or more subsequent doses of the anti-CD20 antibody (e.g., ofatumumab) starting at week 4 and administered every month thereafter.
  • the subject has received at least 1 monthly dose of the anti-CD20 antibody (e.g., ofatumumab).
  • the subject has received at least 12 monthly doses of the anti-CD20 antibody (e.g., ofatumumab).
  • the subject has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 one monthly doses of the anti-CD20 antibody (e.g., ofatumumab).
  • the patient is newly diagnosed.
  • a newly diagnosed patient has not received any previous treatment (e.g. disease-modifying therapy) for multiple sclerosis.
  • the subject has had at least 1 relapse during the year prior to treatment. In some embodiments, the subject has had at least 2 relapses during the 2 years prior to treatment. In some embodiments, the subject has had a positive Gd-enhancing MRI scan during the year prior to treatment. In some embodiments, the subject has active disease, meaning that they have relapses and/or signs of active inflammation on MRI scans.
  • the patient has undergone screening for Hepatitis B virus (HB V) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment. Screening may include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing. This testing may be complemented with other appropriate markers as per local guidelines.
  • the patient does not have an active HBV infection. For instance, the patient does not have active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. Accordingly, the patient to be treated has undergone screening for Hepatitis B virus (HBV) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment and/or does not have an active HBV infection.
  • HBV Hepatitis B virus
  • the patient does not have a known IgE-mediated hypersensitivity to the anti-CD20 antibody (e.g. ofatumumab).
  • the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) or to any of one of the excipients in the anti-CD20 antibody (e.g. ofatumumab) formulation.
  • the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) or to any ingredient in the formulation, including any non-medicinal ingredient, component or container.
  • the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment.
  • the patient is not in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia). Accordingly, the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment and/or is not in a severely immunocompromised state.
  • the patients to be treated can have any one or more of the above characteristics.
  • the patient could have one or more of the following characteristics: a) the patient has undergone screening for Hepatitis B virus (HBV) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment; b) the patient does not have an active HBV infection; c) the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment; d) the patient is not in a severely immunocompromised state (e.g.
  • HBV Hepatitis B virus
  • the patient does not have a known IgE-mediated hypersensitivity to the anti-CD20 antibody (e.g. ofatumumab); and/or f) the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) and/or to any of the excipients of the anti-CD20 antibody (e.g. ofatumumab) formulation, including any non-medicinal ingredient, component or container.
  • a known IgE-mediated hypersensitivity to the anti-CD20 antibody e.g. ofatumumab
  • the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) and/or to any of the excipients of the anti-CD20 antibody (e.g. ofatumumab) formulation, including any non-medicinal ingredient, component or container.
  • a target level of B cell depletion is achieved following treatment according to the methods disclosed herein.
  • the methods provided herein deplete and/or maintain the subject’s B cell counts to ⁇ about 10 cells/pL (e.g., 10 cells/pL).
  • the methods provided herein result in one or more of a) reduction in number of Gd+Tl lesions relative to baseline; b) reduction in number of new or enlarging T2 lesions relative to baselines; and/or c) reduction in annualized relapse rate (ARR) relative to baseline.
  • the methods provided herein e.g., using a subsequent dosing regimen of 135 mg ofatumumab s.c. Q2M
  • a reference maintenance regimen e.g., a subsequent dosing regimen of 20 mg ofatumumab s.c.
  • Q1M in one or more of: a) reduction in number of Gd+Tl lesions; b) reduction in number of new or enlarging T2 lesions; c) reduction in ARR relative to a reference maintenance regimen; d) number and/or severity of injection-related reactions (IRRs); and/or e) immunogenicity (e.g., incidence of anti-drug antibodies (ADA)).
  • the methods provided herein achieve Gd+Tl lesion rates of - 0.25 or less. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of ⁇ 0.1. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of 0.01-0.05. In some embodiments, the methods provided herein Gd+Tl lesion rates of 0.005-0.05. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates ⁇ 0.005. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of ⁇ 0.02. In a preferred embodiment, the methods provided herein achieve Gd+ T1 lesion rates of ⁇ 0.03.
  • the methods provided herein achieve annualized new or enlarging T2 lesions rates of 4 or less. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 2. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 1. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 0.9. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 0.8. In a preferred embodiment, the methods provided herein achieve annualized new or enlarging T2 lesions rates of ⁇ 0.72.
  • the method provided herein achieved annual relapse rates (ARR) of less than 0.25. In some embodiments, the method provided herein achieve ARR of less than 0.22, less than 0.20, less than 0.15. or less than 0.12. In a preferred embodiment, the methods provided herein achieve an ARR of ⁇ 0.11.
  • ARR annual relapse rates
  • the methods provided herein may result in one or more of: a) Gd+ T1 lesion rates of ⁇ 0.03; b) annualized rates of new or enlarging T2 lesions of ⁇ 0.72; and/or c) annualized relapse rates (ARR) of ⁇ 0.11.
  • injection-related systemic reactions occur in less than 24.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein. In some embodiments, injection-related systemic reactions occur in less than 16.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein.
  • the methods provided herein deplete and/or maintain the subject’s B cell counts to ⁇ 10 cell/pL, and/or achieve Gd+Tl lesion rates of 0.01-0.05.
  • the methods provided herein deplete and/or maintain the subject’s B cell count to ⁇ 10 cells/pL, ⁇ 8 cells/pL or ⁇ 5 cells/pL; and/or achieve Gd+Tl lesions rates (number of Gd+Tl lesions per MRI scan) of ⁇ 0.05, or ⁇ 0.02.
  • the fixed single unit dosage comprises about 100 to about 600 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 100 to about 170 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 135 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 600 mg of the anti-CD20 antibody.
  • a preferred anti-CD20 antibody is ofatumumab (or a similar anti-CD20 antibody). Accordingly, in some embodiments, the fixed single unit dosage comprises about 110-160 mg ofatumumab each. In some embodiments, the fixed single unit dosage comprises about 120-150 mg ofatumumab each. In some embodiments, the fixed single unit dosage comprises about 130-140 mg ofatumumab each. In a preferred embodiment, the fixed single unit dosage comprises about 135 mg ofatumumab each. The fixed single unit dosage facilitates efficient depletion and maintenance of low B cell levels for up to 2 months.
  • a fixed single unit dosage of ocrelizumab (or a similar anti-CD20 antibody).
  • the fixed single unit dosage comprises about 135 mg ocrelizumab each.
  • the fixed single unit dosage comprises about 480-720 mg ocrelizumab each.
  • the fixed single unit dosage comprises about 540-660 mg ocrelizumab each.
  • the fixed single unit dosage comprises about 600 mg ocrelizumab each.
  • the fixed single unit dosage comprises about 730-1,110 mg ocrelizumab each.
  • the fixed single unit dosage comprises about 820-1,020 mg.
  • the fixed single unit dosage comprises about 920 mg ocrelizumab each.
  • a fixed single unit dosage of ublituximab (or a similar anti-CD20 antibody).
  • the fixed single unit dosage comprises about 100-170 mg ublituximab each. In some embodiments, the fixed single unit dosage comprises about 135 mg ublituximab each.
  • kits comprising an anti-CD20 antibody at one or more fixed single unit doses as described above.
  • a kit comprising one or more pre-filled pens, i.e., autoinjectors, or pre-filled syringes each containing a fixed single unit dose of the anti-CD20 antibody as described above.
  • the kit further comprises three pre-filled pens, i.e., autoinjectors or pre-filled syringes each containing a fixed single unit dose of about 20 mg of the anti-CD20 antibody (e.g., ofatumumab).
  • each single fixed dose is provided in a total volume of about 0.4 mL. In a preferred embodiment, each single fixed dose is provided in a total volume of about 1.5 mL. In some embodiments, each single fixed dose is provided in a total volume of about 2 mL.
  • Neurofilament light chain may be a useful biomarker of MS disease progression and responsiveness to treatment.
  • higher levels of NFL have been found to correlate with an increase in T2 and Gd+Tl lesions as well as increased frequency of relapse.
  • provided herein is the use of NFL as a prognostic biomarker for MS disease activity in subjects.
  • the subject is undergoing treatment with an anti-CD20 antibody.
  • Also provided herein is a method of predicting MS relapses of a subject comprising detecting NFL levels (pg/mL).
  • the method comprises detecting NFL levels in the cerebrospinal fluid or the blood of the subject.
  • the subject is undergoing treatment with an anti-CD20 antibody.
  • Also provided herein is a method of treating MS in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody to the subject, wherein the subject has elevated NFL levels, e.g., elevated NFL levels in the blood or cerebrospinal fluid.
  • the anti-CD20 antibody is ofatumumab.
  • Also provided herein is a method of treating MS in a subject in need thereof, wherein the method comprises i) subcutaneously administering an anti-CD20 antibody to the subject and ii) monitoring the NFL levels of the subject.
  • the anti- CD20 antibody is ofatumumab.
  • EDSS Expanded Disability Status Scale
  • SDMT Symbol Digit Modalities Test
  • RAVLT Rey Auditory Verbal Learning Test
  • BVMT-R Brief Visuospatial Memory Test-Revised
  • T25-FW timed 25-foot walk test
  • 9-HPT 9-hole pegboard test
  • Oculomotor assessment may involve measuring eye movement parameters obtained from fixation, pro-saccade, anti-saccade, smooth pursuit visual and optokinetic nystagmus tasks. Oculomotor assessment may serve as an eye movement biomarker for disease progression, optionally a digital eye movement biomarker.
  • the method for monitoring disease progression in a subject with MS using oculomotor assessment may comprise tracking eye movement. Suitable methods and systems for tracking eye movement have been described in W02019161503, WO2022232935 (Innodem Neurosciences), US20170276934 (ICSPI Corp.), US20180342066 (Sony Interactive Entertainment), WO2021028858, W02007076479 (Alcon), all of which are incorporated herein in full by reference.
  • an anti-CD20 antibody e.g., ofatumumab, e.g. administered during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of 20 mg once monthly or 135 mg once every 2 months
  • the method comprises oculomotor assessment as described above.
  • the anti-CD20 antibody is ofatumumab, ocrelizumab, rituximab or ublituximab.
  • the anti-CD20 antibody is ofatumumab.
  • day 1 is equivalent to the term “week 0”
  • day 7 is equivalent to “week 1”
  • day 14 is equivalent to “week 2”
  • the term “4 weeks” is equivalent to “1 month”
  • the term “12 weeks” is equivalent to “3 months”
  • the term “24 weeks” is equivalent to “6 months”, unless specifically stated or obvious from context.
  • baseline refers to the baseline measurement recorded prior to the start of treatment, such as baseline numbers of Gd+Tl lesions.
  • the terms “subject” and “patient” are used interchangeably and refer to a human (e.g., an adult human of at least 18 years of age).
  • an “anti-CD20 antibody” is an antibody that specifically binds to the human CD20 antigen expressed on B cells.
  • CD20 is expressed on late pre-B cells, mature B cells, and memory B cells, while not expressed on lymphoid stem or plasma cells.
  • anti-CD20 antibodies include, but are not limited to, ofatumumab, rituximab, tositumomab, ublituximab, ocrelizumab (2H7.vl6), 11B8 or 7D8 (disclosed in W02004/035607), an anti-CD20 antibody disclosed in WO 2005/103081 such as C6, an anti- CD20 antibody disclosed in WO2003/68821 such as IMMU-106 (from Immunomedics), an anti-CD20 antibody disclosed in W02004/103404 such as AME-133 (from Applied Molecular Evolution/Lilly), and anti-CD20 antibody disclosed in US 2003/0118592 such as TRU-015 (from Trubion Pharmaceuticals Inc). [0240] The terms “treating” and “treatment” refer to both therapeutic treatment and prophylactic or preventative therapies.
  • a method of treating multiple sclerosis in a subject in need thereof comprising administering to the subject an anti-CD20 antibody once every two months.
  • the anti-CD20 antibody is selected from the group consisting of ofatumumab (e.g., KESIMPTA® /BONSPRI®), ocrelizumab (e.g., OCREVUS®), rituximab (e.g., RITUXAN®/M AB THERA®) and ublituximab (e g., BRIUMVI®).
  • the anti-CD20 antibody is selected from the group consisting of ofatumumab (e.g., KESIMPTA® /BONSPRI®), ocrelizumab (e.g., OCREVUS®), rituximab (e.g., RITUXAN®/M AB THERA®) and ublituximab (e g., BRIUMVI®).
  • the anti-CD20 antibody e.g. ofatumumab
  • the anti-CD20 antibody is administered at a dose of about 130 to about 140 mg once every 2 months, e.g., 130 to 140 mg (e.g., about 135 mg, e.g., 135 mg) every two months.
  • an anti-CD20 antibody e.g., ofatumumab (e.g., KESIMPTA® /BONSPRI®), ocrelizumab (e.g., OCREVUS®), rituximab (e.g.,
  • RITUXAN®/MAB THERA® or ublituximab (e.g., BRIUMVI®), e.g., ofatumumab (e.g., KESIMPTA®/BONSPRI®).
  • a solution for injection comprising about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., pH about 5.5.
  • pH about 5.0 to about 7.0 e.g., pH 5.0 to 7.0
  • the solution for injection of embodiment 10 comprising about 90 mg/mL ofatumumab (e.g., 90 mg/mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5).
  • pH 5.5 e.g., pH 5.5
  • the pH may be pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4- 5.6), in particular pH 5.3-5.8, or pH 5.3-5.7.
  • a solution for injection consisting of about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5% to 5% (w/v)) arginine free base (e.g.
  • L-arginine about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5 (e.g. with hydrochloric acid).
  • polysorbate e.g., polysorbate 80
  • EDTA e.g., disodium edetate dihydrate
  • pH about 5.0 to about 7.0 e.g., pH 5.0 to 7.0
  • pH 5.5 e.g. with hydrochloric acid
  • the solution for injection of embodiment 12 consisting of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g.
  • L-arginine about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid).
  • the pH may be pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3- 5.7.
  • a pharmaceutical composition comprising about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5.
  • pH about 5.0 to about 7.0 e.g., pH 5.0 to 7.0
  • composition of embodiment 14 comprising about 90 mg/mL ofatumumab (e.g., 90 mg/mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5).
  • pH 5.5 e.g., pH 5.5
  • the pH may be pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3-5.7.
  • a pharmaceutical composition consisting of about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5% to 5% (w/v)) arginine free base (e.g.
  • L- arginine about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5 (e.g. with hydrochloric acid).
  • polysorbate e.g., polysorbate 80
  • EDTA e.g., disodium edetate dihydrate
  • pH about 5.0 to about 7.0 e.g., pH 5.0 to 7.0
  • pH 5.5 e.g. with hydrochloric acid
  • composition of embodiment 16 consisting of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g.
  • L-arginine about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid).
  • the pH may be pH 5.5 ⁇ 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ⁇ 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ⁇ 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3- 5.7.
  • Example 1 B cell profiles and PK exposure
  • a Q2M administration interval is particularly suitable for the s.c. treatment of MS with ofatumumab. It provides the convenience of less frequent dosing while maintaining effective B cell level control but without extending the interval too long so as to require such a high dose of ofatumumab that it cannot comfortably be delivered subcutaneously.
  • PK-B cell profiles for different dosing regimens were simulated using the PK-B cell model established with extensive data obtained in RMS patients from completed Phase 2 and Phase 3 studies as described (Yu H, Graham G, David OJ, et al (2022) Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis. CNS Drugs; 36(3):283-300).
  • the PK profiles for all dosing regimens in the RMS patient population were estimated based on simulations of individual PK profiles using characteristics of all the patients who received subcutaneous administration in the OMS112831, COMB157G2102, COMB157G2301 and COMB157G2302 studies, which corresponds to 1461 patients per simulation. This was considered a good representation of the adult RMS population given similar inclusion/ exclusion criteria for a future phase 3 trial.
  • PK and B cell profiles were simulated for a wide range of potential dosing regimens identified by the inventors.
  • the s.c. autoinjector parameter estimates were used in the PK-B cell model.
  • the results are not limited to an autoinjector presentation and apply also to other forms of administration, e.g., by pre-filled syringe.
  • an initial dosing regimen of 20 mg at weeks 0, 1 and 2 was used with the subsequent dosing regimen starting at week 4.
  • the PK and B cell profiles were simulated over 52 weeks of dosing.
  • the PK and B cell profiles present the median, 5 th and 95 th percentiles of the data.
  • PK and B cell profiles of an extended dosing regimen comprising subsequent dosing of 40 mg ofatumumab s.c. Q2M were simulated (i.e., twice the Q1M dose of 20 mg ofatumumab).
  • Figure 1 shows the B cell depletion profile of the 40 mg s.c. Q2M regimen in comparison to the approved 20 mg s.c. Q1M regimen.
  • the B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen (at week 0, 1 and 2). After week 4, both regimens also demonstrate a fast initial depletion of B cells.
  • the subsequent dosing regimen of 40 mg s.c. Q2M begins to deviate from the B cell depletion profile of the 20 mg s.c. Q1M regimen, in terms of median B cell profile and distribution of the B cells across the population.
  • Both the 20 mg s.c. Q1M and the 40 mg s.c. Q2M regimens are estimated to achieve a median CD19+ B cell count ⁇ 10 cells/pL.
  • the estimated median B cell count for 40 mg s.c. Q2M regimen is higher than the median B cell count achieved by the 20 mg s.c. Q1M regimen. This is because the median B cell count for the 40 mg s.c. Q2M regimen fluctuates during the two-month dosing interval, while the median B cell count for the 20 mg s.c. Q1M regimen remains relatively stable between monthly doses.
  • the median B cell count for the 40 mg s.c. Q2M regimen begins rising about 4 weeks after each subsequent dose is administered and peaks just before the administration of the next subsequent dose.
  • the median B cell count for the 40 mg s.c. Q2M regimen rises from around 1 cell/pL to between about 3 and 2 cells/pL between doses, while the median B cell count for the 20 mg s.c. Q1M regimen consistently remains around 1 cell/pL.
  • the 40 mg s.c. Q2M regimen thus demonstrates higher levels of B cell repletion between doses than the 20 mg s.c Q1M regimen.
  • the 95th percentile (the upper boundary of the light grey shaded interval in Figure 1) for the 40 mg s.c. Q2M regimen exhibits a higher B cell count than the 95th percentile (upper boundary of the dark grey shaded interval in Figure 1) for the 20 mg Q1M regimen.
  • the 95th percentile B cell count for the 40 mg s.c. Q2M regimen peaks above 30 cells/pL between doses, while the 95th percentile B cell count for the 20 mg s.c. Q1M regimen remains ⁇ 10 cells/pL.
  • B cell counts of ⁇ 10 cells/pL are associated with lower Gd+Tl lesion rates and higher treatment efficacy.
  • the 40 mg s.c. Q2M regimen is thus not expected to achieve the same level of B cell depletion (and consequently treatment efficacy) as the 20 mg s.c. Q1M regimen across the patient population.
  • the 40 mg s.c. Q2M dosing regimen also exhibits a less favourable pharmacokinetic profile.
  • the median concentration of ofatumumab in the 40 mg s.c. Q2M regimen drops to below 0.1 mg/L between doses, suggesting a risk of underexposure in the two-month dosing interval.
  • the exposure provided by the 40 mg s.c. Q2M dosing regimen is inferior to the currently approved 20 mg s.c. Q1M dosing regimen.
  • a subsequent dosing regimen of 80 mg ofatumumab s.c. Q2M was simulated (i.e., four-fold the approved Q1M 20 mg dose).
  • Figure 3 shows the B cell depletion profile of the 80 mg s.c. Q2M regimen in comparison to the approved 20 mg s.c. Q1M regimen.
  • the B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen.
  • the subsequent dosing regimen of 80 mg s.c. Q2M shows good agreement to the 20 mg s.c. Q1M profile, in terms of fast initial depletion and the median B cell profile.
  • the 80 mg s.c. Q2M regimen shows a similar median B cell count to the 20 mg s.c. Q1M regimen, which is sustained throughout the two- month dosing interval. Similar to the 20 mg s.c. Q1M regimen, the 80 mg s.c. Q2M regimen is estimated to achieve the desired median CD19+ B cell count of ⁇ 10 cells/pL.
  • the 80 mg s.c. Q2M regimen demonstrates an inferior distribution of B cells across the population compared to the 20 mg s.c. Q1M regimen.
  • the 95th percentile (the upper boundary of the light grey shaded interval in Figure 3) for the 80 mg s.c. Q2M regimen exhibits a higher B cell count than the 95th percentile (upper boundary of the dark grey shaded interval in Figure 3) for the 20 mg s.c. Q1M regimen.
  • the 95th percentile B cell count for the 80 mg s.c. Q2M regimen remains above 10 cells/pL over the simulated 52 weeks of treatment.
  • the pharmacokinetic profile of the 80 mg s.c. Q2M regimen is also inferior to the 20 mg s.c. Q1M regimen.
  • the median Cmin (mg/mL) estimated for the 80 mg s.c. Q2M regimen is lower than the median Cmin for the 20 mg s.c. Q1M regimen.
  • the 80 mg s.c. Q2M regimen is predicted to provide lower exposure levels than the approved monthly regimen.
  • the 80 mg s.c. Q2M regimen provides inferior clinical efficacy to the previously approved regimen.
  • the 135 mg s.c. Q2M regimen produced a surprisingly favourable B cell profile.
  • Figure 5 shows the B cell depletion profile of the 135 mg s.c. Q2M regimen compared to the 20 mg s.c. Q1M regimen.
  • the B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen.
  • the subsequent dosing regimen of 135 mg s.c. Q2M shows good agreement to the 20 mg Q1M profile in terms of fast initial depletion, the median B cell profile and distribution of the B cells across the population.
  • the 135 mg Q2M dosing regimen shows a similar, or even lower, median B cell count which is sustained throughout the two-month dosing interval.
  • the 135 mg regimen is estimated to achieve a median CD19+ B cell count ⁇ 10 cells/pL, similar to the B cell count achieved by the monthly dosing regimen.
  • B cell counts of ⁇ 10 cells/pL are associated with lower Gd+Tl lesion rates and higher treatment efficacy.
  • the 95th percentile (the upper boundary of the dark grey shaded interval in Figure 5) for the 135 mg s.c. Q2M regimen also exhibits a lower B cell count that the 95th percentile (upper boundary of the light grey shaded interval in Figure 5) for the 20 mg Q1M regimen.
  • the 95th percentile B cell count is lower for the 135 mg s.c. Q2M regimen than for the 20 mg s.c. Q1M count during the intervals between subsequent dose administration.
  • the 95th percentile for the 135 mg Q2M regimen shows a B cell count that remains below 10 cells/pL and below that of the 20 mg Q1M regimen, even at the end of each 2M interval immediately prior to the administration of the next subsequent dose.
  • the 135 mg s.c. Q2M regimen also leads to less frequent repletion in B cell count, with B cell depletion levels peaking every two months prior to dose administration as opposed to every month, while allowing for a sufficiently quick repletion, if necessary (e.g., in the event of an infection, etc.).
  • the 135 mg s.c. Q2M dosing regimen also exhibits an appropriate pharmacokinetic profile.
  • Cmin was selected as the most sensitive and clinically relevant target metric to demonstrate non-inferiority of the new regimen throughout the entire Q2M dosing interval compared to the 20 mg s.c. Q1M regimen.
  • Table 1 the lower 5th percentile of Cmin for 135 mg s.c. Q2M and 20 mg s.c. Q1M are comparable, therefore minimizing the risk of underexposure.
  • the 135 mg s.c. Q2M dosing regimen is expected to provide exposure throughout the dosing interval that is at least non-inferior to the approved 20 mg s.c. Q1M dosing regimen.
  • Table 1 Median and (5th, 95th) quantiles of the PK metrics AUCtau (weeks 4-12), Cmax (week 5) and Cmin (pre-dose Week 12) from the PK simulation in an RMS population receiving ofatumumab
  • the 135 mg s.c. Q2M regimen is expected to also show a similar safety profile as the 20 mg s.c. Q1M dose regimen.
  • the inventors have discovered that including the 20 mg s.c. initial regimen at weeks 0, 1 and 2 prior to starting the higher-dose 135 mg s.c. Q2M subsequent regimen at week 4, further reduces the risk of any systemic injection-related reactions (IRRs), the severity of which is likely related to dose and B cell count.
  • IRRs systemic injection-related reactions
  • the initial regimen ensures effective depletion of B cells by week 4 (overall proportion of ofatumumab treated patients with a B cell count ⁇ 10 cells/pL was 81.9% at Week 2 and 91.8% by Week 4, as determined in COMB157G2301 and COMB157G2302), i.e., prior to administration of the first 135 mg subsequent dose, thereby mitigating against the potential risk of an increase in systemic IRRs with higher dose.
  • the 135 mg s.c. Q2M dosing regimen demonstrates an at least non-inferior pharmacokinetics profile and is estimated to lead to at least similar, or even more pronounced, B cell depletion sustained throughout the two-month dosing interval, with fewer patients showings signs of B cell repletion before each subsequent dose administration, while retaining the ability to sufficiently quickly replete B cell levels by interrupting treatment when desired, for example in the event of an infection, etc.
  • the 135 mg s.c. Q2M dosing regimen exhibited superior pharmacokinetic and B cell depletion profiles compared to the other tested dosing regimens, including 40 mg s.c. Q2M and 80 mg s.c. Q2M.
  • Ofatumumab may be provided in a high-concentration antibody formulation, preferably an antibody formulation comprising 90 mg/mL ofatumumab (e.g. 135 mg in 1.5 mL).
  • a high-concentration antibody formulation preferably an antibody formulation comprising 90 mg/mL ofatumumab (e.g. 135 mg in 1.5 mL).
  • such high-concentration antibody formulations may be difficult to produce due to long-term stability issues. Often, significant optimization is required to develop a high-concentration antibody formulation that facilitates long-term storage and pain- free delivery to patients.
  • Formulation A contained 50 mM sodium acetate, 51 mM sodium chloride, 1% (w/v) arginine free base, 0.02% (w/v) polysorbate 80, 0.05 mM EDTA adjusted to pH 5.5. Formulation A thus corresponded to the formulation used for the approved 20 mg/0.4 mL dosage form of ofatumumab.
  • the polysorbate 80 (PS80) concentration was doubled to 0.04% (w/v) in view of the tendency of high-concentration antibody formulations to form aggregates.
  • Methionine was added to formulation C at a concentration of 5 mM to account for the aggregation, particle formation and oxidative stress that may be observed in high-concentration antibody formulations.
  • Table 5 demonstrates that the relative potency remained stable for all three formulations for at least six months at the intended condition and at the accelerated condition.
  • the three formulations demonstrated a relative CDC potency of at least 90% after six months of storage at 5°C ⁇ 3°C.
  • USP 787 Subvisible Particulate Matter in Therapeutic Protein Injections
  • USP 787 requires that a container has ⁇ 6000 particles >10pm in size, and ⁇ 600 particles >25pm in size.
  • Formulations A, B and C all met the requirements of USP 787 at all conditions and times. There was no significant change in the number of subvisible particles per mL in either of the three formulations over 6 months of storage at the intended condition (5°C ⁇ 3°C), and only minor changes were observed at the accelerated condition (25°C ⁇ 2°C).
  • the primary objective and purpose of this Phase 3 study is to confirm noninferior PK (Cmin) profile at week 12 (pre-administration) concentration of the new 135 mg s.c. Q2M versus the approved subsequent regimen of 20 mg s.c. Q1M.
  • Cmin was selected as the most sensitive and clinically relevant target metric to demonstrate non-inferiority of the new regimen throughout entire Q2M dosing interval.
  • the non-inferior PK profile (exposure), along with pharmacodynamic profile (B cell depletion) consistent with the approved regimen, will further support the demonstration of comparability of the less-frequent subsequent dosing regimen.
  • Other objectives of this study are described below (Table 7).
  • the core study includes a screening period, a treatment period and a safety follow up period.
  • the first approximately 100 study participants enrolled will be randomized 1 : 1 (50 per arm) to either the 135mg Q2M or 20 mg Q1M arm in the 12-week parallel-group part of the study.
  • the primary (PK) non-inferiority (NI) endpoint is based on Cmin plasma levels observed at week 12.
  • NI non-inferiority
  • the study will involve 180 adult patients with relapsing Multiple Sclerosis, age 18-55 (inclusive), male or female, and an EDSS score of 0-5.5 (inclusive).
  • relapsing MS relapsing-remitting course (RRMS), or Secondary progressive (SPMS) course with disease activity; disability status at Screening with an EDSS score of 0 to 5.5 (inclusive); documentation of at least: 1 relapse during the previous year OR 2 relapses during the previous 2 years prior to Screening OR a positive Gd- enhancing MRI scan during the year prior to randomization; and neurologically stable within 1 month prior to randomization.
  • Patients are excluded from the study if they meet any of the following key exclusion criteria: patients with primary progressive MS (PPMS) or secondary progressive multiple sclerosis (SPMS) without disease activity (however, the disclosed therapy is expected to be useful also for these forms of MS and other anti-CD20 antibodies such as ocrelizumab are authorized to treat these forms of MS as well as RMS); patients meeting criteria for neuromyelitis optica; disease duration of more than 10 years in patients with an EDSS score of 2 or less; pregnant or nursing (lactating) women; women of child-bearing potential unless using highly effective methods of contraception during study drug dosing and for 12 months post-dosing; sexually active males unless they agree to use condom during intercourse while on study drug; patients with an active chronic disease of the immune system other than MS; patients with neurological findings consistent with progressive multifocal leukoencephalopathy (PML) or confirmed PML; patients at risk of developing or having reactivation of hepatitis: positive results at Screening for ser
  • corticosteroids ofatumumab, rituximab, ocrelizumab, alemtuzumab, natalizumab, cyclophosphamide, teriflunomide, leflunomide, etc.
  • any other disease or condition that could interfere with participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures; and/or patients with prespecified neurological/psychiatric disorder prior to randomization (e.g. suicidality, substance abuse, or clinically significant CNS disease or neurological disorders that mimic MS).
  • the investigational drug will be provided in an autoinjector containing 135 mg ofatumumab for subcutaneous administration.
  • the comparator drug will be provided in an autoinjector containing 20 mg ofatumumab for subcutaneous administration.
  • All patients will start with an initial dosing regimen of 20 mg ofatumumab at Day 1 (week 0), Day 7 (week 1), and Day 14 (week 2) followed by 135 mg ofatumumab subsequent dose once every 2 months or 20 mg ofatumumab subsequent dose every month, starting at Month 1 (week 4), depending on randomization arm.
  • Eligible patients will be randomized at visit Day 1 to one of the following 2 treatment arms in a 1 : 1 randomization ratio:
  • premedication with corticosteroids, antihistamines, or acetaminophen has been observed in RMS clinical studies. Therefore, premedication with corticosteroids, acetaminophen and/or antihistamines (or equivalent) is optional and may be administered at the discretion of the investigator. If the investigator chooses to administer premedication, it should be administered 30 to 60 min prior to study drug injection.
  • MS relapses should be based on the Investigator’s judgement and or local clinical practices. If MS relapses require treatment, the standard treatment should consist of a short course of corticosteroids of 3-5 days and up to 1,000 mg methylprednisolone/day or equivalent on an inpatient or outpatient basis. Standard of care will be followed during treatment. Prohibited medications
  • the overall number of participants planned to be enrolled in the study is 180.
  • the core part of the study will randomize the first approximately 100 study participants in a 1 : 1 ratio (50 per arm) to either the 135 mg Q2M or 20mg Q1M arms for the primary analysis purpose.
  • This sample size of 100 will have more than 90% power to test the noninferiority on PK parameter Cmin at week 12 of 135mg Q2M regimen versus the 20mg Q1M regimen, using an NI margin of log (0.8) and one-sided false positive rate of 2.5%.
  • Exposure to 135 mg Q2M will be increased by an additional approximately 80 participants who will be enrolled in the 135 mg Q2M arm (once recruitment of approximately 100 participants is completed for the parallel -group part) and by patients in the 20 mg Q1M arm who will switch to the 135 mg Q2M regimen at week 12.
  • administering ofatumumab in a dosage regimen comprising a) an initial dosing regimen, wherein the initial dosing regimen comprises administering 20 mg ofatumumab at weeks 0, 1 and 2, followed by b) administering ofatumumab during a subsequent dosing regimen, wherein the subsequent dosing regimen comprises administering 135 mg ofatumumab at week four and once every 2 months thereafter, is as effective, or even more effective, at treating multiple sclerosis, compared to the established dosage regimen comprising the same initial dosing regimen followed by 20 mg ofatumumab monthly subsequent dosing regimen.
  • Example 4 Subcutaneous dosing of ocrelizumab
  • Ocrelizumab (OCREVUS®) is approved in the treatment of MS by intravenous infusion.
  • An initial 600 mg dose is administered as two separate intravenous infusions (300 mg followed 2 weeks later by a second 300 mg infusion), followed by single 600 mg intravenous infusion every 6 months, with the first dose of 600 mg administered 6 months after the first infusion of the initial dose.
  • Ocrelizumab can be administered subcutaneously every 6 months, for example at a dose of 600 mg.
  • a particularly useful ocrelizumab dosing regimen is 920 mg administered subcutaneously once every 6 months.
  • the inventors propose the use of a particular formulation to enable the subcutaneous administration of ocrelizumab at 6-monthly intervals as described herein.
  • An exemplary such formulation comprises, in addition to ocrelizumab, 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w/v) polysorbate 20, and 1,500-12,000 U/mL rHuPH20, pH 5.3.
  • a particularly useful formulation for subcutaneous administration of ocrelizumab comprises 40 mg/mL ocrelizumab (e.g., 920 mg in 23 mL), 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w/v) polysorbate 20, and 1,500-12,000 U/mL rHuPH20, pH 5.3.
  • Ocrelizumab administered as described herein is expected to achieve B cell count to ⁇ 10 cells/pL (e.g., ⁇ 5 cells/pL) or and Gd+Tl lesions rates of ⁇ 0.05 (e.g., ⁇ 0.02).
  • HCDR heavy chain complementarity determining region
  • LCDR light chain complementarity determining region
  • K indicates that the C-terminal lysine residues of the heavy chains (Lys452) may be removed by the action of basic carboxypeptidases during the cell culture process.
  • HCDR and LCDRs are recited in the Kabat format.

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Abstract

The disclosure is directed to treatment regimens for treating Multiple Sclerosis (MS). These methods include subcutaneous administration of anti-CD20 antibodies and provide efficacy and safety at extended subcutaneous dosing intervals.

Description

EXTENDED DOSING REGIMENS FOR ANTI-CD20 ANTIBODIES IN THE TREATMENT OF MULTIPLE SCLEROSIS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional application
No. 63/588,851 filed 9th October 2023 entitled “Extended dosing regimens for anti-CD20 antibodies in the treatment of multiple sclerosis”, and U.S. provisional application
No. 63/558,544 filed 27th February 2024 entitled “Extended dosing regimens for anti-CD20 antibodies in the treatment of multiple sclerosis”, the contents of each of which are incorporated by reference in their entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure provides regimens in the treatment of multiple sclerosis for (e.g., subcutaneously) administering an anti-CD20 antibody at extended dosing intervals. Exemplary extended dosing regimens are provided, including for the monoclonal anti-CD20 antibody ofatumumab.
BACKGROUND
[0003] Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and axonal/neuronal destruction, ultimately leading to severe disability. Relapsing MS (RMS) is the most common form of MS.
[0004] Anti-CD20 monoclonal antibodies target CD20 expressed on B cells, which are thought to play a key role in myelin and axonal damage in MS, thereby suppressing disease inflammatory activity. Exemplary anti-CD20 antibodies used in clinical practice in the treatment of MS include ofatumumab (KESIMPTA®/BONSPRI®), ocrelizumab (OCREVUS®), rituximab (RITUXAN®/MAB THERA®) and ublituximab (BRIUMVI®).
[0005] Ofatumumab (also known as 0MB 157) is a fully human type 1 immunoglobulin G1 kappa (IgGlx) monoclonal antibody. Subcutaneous (s.c.) administration of ofatumumab leads to a rapid, frequency- and dose-dependent, B cell reduction. Phase III clinical trials COMB157G2301 and COMB157G2302 (Hauser SL, Bar-Or A, Cohen JA, et al (2020) Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med; 383(6):546- 57) demonstrated that disease inflammatory activity in relapsing MS patients was potently suppressed by subsequent (maintenance) doses of 20 mg s.c. ofatumumab every 4 weeks (i.e., every month), following an initial dosing (loading dose) regimen of three 20 mg doses at days 1, 7, and 14 (weeks 0, 1 and 2). Based on this data, ofatumumab has been approved in over 80 countries for the treatment of adult patients with RMS.
[0006] There is a need for safe and effective extended dosing regimens for ofatumumab and other anti-CD20 antibodies in the treatment of MS. However, such regimens are difficult to provide inter alia because of the complex nature of the MS condition and the important role of the drug target, i.e., B cells, in both health and disease.
SUMMARY OF THE DISCLOSURE
[0007] While the low 20 mg s.c. monthly subsequent dose of ofatumumab has been shown to be highly effective and safe, less frequent subsequent dosing may further improve patient experience and clinical outcomes. For example, less frequent subsequent injections may further reduce the risk of any local injection site reactions, such as bruising, skin irritations, tissue damage or infections, thereby improving patient experience. In addition, less frequent subsequent dosing may decrease the treatment burden on patients and their caregivers. This, in turn, may lead to increased compliance with the prescribed treatment regimen and improved clinical outcomes. Less frequent administration may also decrease the cost of distribution and reduce the environmental footprint of the distribution.
[0008] While less frequent administration can provide these and other advantages, extended dosing intervals may reduce the ability to tightly control B cell depletion levels and thereby reduce the ability to interrupt MS treatment to enable sufficiently quick B cell repletion when desired, for example in the event of an infection or risk of infection, or emergence of other adverse events/conditions, which may represent a risk to patient safety (e.g. malignancy, pregnancy), or when switching MS therapy. At the same time, an extended dosing regimen should provide at least non-inferior clinical efficacy and safety to any previously approved regimen.
[0009] An additional challenge in developing an extended dosing regimen is the delicate interplay between the regimen (i.e., antibody dose, route of administration, and frequency of administration) and the antibody formulation. For an extended dosing regimen to achieve non-inferior clinical efficacy to any previously approved regimen, the antibody dose should be high enough to sustain exposure throughout the entire dosing interval, and thus maintain B cell depletion levels between doses. However, high antibody doses may result in unstable formulations, especially when formulated for subcutaneous administration, as subcutaneous formulations are typically restricted in volume. The preferred volume for subcutaneous injections is currently deemed to be around 2 mL or less, with larger volumes typically requiring additional agents that locally degrade the extracellular matrix (e.g., endoglycosidases, such as hyaluronidase). Reformulating antibodies for higher doses in smaller volumes can introduce changes in viscosity and stability, which can lead to aggregation, particle formation, and adverse events (e.g. injection-related reactions).
[0010] Thus, developing a clinically effective extended dosing regimen for subcutaneous administration of anti-CD20 antibodies in the treatment of MS requires careful balancing of the pharmacokinetic and pharmacodynamic profiles of the regimen and its formulation properties.
[0011] The present disclosure provides a novel and advantageous extended dosing regimen for subcutaneous (s.c.) administration of an anti-CD20 antibody (e.g., ofatumumab) in the treatment of MS. Using pharmacokinetic and pharmacodynamic population B cell modelling, the inventors determined an advantageous combination of anti-CD20 antibody (e.g., ofatumumab) dose and interval of administration which decreases the burden of treatment on patients without compromising the safety and/or efficacy of the treatment.
[0012] In particular, the inventors showed that a subsequent (e.g., maintenance) dosing regimen of 135 mg ofatumumab s.c. administered once every two months (Q2M) offers MS patients a less frequent, yet safe and effective, ofatumumab dosing option. The estimated pharmacokinetic and pharmacodynamic profiles for the 135 mg s.c. Q2M regimen show that it provides exposure coverage throughout the entire two-month dosing interval that is at least comparable (e.g., non-inferior) to the approved subsequent (e.g., maintenance) dosing regimen of ofatumumab of 20 mg s.c. once per month (Q1M). The inventors assessed many different regimens and found that, surprisingly, the 135 mg s.c. Q2M regimen disclosed herein is a particularly advantageous maintenance regimen because it also provides comparable or even better levels of sustained B cell depletion compared to the approved once- monthly maintenance regimen. The Q2M dosing regimens provided herein thus allow for extended subsequent (e.g., maintenance) dosing while retaining the ability to tightly control B cell levels to allow for quick B cell repletion by treatment interruption, if necessary.
[0013] According to certain embodiments described herein, a subsequent regimen of ofatumumab 135 mg s.c. once every two months after three s.c. 20 mg initial (e.g., loading) doses for three consecutive weeks (e.g., at weeks 0, 1 and 2) is estimated to deplete B cell levels to < 10 cells/pL and maintain the B cell levels below that threshold during each entire two-month period between injections, and in some patients even below the B cell levels achieved with the Q1M regimen. B cell levels achieved at the end of each 135 mg Q2M interval are similar to the B cell levels achieved at the end of each 20 mg Q1M interval. As such, the 135 mg Q2M interval retains the above-mentioned ability to tightly control B cell levels and allow for repletion, if necessary, by discontinuation of treatment. In addition, the 135 mg dose can be formulated in a stable, low-volume formulation suitable for subcutaneous administration.
[0014] As demonstrated by a Phase 2 study of ofatumumab s.c. in relapsing MS patients (OMS112831 - MIRROR study), lower peripheral B cell levels lead to lower lesion volumes (Gd+Tl). The B cell count cut-off of 8 cells/pL was identified in B cell - Gd+Tl lesion modeling of the OMS112831 study data for dose selection of a phase 3 dose regimen. Later analyses based on COMB157G2301 and COMB157G2302 data (ASCLEPIOS I and II) used a B cell count cut-off of 10 cells/pL to assess the extent of B cell depletion across the trial population. Both of these cut-offs correspond to an approximate 95% reduction in peripheral B cell counts from a typical baseline B cell count of 200 cells/pL.
[0015] It is therefore anticipated that the B cell depletion levels associated with the 135 mg s.c. Q2M regimen result in at least non-inferior clinical efficacy compared to the 20 mg s.c. Q1M regimen.
[0016] Thus, the extended dosing regimen for the treatment of multiple sclerosis disclosed herein leads to comparable (or even improved) clinical efficacy coupled with improved patient experience and other advantages.
[0017] As such, provided herein is a method of stabilizing, e.g., maintaining, the B cell count in a subject in need thereof, during dosing intervals, the method comprising dosing the subject with ofatumumab at two-month intervals, to thereby stabilize, e.g., maintain, the B cell count in the subject. In an embodiment, the subject is dosed with ofatumumab at 135 mg subcutaneously at two-month intervals, e.g. every two months (Q2M). In some embodiments, the method maintains the subject’s B cell count to <10 cells/pL. In an embodiment, the subject has multiple sclerosis (MS).
[0018] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS). [0019] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0020] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0021] Therefore, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject at a dose of about 100-150 mg ((e.g., 100-150) e.g., about 110 mg (e.g., 110 mg) ofatumumab or about 130 mg (e.g., 130 mg) ofatumumab), e.g., about 120-150 mg (e.g., 120-150), e.g., about 130-140 mg ((e.g., 130-140 mg) (e.g., about 135 mg (e.g., 135 mg)) ofatumumab once about every two months (Q2M).
[0022] In some aspects, the method of treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) includes (a) subcutaneously administering ofatumumab to the subject during an initial (e.g., loading) dosing regimen of three once-weekly about 19 mg to about 21 mg doses (e.g., about 20 mg doses, e.g., 20 mg) for three consecutive weeks (e.g., at weeks 0, 1 and 2) followed by (b) subcutaneously administering ofatumumab to the subject during a subsequent (e.g., maintenance) dosing regimen of about 130 mg to about 140 mg (e.g., about 135 mg, e.g., 135 mg) two weeks after the final 19-21 mg dose (e.g., at week 4) and once every two months thereafter (or once every eight weeks thereafter; Q2M).
[0023] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0024] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0025] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS). [0026] In some aspects of the invention, provided is a method of treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) by administering a subsequent (e.g., maintenance) dose regimen of ofatumumab to a subject who has received an initial (e.g., loading) dose regimen, wherein (a) the loading dose regimen comprises three consecutive weekly loading doses of about 20 mg (e.g., 20 mg) ofatumumab each, and (b) the maintenance dose regimen comprises about 130 mg to about 140 mg (e.g., 130-140 mg, e.g., about 135 mg, e.g., 135 mg) ofatumumab administered once every two months (or once every eight weeks; Q2M). In some embodiments, the loading dose and the maintenance dose are administered subcutaneously.
[0027] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0028] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0029] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0030] In some aspects, the invention includes methods of treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) by administering about 130 mg to about 140 mg (e.g., 130-140 mg, e.g., about 135 mg, e.g., 135 mg) ofatumumab once every two months (or once every eight weeks; Q2M). In some embodiments, the administration is subcutaneous.
[0031] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0032] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0033] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0034] In some embodiments of any of the preceding aspects, the method depletes and/or maintains the subject’s B cell count (e.g., circulating B cell count or peripheral B cell count) to about <10 cells/pL, e.g., <10 cells/pL.
[0035] In some embodiments of any of the preceding aspects, the ofatumumab is administered in a pharmaceutical composition having pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0, e.g., pH 5.3 to 5.7, e.g., 5.4 to 5.6, e.g., about pH 5.5, about pH 5.2, about pH 5.3, about pH 5.4, about pH 5.6, about pH 5.7, or about pH 5.8.), e.g., about pH 5.5. As used herein and in any of the aspects, embodiments and claims that follow, a pH of about 5.5 encompasses, e.g., pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), e.g., pH 5.5. In some embodiments, from a manufacturing perspective, a pH of 5.5 ± 0.2 (5.3-5.7) is acceptable. In some embodiments, for release of the composition (drug product) for clinical use, a pH range of 5.3-5.8 (or 5.2- 5.8) is acceptable.
[0036] In some embodiments, the pharmaceutical composition further includes arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), optionally wherein the pharmaceutical composition further comprises EDTA. In some embodiments, the pharmaceutical composition comprises about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally wherein the pharmaceutical composition further comprises about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), optionally wherein the pharmaceutical composition further comprises about 0.05 mM (e.g., 0.05 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), and has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2 cP to about 3 cP (e.g., about 2.3 cP, e.g., 2.3 cP). In some embodiments, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5). In some embodiments, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g., pH 5.5), and has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2 cP to about 3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
[0037] In some embodiments of any of the preceding pharmaceutical compositions, the pharmaceutical composition comprises no more than about 0.2% (w/v) (e.g., 0.2% (w/v)) polysorbate (e.g., polysorbate 80). Additionally, or alternatively, the pharmaceutical composition contains no methionine.
[0038] In some embodiments, the subsequent (e.g., maintenance) doses of ofatumumab are administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL, e.g., 80-100 mg/mL, e.g., about 90 mg/mL, e.g., 90 mg/mL. In some embodiments, subsequent (e.g., maintenance) doses of ofatumumab are administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL, e.g., 80-100 mg/mL, e.g., about 90 mg/mL, e.g., 90 mg/mL, wherein the pharmaceutical composition has a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., from about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
[0039] In some embodiments of any of the preceding aspects, the ofatumumab is administered in a pharmaceutical composition that does not comprise an endoglycosidase, e.g., hyaluronidase.
[0040] In some embodiments of any of the preceding aspects, the ofatumumab is administered using a pre-filled pen (autoinjector). In some embodiments, the pre-filled pen contains a fixed single unit dose of about 135 mg (e.g., 135 mg) ofatumumab.
[0041] In some embodiments of any of the preceding aspects, the method results in one or more of (a) reduction in number of Gd+Tl lesions relative to baseline; (b) reduction in number of new or enlarging T2 lesions relative to baseline; and/or (c) reduction in annualized relapse rate (ARR) relative to baseline. Accordingly, the methods provided herein may result in one or more of: a) Gd+ T1 lesion rates of < 0.03; b) annualized rates of new or enlarging T2 lesions of < 0.72; and/or c) annualized relapse rates (ARR) of < 0.11.
[0042] In some embodiments, a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein is non-inferior to a reference maintenance regimen (e.g., a maintenance regimen of 20 mg ofatumumab s.c. Q1M) in one or more of (a) reduction in number of Gd+Tl lesions; (b) reduction in number of new or enlarging T2 lesions; (c) reduction in ARR relative to a reference maintenance regimen; (d) number and/or severity of injection-related reactions (IRRs); and/or (e) immunogenicity (e.g., incidence of anti-drug antibodies (ADA)). In some embodiments, the IRR number or severity that is non-inferior is an injection-related systemic reaction, which is a reaction or symptom that occurred within 24 hours after injection of ofatumumab. In some embodiments, injection-related systemic reactions occur in less than 24.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein. In some embodiments, injection-related systemic reactions occur in less than 16.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein.
[0043] In some embodiments, of any of the preceding aspects, the method further includes administering a concomitant therapy, for example selected from a corticosteroid, an antihistamine, and acetaminophen. In some instances, the concomitant therapy is administered before administration of ofatumumab, e.g., about 30 minutes to about 60 minutes before administration of ofatumumab.
[0044] Also provided herein is a solution for injection containing about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) of an anti-CD20 antibody (e.g., ofatumumab), e.g., in a pharmaceutical composition as disclosed herein. The solution for injection is for subcutaneous administration. In some embodiments, the solution for injection is pH about 5.0 to about 7.0, e.g. pH 5.0-7.0, e.g., pH about 5.5., e.g., pH 5.5.
[0045] In some embodiments the solution for injection further includes arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), optionally wherein the solution further comprises EDTA. In some embodiments, the solution for injection comprises about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally wherein the solution further comprises about 0.02 to about 0.2 mM (e.g. 0.02 to 0.2 mM) EDTA. In some embodiments, the solution comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.5 (e.g. pH 5.5), optionally wherein the solution further comprises about 0.05 mM (e.g., 0.05 mM) EDTA. In some embodiments, the solution includes ofatumumab at a concentration of about 80-100 mg/mL, e.g., 80-100 mg/mL, e.g., about 90 mg/mL, e.g., 90 mg/mL. In some embodiments, the solution for injection described above has a viscosity from no more than about 3 cP (e.g., no more than 3 cP), e.g., about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).
[0046] In some aspects of the invention, a pre-filled syringe or pre-filled pen (e.g., an autoinjector containing a pre-filled syringe) contains the solution as described above, e.g., in a total volume of around 1.5 mL (e.g., 1.5 mL), e.g., formulated for subcutaneous administration.
[0047] Also provided herein is a pre-filled syringe or a pre-filled pen (autoinjector) containing about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) of an anti-CD20 antibody (e.g., ofatumumab), e.g., in around 1.5 mL, e.g., 1.5 mL (e.g., at a concentration of about 90 mg (e.g., 90 mg) ofatumumab per mL, e.g., in a total volume of around 1.5 mL (e.g., 1.5 mL)).
[0048] Also provided herein is a kit comprising an anti-CD20 antibody (e.g., ofatumumab) at one or more fixed single unit doses of about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) each.
[0049] Also provided herein is a kit comprising one or more pre-filled syringes or prefilled pens (autoinjectors) each containing a fixed single unit dose of about 120-150 mg, e.g., about 130-140 mg (e.g., about 135 mg) of an anti-CD20 antibody (e.g., ofatumumab), optionally wherein the kit further comprises three pre-filled syringes or pre-filled pens (autoinjectors) each containing a fixed single unit dose of about 18-22 mg, e.g., about 19-21 mg (e.g., about 20 mg) of an anti-CD20 antibody (e.g., ofatumumab). Kits provided herein may further include instructions for use, e.g., instructions including any of the methods of treating MS described herein.
[0050] These and other aspects and embodiments of the disclosure are further described below. BRIEF DESCRIPTION OF THE DRAWINGS
[0051] Figure 1 shows the simulated population B cell profiles of a subsequent dosing regimen (maintenance dose regimen) of 40 mg ofatumumab s.c. once every two months (Q2M) versus 20 mg ofatumumab s.c. once every month (Q1M). Both subsequent dosing regimens start at week 4, following an initial dosing regimen (loading dose regimen) of three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2. Black line = median B cell profile for subsequent dosing regimen of 20 mg Q1M; dark grey shaded area = 5%-95% interval of simulated B cell data for that regimen. Dark grey line = median B cell profile for subsequent dosing regimen of 40 mg Q2M; light grey shaded area = 5%-95% interval of simulated B cell data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines).
[0052] Figure 2 shows the simulated population PK profiles for the 40 mg ofatumumab s.c. Q2M subsequent regimen versus the 20 mg ofatumumab s.c. Q1M subsequent regimen. Both subsequent dosing regimens start at week 4, following three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2 (log scale). Black line = 20 mg Q1M median PK profile; dark grey shaded area = 5-95% interval of simulated concentration data for that regimen. Dark grey line = median PK profile for subsequent dosing regimen of 40 mg Q2M; light grey shaded area = 5-95% interval of simulated concentration data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines). The vertical axis shows the concentration of ofatumumab (mg/mL), while the horizontal axis shows the time since the first dose of ofatumumab was administered.
[0053] Figure 3 shows the simulated population B cell profiles of a subsequent dosing regimen (maintenance dose regimen) of 80 mg ofatumumab s.c. once every two months (Q2M) versus 20 mg ofatumumab s.c. once every month (Q1M). Both subsequent dosing regimens start at week 4, following an initial dosing regimen (loading dose regimen) of three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2. Black line = median B cell profile for subsequent dosing regimen of 20 mg Q1M; dark grey shaded area = 5%-95% interval of simulated B cell data for that regimen. Light grey line = median B cell profile for subsequent dosing regimen of 80 mg Q2M; light grey shaded area = 5%-95% interval of simulated B cell data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines).
[0054] Figure 4 shows the simulated population PK profiles for the 80 mg ofatumumab s.c. Q2M subsequent regimen versus the 20 mg ofatumumab s.c. Q1M subsequent regimen. Both subsequent dosing regimens start at week 4, following three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2 (log scale). Black line = 20 mg Q1M median PK profile; dark grey shaded area = 5-95% interval of simulated concentration data for that regimen. Dark grey line = median PK profile for subsequent dosing regimen of 80 mg Q2M; light grey shaded area = 5-95% interval of simulated concentration data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines). The vertical axis shows the concentration of ofatumumab (mg/mL), while the horizontal axis shows the time since the first dose of ofatumumab was administered.
[0055] Figure 5 shows the simulated population B cell profiles of a subsequent dosing regimen (maintenance dose regimen) of 135 mg ofatumumab s.c. once every two months (Q2M) versus 20 mg ofatumumab s.c. once every month (Q1M). Both subsequent dosing regimens start at week 4, following an initial dosing regimen (loading dose regimen) of three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2. Black line = median B cell profile for subsequent dosing regimen of 20 mg Q1M; light grey shaded area = 5%-95% interval of simulated B cell data for that regimen. Light grey line = median B cell profile for subsequent dosing regimen of 135 mg Q2M; dark grey shaded area = 5%-95% interval of simulated B cell data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines).
[0056] Figure 6 shows the simulated population PK profiles for the 135 mg ofatumumab s.c. Q2M subsequent regimen versus the 20 mg ofatumumab s.c. Q1M subsequent regimen. Both subsequent dosing regimens start at week 4, following three consecutive doses of 20 mg ofatumumab at week 0, 1 and 2 (log scale). Black line = 20 mg Q1M median PK profile; dark grey shaded area = 5-95% interval of simulated concentration data for that regimen. Dark grey line = median PK profile for subsequent dosing regimen of 135 mg Q2M; light grey shaded area = 5-95% interval of simulated concentration data for that regimen. The arrows point to the 95% percentile (shaded areas) and the median (solid lines). The vertical axis shows the concentration of ofatumumab (mg/mL), while the horizontal axis shows the time since the first dose of ofatumumab was administered. [0057] Figure 7 shows the overview of a study design of a phase III clinical trial to compare subsequent dosage regimens of ofatumumab 135 mg s.c. (autoinjector) Q2M versus ofatumumab 20 mg s.c. (autoinjector) Q1M. Eligible study participants will be randomized at visit Day 1 to one of the two treatment arms in a 1 : 1 randomization ratio. The study consists of two parts: a core part and an extension part. At the end of the parallel group part, patients in the 20 mg Q1M arm will switch to receive 135 Q2M starting at week 12.
DETAILED DESCRIPTION OF THE DISCLOSURE
Anti-CD20 antibody
[0058] The antibody used in the methods of the disclosure is an anti-CD20 antibody. The anti-CD20 antibody is capable of inducing B cell depletion of CD20 positive B cells. The antibody is a monoclonal anti-CD20 antibody.
[0059] In some embodiments, the anti-CD20 antibody is a full-length antibody. In some embodiments, the anti-CD20 antibody is a full-length IgGl antibody, comprising a human Fc region. In some embodiments, the anti-CD20 antibody is fully human. In some embodiments, the anti-CD20 antibody is humanized. In other embodiments, the anti-CD20 antibody is a chimeric antibody.
[0060] In one embodiment, the anti-CD20 antibody is ofatumumab, or a variant thereof as defined below (i.e., a similar antibody). In another embodiments, the anti-CD20 antibody is ocrelizumab, or a variant thereof as defined below (i.e., a similar antibody). In another embodiment, the anti-CD20 antibody is ublituximab, or a variant thereof as defined below (i.e., a similar antibody). Having been provided with the present disclosure, suitable anti-CD20 antibodies for use in the disclosed methods can be provided by those skilled in the art.
Ofatumumab
[0061] In a preferred embodiment, the anti-CD20 antibody is ofatumumab. Ofatumumab (0MB 157) is a fully human type 1 immunoglobulin G1 kappa (IgGlx) monoclonal antibody (mAb) that targets CD20 expressed on B cells and has been developed for the treatment of MS, particularly relapsing MS (RMS). Ofatumumab specifically recognizes a conformational (i.e., non-continuous) epitope encompassing both the large and small extracellular loops on the human CD20 molecule, which allows ofatumumab to bind very close to the plasma membrane. The binding of ofatumumab to CD20 induces B cell lysis primarily through complement-dependent cytotoxicity (CDC) and, to a lesser extent, by antibody-dependent cell-mediated cytotoxicity (ADCC). The pharmacokinetics (PK) of ofatumumab have been reported as having low clearance, a small volume of distribution, and a relatively long half-life (Tl/2) of 16 days. Binding to human B cells has been reported to occur with a concentration of a drug that gives half-maximal response (EC50) of 287 ng/mL. The theoretical molecular mass is 146 kDa, calculated from the amino acid composition deduced from the DNA sequence. Ofatumumab is typically produced in a murine cell line (NSO). Ofatumumab is defined by SEQ ID Nos 1-10 (Table 9). As the skilled person will be aware, during production in cell culture, such as in NSO cells, post-translational modifications may occur, including glycosylation and C-terminal lysine clipping of the heavy chain.
[0062] In some embodiments, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the light chain complementarity determining regions of SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8. In some embodiments, the anti-CD20 antibody comprises the variable heavy chain sequence of SEQ ID NO: 4 and the variable light chain sequence of SEQ ID NO: 9, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 4 and/or SEQ ID NO: 9. In some embodiments, the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5 and/or SEQ ID NO: 10. In other embodiments, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the light chain complementarity determining regions of SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, wherein the variable heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 4, and the variable light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 9. In another embodiment, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the light chain complementarity determining regions of SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, wherein the heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5, and the light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 10. Any one of these anti-CD20 antibodies can be considered similar to ofatumumab, the full sequence of which is defined by SEQ ID NOs 5 and 10.
[0063] The skilled person would understand that percentage sequence identity as used herein refers to the percentage of identical amino acid residues when two sequences are aligned and compared across their full length. Accordingly, the percentage sequence identity can be calculated using global pairwise sequence alignment tools (end-to-end alignment of the sequences to be aligned), such as Needle (EMBOSS), which creates an optimal global alignment of two sequences using the Needleman-Wunsch algorithm. The default settings are BLOSUM62 matrix, GAP OPEN PENALTY 10, GAP EXTEND PENALTY 0.5, END GAP PENALTY false, END GAP OPEN PENALTY 10, END GAP EXTEND PENALTY 0.5.
Ocrelizumab
[0064] Ocrelizumab (also known as 2H7) is a humanized monoclonal antibody based on the human immunoglobulin G1 (IgGl) framework that contains heavy chain VHIII and light chain VKI subgroup sequences. Ocrelizumab selectively targets CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis.
[0065] Ocrelizumab has been reported as having a half-life of around 26 days. The molecular formula of intact ocrelizumab is C6482H9952N1712O2014S46. The calculated molecular mass of intact deglycosylated ocrelizumab is approximately 145,564 Da (peptide chains only, without heavy chain C-terminal lysine residues). Ocrelizumab is typically produced in Chinese Hamster Ovary cells by recombinant DNA technology. Ocrelizumab is defined by SEQ ID NOs 11-20 (Table 9).
[0066] In some embodiments, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18. In some embodiments, the anti-CD20 antibody comprises the variable heavy chain sequence of SEQ ID NO: 14 and the variable light chain sequence of SEQ ID NO: 19, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 14 and/or SEQ ID NO: 19. In some embodiments, the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 15 and the light chain sequence of SEQ ID NO: 20, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15 and/or SEQ ID NO: 20. In other embodiments, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the variable heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 14, and the variable light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 19. In another embodiment, the anti-CD20 antibody comprises the heavy chain complementarity determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and the light chain complementarity determining regions of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the heavy chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15, and the light chain sequence excluding the CDRs is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 20. Any one of these anti-CD20 antibodies can be considered similar to ocrelizumab, the full sequence of which is defined by SEQ ID NOs 15 and 20.
Ublituximab
[0067] Ublituximab is a chimeric monoclonal antibody. It is produced in the rat cell line YB2/0. Ublituximab selectively targets CD20-expressing B cells and induces their lysis. Ublituximab depletes B cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
[0068] Ublituximab has been reported as having an estimated half-life of around 22 days. The molecular formula of intact ublituximab is C6418H9866N1702O2006S48. The calculated molecular mass of ublituximab is 144,504 Da.
[0069] In some embodiments, the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22, or a sequence that is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 21 and/or SEQ ID NO: 22.
Regimens
[0070] Provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody to the subject once every about 2 months, e.g., at a dose of about 100-600 mg (e.g., about 600 mg, about 200 mg or about 135 mg). Also provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody to the subject at a dose of about 100-600 mg once every about 2-6 months. In some embodiments, the anti-CD20 antibody is subcutaneously administered to the subject once every 2 months (Q2M). In some embodiments, the anti-CD20 antibody is subcutaneously administered to the subject at a dose of about 135 mg. With reference to the embodiments described herein, the skilled person would understand that the term “4 weeks” is equivalent to “1 month”, the term “12 weeks” is equivalent to “3 months”, the term “24 weeks” is equivalent to “6 months”, unless specifically stated otherwise or obvious from context. The skilled person would also understand that in clinical practice, “about 2 months” can mean between 6 and 10 weeks, and “2 months” can mean between 7 and 9 weeks, typically 8 weeks. Similarly, the skilled person would understand that in clinical practice, “about 6 months” can mean between 20 and 28 weeks and “6 months” can mean between 22 and 26 weeks, typically 24 weeks. The skilled person would also understand that the term “every 2 months” means “once every 2 months”, and “every about 2 months” means “once every about 2 months”, and so on, unless specifically stated otherwise or obvious from the context.
[0071] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0072] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0073] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0074] Thus, in some embodiments, the anti-CD20 antibody is administered at a dose of about 100-600 mg once every 6-28 weeks.
[0075] In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 100-170 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 110-160 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti- CD20 antibody (e.g., ofatumumab) is administered at a dose of about 120-150 mg once every
6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 130-140 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 135 mg once every 6-10 weeks (about 2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0076] In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 100-170 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 110-160 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 120-150 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 130-140 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 135 mg once every
7-9 weeks (2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0077] In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 100-170 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 110-160 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 120-150 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered at a dose of about 130-140 mg once every 8 weeks (2 months). In some embodiments, the anti- CD20 antibody (e.g., ofatumumab) is administered at a dose of about 135 mg once every 8 weeks (2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0078] In a preferred embodiment, provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering ofatumumab at a dose of about 130-140 mg once every 2 months. [0079] In a specific embodiment, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering ofatumumab at a dose of about 135 mg once every 2 months.
[0080] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0081] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0082] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0083] The inventors have additionally discovered that combining an initial (lower)- dose regimen (i.e., loading dose regimen) prior to the above-described subsequent (higher) dosing regimens (i.e., maintenance dose regimens) provides for a particularly efficacious and safe treatment because the initial regimen efficiently, safely and quickly depletes B cell levels prior to administering the first subsequent (higher) dose. This initial regimen thereby further reduces the risk of any systemic injection-related reactions (IRRs). Without being bound by any theory, it is believed that the severity of the IRRs is likely related to a higher relative number of circulating numbers of B cells available for depletion at the time of ofatumumab dosing. The skilled person would understand that the initial dosing regimen may refer to a loading dose regimen, and the subsequent dosing regimen may refer to a maintenance dose regimen.
[0084] Thus, also provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody to the subject during an initial dosing regimen, followed by a subsequent dosing regimen as disclosed herein. The disclosure therefore encompasses subcutaneously administering one or more doses of an anti-CD20 antibody (e.g., ofatumumab) to the subject at specific time intervals during an initial dosing regimen, followed by subcutaneously administering the anti-CD20 antibody to the subject at specific time intervals during a subsequent dosing regimen. In some embodiments, the initial dosing regimen comprises administering three doses of the anti-CD20 antibody at weeks 0, 1 and 2. In some embodiments, the subsequent dosing of the anti-CD20 antibody is higher than the initial dosing of the anti-CD20 antibody. For example, the initial dose of the anti-CD20 antibody may be about 15-25 mg, 16-24 mg, 18-22 mg, 19-21 mg, e.g., 20 mg. One or more of these initial doses may be administered. In the examples, 3 initial doses are administered. The initial dose interval is typically more frequent than the subsequent dose interval. Weekly initial doses are used in the examples. A specific embodiment of an initial regimen for use in the disclosed methods is therefore 3 weekly doses (at weeks 0, 1 and 2) of about 20 mg of anti-CD20 antibody (e.g., ofatumumab). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0085] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0086] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0087] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0088] Accordingly, also provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate initial doses at weeks 0, 1 and 2, followed by subcutaneously administering an anti- CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen starting at week 4. In some embodiments, the anti-CD20 antibody is administered during an initial dosing regimen of 3 separate 15-25 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 100-170 mg at week 4 and once every 6-10 weeks (about 2 months) thereafter. In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 16-24 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 110-160 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 18-22 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 120-150 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 19-21 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 130-140 mg once every 6-10 weeks (about 2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 135 mg once every 6-10 weeks (about 2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0089] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0090] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0091] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0092] In some embodiments, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate 15-25 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 100-170 mg at week 4 and once every 7-9 weeks (2 months) thereafter. In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 16-24 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 110-160 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 18-22 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 120-150 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 19-21 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 130-140 mg once every 7-9 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 135 mg once every 7-9 weeks (2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0093] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0094] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0095] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0096] In some embodiments, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate 15-25 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 100-170 mg at week 4 and once every 8 weeks (2 months) thereafter. In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 16-24 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 110-160 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 18-22 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 120-150 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 19-21 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 130-140 mg once every 8 weeks (2 months). In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of about 135 mg once every 8 weeks (2 months). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0097] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0098] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0099] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0100] In a preferred embodiment, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering ofatumumab to the subject during an initial dosing regimen of 3 separate 19-21 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering ofatumumab to the subject during a subsequent dosing regimen of about 130-140 mg at week 4 and once every 2 months thereafter.
[0101] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0102] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0103] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS). [0104] In a specific embodiment, provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, the method comprising subcutaneously administering ofatumumab to the subject during an initial dosing regimen of 3 separate 20 mg doses for three consecutive weeks (e.g., at weeks 0, 1 and 2), followed by subcutaneously administering ofatumumab to the subject during a subsequent dosing regimen of about 135 mg two weeks after the third 20 mg dose (e.g., at week 4) and once every 2 months (e.g., every 8 weeks) thereafter.
[0105] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0106] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0107] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0108] This disclosure also provides useful extended s.c. dosing regimens for anti- CD20 antibodies, such as ocrelizumab and similar anti-CD20 antibodies.
[0109] Thus, also provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ocrelizumab) to the subject once every about 2 months. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered once every about 2 months at a dose of about 100-600 mg (e.g., about 600 mg, about 200 mg, or about 135 mg). Thus, in some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 600 mg once about every 2 months. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 200 mg once about every 2 months. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 100-170 mg once about every 2 months. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 135 mg once about every 2 months. In some embodiments, subcutaneous dosing regimens for anti-CD20 antibodies, such as ocrelizumab and similar anti-CD20 antibodies, may require a higher dose, for example because of differences in half-life, EC50, potency etc. Thus, also provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising administering an anti-CD20 antibody (e.g., ocrelizumab) at a dose of about 600-1,200 mg once about every 6 months. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 1,200 mg once about every 6 months.
[0110] A particularly useful dose for an anti-CD20 antibody such as ocrelizumab is 920 mg. In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 920 mg once every 20-28 weeks (about 6 months). In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 920 mg once every 22-26 weeks (about 6 months). In particularly useful embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is administered at a dose of about 920 mg once every 24 weeks (about 6 months). While a dose of about 920 mg is typical, these embodiments also encompass the use of a dose within a reasonable range, in particular, 690-1,150 mg, 730-1,110 mg, 820-1,020 mg, 870-960 mg, e.g., 920 mg of the anti-CD20 antibody (e.g., ocrelizumab). These embodiments are especially suitable for ocrelizumab and similar anti-CD20 antibodies. Therefore, in a preferred embodiment, provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering ocrelizumab to the subject at a dose of about 920 mg once about every 6 months.
[OHl] Thus, also provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising administering an anti-CD20 antibody (e.g., ocrelizumab) at a dose of about 600 mg once every 20-28 weeks (about 6 months). In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is subcutaneously administered to the subject at a dose of about 600 mg once every 22-26 weeks (6 months). In some embodiments, the anti-CD20 antibody (e.g., ocrelizumab) is subcutaneously administered to the subject at a dose of about 600 mg once every 24 weeks (6 months). While a dose of about 600 mg is typical, these embodiments also encompass the use of a dose within a reasonable range, in particular, 450-750 mg, 480-720 mg, 540-660 mg, 570-630 mg, e.g., 600 mg of the anti-CD20 antibody. These embodiments are particularly suitable for ocrelizumab and similar anti-CD20 antibodies. In a specific embodiment therefore, provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering ocrelizumab to the subject at a dose of about 600 mg once every 6 months. [0112] This disclosure also provides useful extended s.c. dosing regimens for anti- CD20 antibodies, such as ublituximab and similar anti-CD20 antibodies.
[0113] Thus, also provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ublituximab) to the subject once about every 2 months. In some embodiments, the anti-CD20 antibody (e.g., ublituximab) is administered at a dose of about 100-170 mg once about every 2 months. In some embodiments, the anti-CD20 antibody (e.g., ublituximab) is administered at a dose of about 135 mg once about every 2 months.
Compositions
[0114] Also provided herein are compositions, i.e., pharmaceutical compositions, comprising an anti-CD20 antibody (e.g., ofatumumab) for use in any of the methods of the disclosure. Accordingly, in some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered subcutaneously in a pharmaceutical composition.
Antibody concentrations
[0115] In some embodiments, the anti-CD20 antibody is subcutaneously administered in a pharmaceutical composition that comprises the anti-CD20 antibody at a concentration of 20 to 400 mg/mL, e.g., 30-350 mg/mL, e.g., 40-300 mg/mL.
[0116] In an exemplary embodiment, the anti-CD20 antibody (e.g., ofatumumab) is administered during a subsequent (e.g., maintenance) dosing regimen at a concentration of about 65-115 mg/mL, 70-110 mg/mL, 80-100 mg/mL, 85-95 mg/mL, preferably 90 mg/mL (e.g., about 135 mg antibody in about 1.5 mL (e.g., 1.5 mL) total volume), and during the initial (e.g., loading) dosing regimen at a concentration of about 35-65 mg/mL, 40-60 mg/mL, 45-55 mg/mL, 47-53 mg/mL, preferably 50 mg/mL (e.g., about 20 mg antibody in 0.4 mL total volume). In a specific embodiment, the initial (e.g., loading) dose(s) of the anti-CD20 antibody is/are administered in a pharmaceutical composition that comprises the anti-CD20 antibody at a concentration of 50 mg/ml, and the subsequent (e.g., maintenance) dose(s) of the anti-CD20 antibody is/are administered in a pharmaceutical composition that comprises the anti-CD20 antibody at a concentration of about 90 mg/mL (e.g., 90 mg/mL).
[0117] Accordingly, in some embodiments, the pharmaceutical composition for use in the initial dosing regimen differs from the pharmaceutical composition for use in the subsequent dosing regimen. In some embodiments, the pharmaceutical composition for use in the subsequent (e.g., maintenance) dosing regimen comprises a higher concentration of the anti-CD20 antibody than the pharmaceutical composition for use in the initial (e.g., loading) dosing regimen.
[0118] A preferred anti-CD20 antibody is ofatumumab. Accordingly, in some embodiments, ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 65-115 mg/mL. In some embodiment, ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 70-110 mg/mL. In some embodiments, ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL. In some embodiments, ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 85-95 mg/mL. In some embodiments, ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 90 mg/mL (e.g., ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 90 mg/mL).
[0119] In some embodiments therefore, the initial (e.g., loading) dose of ofatumumab is administered as a pharmaceutical composition that comprises ofatumumab at a concentration of 50 mg/mL, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 65-115 mg/mL. In some embodiments, the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 70-110 mg/mL. In some embodiments, the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL. In some embodiments, the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 85-95 mg/mL. In some embodiments, the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 90 mg/mL.
[0120] In some embodiments, the initial (e.g., loading) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 35-65 mg/ml, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 65- 115 mg/mL. In some embodiments, the initial (e.g., loading) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 40-60 mg/ml, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 70- 110 mg/mL. In some embodiments, the initial (e.g., loading) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 45-55 mg/ml, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80- 100 mg/mL. In some embodiments, the initial (e.g., loading) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 47-53 mg/ml, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 85- 95 mg/mL.
[0121] In a preferred embodiment, the initial (e.g., loading) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of 50 mg/ml, and the subsequent (e.g., maintenance) dose of ofatumumab is administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 90 mg/mL.
[0122] Also provided herein are pharmaceutical compositions comprising ocrelizumab. In one embodiment, the dose of ocrelizumab is administered in a pharmaceutical composition that comprises ocrelizumab at a concentration of about 90 mg/ml (e.g., about 135 mg in 2 mL total volume). In another embodiment, ocrelizumab and other anti-CD20 antibodies may require a high dose and so are administered at a high concentration to enable subcutaneous use (i.e., small injection volumes). In such instances, the concentration may be up to 400 mg/mL, up to 350 mg/mL, or up to 300 mg/mL (e.g., about 600 mg antibody in 1.5- 2 mL total volume). Larger volumes may be used, such as 5-15 mL, for example when coadministering hyaluronidase, then the antibody concentration may be about 100-150 mg/mL, e.g., 120 mg/mL (e.g., about 600 mg in 5 mL total volume), or 30-50 mg/mL, e.g., 40 mg/mL (e.g., about 600 mg in 15 mL total volume). In one embodiment therefore, the pharmaceutical composition comprises about 30-150 mg/mL, or about 40-120 mg/mL, preferably about 120 mg/mL of the anti-CD20 antibody (e.g., ocrelizumab). In a more preferred embodiment, the anti-CD20 antibody (e.g., ocrelizumab) concentration is about 40 mg/mL (e.g., about 920 ml in 23 ml).
[0123] Also provided herein are pharmaceutical compositions comprising ublituximab. In one embodiment, the dose of ublituximab is administered in a pharmaceutical composition that comprises ublituximab at a concentration of 90 mg/ml (e.g., about 135 mg in 2 mL total volume)
Other components in the pharmaceutical compositions
[0124] The pharmaceutical compositions disclosed herein comprise, in addition to the anti-CD20 antibody (e.g., ofatumumab), a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other materials well known to those skilled in the art (e.g., water for injection). Such materials are non-toxic and do not interfere with the efficacy of the anti- CD20 antibody.
[0125] In some embodiments, the anti-CD20 antibody (e.g., ofatumumab) is administered to the subject in a pharmaceutical composition further comprising L-arginine, sodium acetate, sodium chloride, and/or (e.g., and) polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0). In some embodiments, the pharmaceutical composition further comprises EDTA. In some embodiments, the composition does not comprise EDTA. In some embodiments, the pharmaceutical composition does not comprise an endoglycosidase (e.g., a hyaluronidase, e.g., rHupH20). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0126] In some embodiments, the pharmaceutical composition comprises about 10 to about 100 mM (e.g., 10 to 100 mM), about 20 to about 100 mM (e.g., 20 to 100 mM), about 30 to about 100 mM (e.g., 30 to 100 mM), about 40 to about 100 mM (e.g., 40 to 100 mM), about 50 to about 100 mM (e.g., 50 to 100 mM), about 60 to about 100 mM (e.g., 60 to 100 mM), about 70 to about 100 mM (e.g., 70 to 100 mM), about 25 to about 80 mM (e.g., 25 to 80 mM), or about 30 to about 70 mM (e.g., 30 to 70 mM) sodium acetate. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM), about 40 mM (e.g., 40 mM), about 45 mM (e.g., 45 mM), about 55 mM (e.g., 55 mM), or about 60 mM (e.g., 60 mM) sodium acetate. In a preferred embodiment, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate. Sodium acetate can conveniently be incorporated into the composition using sodium acetate trihydrate. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies. [0127] In some embodiments, the pharmaceutical composition comprises about 25 to about 100 mM (e.g., 25 to 100 mM), about 35 to about 90 mM (e.g., 35 to 90 mM), about 45 to about 80 mM (e.g., 45 to 80 mM), about 25 to about 70 mM (e.g., 25 to 70 mM), or about 45 to about 70 mM (e.g., 45 to 70 mM) sodium chloride. In some embodiments, the pharmaceutical composition comprises about 45 mM (e.g., 45 mM), about 46 mM (e.g., 46 mM), about 47 mM (e.g., 47 mM), about 48 mM (e.g., 48 mM), about 49 mM (e.g., 49 mM), about 50 mM (e.g., 50 mM), about 51 mM (e.g., 51 mM), about 52 mM (e.g., 52 mM), about 53 mM (e.g., 53 mM), about 54 mM (e.g., 54 mM), about 55 mM (e.g., 55 mM) sodium chloride. In a preferred embodiment, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0128] In some embodiments, the pharmaceutical composition comprises (w/v) between about 0.5 and about 5.0% (e.g., 0.5 and 5.0%), about 0.5 to about 2.0% (e.g., 0.5 to 2.0%), about 0.5 to about 2.5% (e.g., 0.5 to 2.5%), about 0.5 to about 3.0% (e.g., 0.5 to 3.0%), about 0.5 to about 3.5% (e.g., 0.5 to 3.5%), about 0.5 to about 4.0% (e.g., 0.5 to 4.0%), or about 0.5 to about 4.5% (e.g., 0.5 to 4.5%) arginine free base (L-arginine). In some embodiments, the pharmaceutical composition comprises (w/v) about 1% (e.g., 1%), about 0.7% (e.g., 0.7%), about 1.3% (e.g., 1.3%), or about 2.0% (e.g., 2.0%) arginine free base. In a preferred embodiment, the pharmaceutical composition comprises about 1% (w/v) (e.g., 1% (w/v)) arginine free base. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0129] In some embodiments, the pharmaceutical composition comprises (w/v) about 0.01 to about 0.2% (e.g., 0.01 to 0.2%), about 0.01 to about 0.15% (.e.g., 0.01 to 0.15%), about 0.02 to about 0.2% (e.g., 0.02 to 0.2%), about 0.02 to about 0.15% (e.g., 0.02 to 0.15%), about 0.01 to about 0.25% (e.g., 0.01 to 0.25%), or about 0.01 to about 0.05% (e.g., 0.01 to 0.05%) polysorbate (e.g., polysorbate 80). In some embodiments, the pharmaceutical composition comprises (w/v) about 0.02% (e.g., 0.02%), about 0.015% (e.g., 0.015%), or about 0.025% (e.g., 0.025%) polysorbate (e.g., polysorbate 80). In a preferred embodiment, the pharmaceutical composition comprises about 0.02% (w/v) (e.g., 0.02% (w/v) polysorbate (e.g., polysorbate 80). In another embodiment, the pharmaceutical composition comprises (w/v) about 0.02 to about 0.04% (e.g., 0.02 to 0.04%) polysorbate (e.g., polysorbate 80), for example about 0.04% (e.g., 0.04%) (w/v) polysorbate (e.g., polysorbate 80). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0130] In some embodiments, the pharmaceutical composition comprises about 0.02 mM to about 0.2 mM (e.g., 0.02 to 0.2 mM), about 0.02 mM to about 0.1 mM (e.g., 0.02 mM to 0.1 mM), about 0.02 mM to about 0.15 mM (e.g., 0.02 mM to 0.15 mM), about 0.04 mM to about 0.1 mM (e.g., 0.04 mM to 0.1 mM), about 0.03 mM to about 0.15 mM (e.g., 0.03 mM to 0.15 mM), or about 0.03 mM to about 0.2 mM (e.g., 0.03 mM to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM), about 0.03 mM (e.g., 0.03 mM), about 0.04 mM (e.g., 0.04 mM), or about 0.06 mM (e.g., 0.06 mM) EDTA. In a preferred embodiment, the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM) EDTA. EDTA can conveniently be incorporated into the composition using disodium edetate dihydrate. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0131] The pH of the pharmaceutical compositions disclosed herein, in particular those comprising ofatumumab, can be about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), e.g., about pH 5.5, e.g., pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3- 5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), e.g., pH 5.5. Thus, in some embodiments, the pharmaceutical composition is adjusted to pH 5.0 to 7.0. In some embodiments, the pharmaceutical composition is adjusted to pH 5.0, 5.5, 6.0, 6.5 or 7.0. In a preferred embodiment, the pharmaceutical composition is adjusted to pH 5.5. These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0132] In some embodiments, the pharmaceutical composition may comprise about 0.1 mM to about 20 mM (e.g., 0.1 mM to 20 mM), about 1 mM to about 15 mM (e.g., 1 mM to 15 mM), about 2 mM to about 10 mM (e.g., 2 mM to 10 mM), or about 4 mM to about 6 mM (e.g., 4 mM to 6 mM) methionine (e.g., L-methionine). The pharmaceutical composition may thus comprise about 1 mM (e.g., 1 mM), about 5 mM (e.g., 5 mM), about 10 mM (e.g., 10 mM), about 15 mM (e.g., 15 mM) or about 20 mM (e.g., 20 mM) methionine (e.g., L- methionine). In a preferred embodiment, the pharmaceutical composition comprises about 5 mM (e.g., 5 mM) methionine (e.g., L-methionine). These embodiments are particularly suitable for ofatumumab and similar anti-CD20 antibodies.
[0133] In some embodiments, the pharmaceutical composition comprises about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM ) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), and optionally about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v) polysorbate (e.g., polysorbate 80), and adjusted to pH about 5.5 (e.g., pH 5.5), and optionally about 0.05 mM (e.g., 0.05 mM) EDTA.
[0134] In a preferred embodiment, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g. polysorbate 80), and adjusted to pH about 5.5 (e.g., pH 5.5), and optionally about 0.05 mM (e.g., 0.05 mM) EDTA.
[0135] Pharmaceutical compositions described herein include low-viscosity formulations of relatively high concentrations of ofatumumab, which can be conducive for subcutaneous administration. In some instances, provided herein are pharmaceutical compositions comprising ofatumumab (e.g., about 90 mg/mL ofatumumab, e.g., 90 mg/mL) that have a viscosity of no more than about 3 cP (e.g., no more than 3 cP), e.g., about 2.3 centipoise (cP) (e.g., 2.3 cP).
[0136] Accordingly, provided herein is a pharmaceutical composition comprising about 80-100 mg/mL, (e.g., 80-100 mg/mL), e.g., about 90 mg/mL (e.g. 90 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0). This composition can be used to deliver about 135 mg (e.g., 135 mg) ofatumumab in a volume convenient for s.c. administration.
[0137] Also provided herein is a pharmaceutical composition consisting of about 80- 100 mg/mL (e.g., 80-100 mg/mL), e.g., about 90 mg/mL (e.g. 90 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base (e.g. L-arginine), about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) (e.g., with hydrochloric acid). This composition can be used to deliver about 135 mg (e.g., 135 mg) ofatumumab in a volume convenient for s.c. administration.
[0138] In a preferred embodiment, the pharmaceutical composition comprises about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to pH about 5.5 (e.g., pH 5.5). About 1.5 mL (e.g., 1.5 mL) of this composition provides about 135 mg (e.g., 135 mg) ofatumumab. For example, the pharmaceutical composition may consist of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g. L- arginine), about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid). About 1.5 mL (e.g., 1.5 mL) of this composition provides about 135 mg (e.g., 135 mg) ofatumumab in a suitably stable formulation acceptable for subcutaneous administration. Indeed, as shown in Example 2, this formulation remains stable for at least 6 months at its intended storage conditions (e.g. 5°C ± 3°C).
[0139] In a preferred embodiment, the anti-CD20 antibody is ofatumumab, and may be present in the compositions at any of the concentrations described above, e.g., about 35-115 mg/mL (e.g., 35-115 mg/mL), such as about 50 mg/mL (e.g., 50 mg/mL) or about 90 mg/mL (e.g., 90 mg/mL). Accordingly, provided herein is a pharmaceutical composition comprising about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL). Also provided herein is a solution for injection comprising about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).
[0140] In other embodiments, the anti-CD20 antibody is ocrelizumab. In such embodiments, particularly, where larger volumes are used, e.g., about 5-15 mL (e.g., 5-15 mL), the anti-CD20 antibody is typically administered in a pharmaceutical composition that further comprises an agent that locally degrades the extracellular matrix, to allow the subcutaneous space to receive such larger volume. In a preferred embodiment, the anti-CD20 antibody (e.g., ocrelizumab) is administered in a volume of about 23 mL. An exemplary agent is hyaluronidase, preferably recombinant human hyaluronidase, such as rHuPH20.
[0141] Specifically, the enzyme hyaluronidase can be used to induce local and transient modification of the subcutaneous space through degradation of hyaluronan (i.e., hyaluronic acid), which is a naturally occurring glycosaminoglycan found throughout the body that creates resistance to bulk fluid flow in the extracellular matrix and limits large- volume subcutaneous drug delivery. By degrading the hyaluronan at the local injection site, the hyaluronidase enables subcutaneous bulk fluid flow and facilitates the subcutaneous delivery of large volumes.
[0142] A purified recombinant human form of hyaluronidase (recombinant human hyaluronidase [rHuPH20]) has been commercially available in the US since 2005 (HYLENEX® recombinant) and has been co-formulated with other therapeutic products using the ENHANZE® drug delivery technology. ENHANZE® has been shown to reduce dose administration time and dosing frequency and enable the delivery of large volumes for rapid SC injections (5 to 15 mL).
[0143] Thus, in some embodiments, ocrelizumab is administered in a pharmaceutical composition that further comprises recombinant human hyaluronidase (e.g., rHupH20), and optionally sodium acetate, trehalose, polysorbate (e.g., polysorbate 20), typically at pH about 5.0-6.0. The ocrelizumab pharmaceutical composition may further comprise glacial acetic acid.
[0144] In some embodiments, the pharmaceutical composition comprises about 1,000 to about 16,000 U/mL (e.g., 1,000 to 16,000 U/mL) hyaluronidase enzyme (e.g., rHupH20), wherein the said amount corresponds to about 0.01 mg to 0.15 mg hyaluronidase enzyme based on an assumed specific activity of about 100,000 U/mg (e.g., 100,000 U/mg). In some embodiments, the pharmaceutical composition comprises about 1,500 to about 12,000 U/ml (e.g., 1,500 to 12,000 U/ml) hyaluronidase (e.g., rHupH20). In some embodiments, the pharmaceutical composition comprises about 2,000 to about 12,000 U/mL (e.g., 2,000 to 12,000 U/mL) hyaluronidase (e.g., rHupH20).
[0145] In some embodiments, the pharmaceutical composition comprises about 1 mM mM to about 15 mM (e.g., 1 mM to 15 mM) glacial acetic acid, about 2 mM to about 10 mM (e.g., 2 mM to 10 mM) glacial acetic acid, or about 3 mM to about 5 mM (e.g., 3 mM to 5 mM) glacial acetic acid. In preferred embodiments, the pharmaceutical composition comprises about 4 mM (e.g., 4 mM) glacial acetic acid.
[0146] In some embodiments, the pharmaceutical composition comprises about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g.,
1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3).
[0147] In some embodiments, the pharmaceutical composition comprises about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3).
[0148] In some embodiments, ocrelizumab is administered in a pharmaceutical composition that comprises about 30-350 mg/mL (e.g., 30-350 mg/mL) ocrelizumab, about 1- 100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). For example, the pharmaceutical composition may comprise about 30-350 mg/mL, e.g., 30-350 mg/mL. (e.g., about 120 mg/mL) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate 20, and about
1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) rHuPH20, pH about 5.3 (e.g., pH 5.3).
[0149] In some embodiments, ocrelizumab is administered in a pharmaceutical composition that comprises about 30-150 mg/mL (e.g., 30-150 mg/mL), e.g., about 40-120 mg/mL (e.g., 40-120 mg/mL), preferably about 120 mg/mL ocrelizumab, about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01- 0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g.,
1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). In some embodiments, the pharmaceutical composition comprises about 30-150 mg/mL (e.g., 30-150 mg/mL), e.g., about 40-120 mg/mL (e.g., 40-120 mg/mL), preferably about 120 mg/mL ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). [0150] In a more preferred embodiment, ocrelizumab is administered in a pharmaceutical composition that comprises about 40 mg/mL ocrelizumab, about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01- 0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). In some embodiments, the pharmaceutical composition comprises about 40 mg/mL (e.g., 40 mg/mL) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). This pharmaceutical composition is particularly useful for treating multiple sclerosis in a subject in need thereof.
[0151] One particularly useful pharmaceutical composition comprises about 40 mg/mL ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 1,500 U/ml (e.g., 1,500 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3). Another particularly useful pharmaceutical composition comprises about 40 mg/mL ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 2,300 U/ml (e.g., 2,300 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3). Also particularly useful is a pharmaceutical composition comprising about 40 mg/mL ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 3,000 U/ml (e.g., 3,000 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3). An additional particularly useful pharmaceutical composition comprises about 40 mg/ml ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 12,000 U/ml (e.g., 12,000 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3).
[0152] In some embodiments, the pharmaceutical composition comprises about 120 mg/mL (e.g., 120 mg/mL) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (e.g., 0.02% (w/v)) (w/v) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). [0153] In some embodiments, the pharmaceutical composition comprises about 50 mg/ml (e.g., 50 mg/ml) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 1,500 U/ml (e.g., 1,500 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3).
[0154] In some embodiments, the pharmaceutical composition comprises about 100 mg/ml (100 mg/ml) ocrelizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (e.g., 0.02% (w/v)) polysorbate 20, about 12,000 U/ml (e.g., 12,000 U/ml) of hyaluronidase (e.g., rhuPH20), at pH about 5.3 (e.g., pH 5.3).
[0155] Thus, provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering ocrelizumab to the subject at a dose of about 920 mg once about every 6 months, wherein ocrelizumab is administered in a formulation comprising about 40 mg/mL ocrelizumab, about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w/v) (e.g., 0.01-0.1% (w/v)) polysorbate 20, and about 1,500-12,000 U/mL (e.g., 1,500-12,000 U/mL) hyaluronidase (e.g., rHuPH20), pH about 5.3 (e.g., pH 5.3). This is a particularly stable pharmaceutical formulation suitable for subcutaneous injection.
[0156] In another embodiment, the anti-CD20 antibody is ublituximab.
[0157] In some embodiments, the pharmaceutical composition containing ocrelizumab may further comprise about 15-250 mM (e.g., 15-250 mM) or about 150-250 mM (e.g., 150- 250 mM) methionine, e.g., about 210 mM (e.g., 210 mM) methionine.
Delivery
[0158] The anti-CD20 antibody disclosed herein may be administered via any suitable route, but is typically administered subcutaneously (s.c.), typically via injection.
[0159] In some embodiments, the anti-CD20 antibody is self-administered by subcutaneous injection. In some embodiments, the initial doses and/or subsequent doses of the anti-CD20 antibody are self-administered by subcutaneous injection. In some embodiments, the anti-CD20 antibody is administered in an outpatient setting.
[0160] In some embodiments, the anti-CD20 antibody is administered in the abdomen, thigh, or upper outer arm of the subject.
[0161] In one embodiment, subcutaneous administration of the anti-CD20 antibody is achieved using a pre-filled syringe. In a preferred embodiment, subcutaneous administration of the anti-CD20 antibody is achieved using a pre-filled pen, i.e., autoinjector. A non-limiting example of an autoinjector suitable for use according to the present disclosure is the Sensoready® pen. A pre-filled syringe consists of a bulk pre-filled syringe assembled into a needle safety device. A pre-filled pen consists of a bulk pre-filled syringe assembled into an auto-injector (Al).
[0162] Thus, provided herein is a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing the anti-CD20 antibody (e.g., ofatumumab or similar anti-CD20 antibodies). In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 100-170 mg of the anti-CD20 antibody. In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 110-160 mg of the anti-CD20 antibody. In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 120-150 mg of the anti-CD20 antibody. In a preferred embodiment, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 130-140 mg of the anti-CD20 antibody. In another preferred embodiment, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of about 135 mg of the anti-CD20 antibody.
[0163] A preferred anti-CD20 antibody is ofatumumab. Accordingly, in some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 100-170 mg ofatumumab. In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 110-170 mg ofatumumab. In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 120-150 mg ofatumumab. In some embodiments, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of between about 130-140 mg ofatumumab. In a preferred embodiment, the pre-filled syringe or the pre-filled pen, i.e., autoinjector, contains a single unit dose of about 135 mg ofatumumab.
[0164] A pre-filled pen (autoinjector) is particularly preferred. In a specific embodiment, ofatumumab is provided in a prefilled-pen (autoinjector) containing a single unit dose of about 130-140 mg (e.g., about 135 mg, e.g., 135 mg) of the antibody. The single unit dose is intended for use in the subsequent regimen, as described herein. [0165] In some embodiments, the anti-CD20 antibody is administered to the subject in a pharmaceutical composition, as described herein. In one embodiment, the pharmaceutical composition comprising the anti-CD20 antibody is provided in a pre-filled syringe. In a preferred embodiment, the pharmaceutical composition comprising the anti-CD20 antibody is provided in a pre-filled pen, i.e., autoinjector. A non-limiting example of an autoinjector suitable for use according to the present disclosure is the Sensoready® pen. Preferably, the anti-CD20 antibody is ofatumumab.
[0166] The pharmaceutical composition comprising the anti-CD20 antibody may be provided in the form of a solution for injection. In one embodiment, the solution for injection is provided in a pre-filled syringe. In a preferred embodiment, the solution for injection is provided in a pre-filled pen, i.e., autoinjector. A non-limiting example of an autoinjector suitable for use according to the present disclosure is the Sensoready® pen. Preferably, the anti-CD20 antibody is ofatumumab.
[0167] In some embodiments, the solution for injection comprises between about 100 and about 600 mg of the anti-CD20 antibody in a pharmaceutical composition as disclosed herein. In some embodiments, the solution for injection comprises between about 100 and about 170 mg of the anti-CD20 antibody in a pharmaceutical composition as disclosed herein. In some embodiments, the solution for injection comprises about 135 mg of the anti-CD20 antibody in a pharmaceutical composition as disclosed herein. In some embodiments, the solution for injection comprises about 600 mg of the anti-CD20 antibody in a pharmaceutical composition as disclosed herein.
[0168] A preferred anti-CD20 antibody is ofatumumab. Accordingly, in some embodiments, the solution for injection comprises between about 110 and about 160 mg ofatumumab in a pharmaceutical composition as disclosed herein. In some embodiments, the solution for injection comprises between about 120 and about 150 mg ofatumumab in a pharmaceutical composition as disclosed herein. In some embodiments, the solution for injection comprises between about 130 and about 140 mg ofatumumab in a pharmaceutical composition as disclosed herein. In a preferred embodiment, the solution for injection comprises about 135 mg ofatumumab in a pharmaceutical composition as disclosed herein.
[0169] In some embodiments, the anti-CD20 antibody may be administered in a volume of about 0.4 mL to about 1.5 mL. In some embodiments, the initial dose of the anti- CD20 antibody is administered in a volume of about 0.4 mL. In some embodiments, the subsequent dose of the anti-CD20 antibody is administered in a volume of about 1.5 mL.
[0170] In some embodiment, the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 0.4 mL solution for injection wherein the solution for injection comprises the anti-CD20 antibody in a pharmaceutical composition as disclosed herein. In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 0.4 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 50 mg/mL. In some embodiments, the initial doses of the anti-CD20 antibody are administered in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 0.4 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 50 mg/mL.
[0171] In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises the anti-CD20 antibody in a pharmaceutical composition as disclosed herein. In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 90 mg/mL. In some embodiments, the subsequent doses of the anti-CD20 antibody are administered in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises the anti-CD20 antibody at a concentration of about 90 mg/mL.
[0172] A preferred anti-CD20 antibody is ofatumumab. Accordingly, the initial dose of ofatumumab may be administered in a volume of about 0.4 mL; the subsequent dose of ofatumumab may be administered in a volume of about 1.5 mL.
[0173] In some embodiments, ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 0.4 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of about 50 mg/mL. In a preferred embodiment, the initial dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 0.4 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of about 50 mg/mL. [0174] In some embodiments, ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of between about 70 and about 110 mg/mL. In some embodiments, the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of between about 70 and about 110 mg/mL.
[0175] In some embodiments, ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of between about 80 and about 100 mg/mL. In some embodiments, the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of between about 80 and about 100 mg/mL.
[0176] In some embodiments, ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of between about 85 and about 95 mg/mL. In some embodiments, the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of between about 85 and about 95 mg/mL.
[0177] In some embodiments, ofatumumab is provided in a pre-filled syringe or a prefilled pen, i.e., autoinjector, containing about 1.5 mL solution for injection wherein the solution for injection comprises ofatumumab at a concentration of about 90 mg/mL. In a preferred embodiment, the subsequent dose of ofatumumab is provided in a pre-filled syringe or a pre-filled pen, i.e., autoinjector, containing about 1.5 mL solution for injection, wherein the solution comprises ofatumumab at a concentration of about 90 mg/mL.
Multiple Sclerosis
[0178] Provided herein is a method of treating multiple sclerosis (MS) in a subject in need thereof, wherein the method comprises subcutaneously administering an anti-CD20 antibody to the subject. In an embodiment, the MS is RMS. In an embodiment, the MS is RRMS. In an embodiment, the MS is PPMS. In an embodiment, the MS is SPMS. In an embodiment, the MS is CIS.
[0179] Any reference to a method for treatment herein also discloses the anti-CD20 antibody for use in said method for treatment, the use of the anti-CD20 antibody in said method for treatment, and the use of the anti-CD20 antibody in the manufacture of a medicament for said treatment.
[0180] Therefore, also provided herein is an anti-CD20 antibody for use in treating multiple sclerosis (MS) in a subject. Also provided herein is the use of an anti-CD20 antibody for treating multiple sclerosis. Additionally, provided herein is the use of an anti-CD20 antibody for the manufacture of a medicament for the treatment of multiple sclerosis.
[0181] In some preferred embodiments, the MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
[0182] In some embodiments, the MS is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the MS is active secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is clinically isolated syndrome (CIS).
[0183] In some embodiments, the MS is progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressing multiple sclerosis (PPMS). In some embodiments, the MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, the MS is primary progressing multiple sclerosis (PPMS).
[0184] In an illustrative embodiment, provided herein is a method of treating relapsing multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate about 19-21 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering the anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 130-140 mg at week 4 and once every 2 months thereafter.
[0185] In another illustrative embodiment, provided herein is a method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofatumumab) to the subject during an initial dosing regimen of 3 separate about 20 mg doses at weeks 0, 1 and 2, followed by subcutaneously administering the anti-CD20 antibody (e.g., ofatumumab) to the subject during a subsequent dosing regimen of about 135 mg at week 4 and once every 2 months thereafter.
Concomitant therapies
[0186] In some embodiments, the methods disclosed herein further comprise administering a concomitant therapy, for example selected from the group of a corticosteroid, an antihistamine, an acetaminophen. In some embodiments, the concomitant therapy is a corticosteroid. In some embodiments, the concomitant therapy is an antihistamine. In some embodiments, the concomitant therapy is an acetaminophen.
[0187] The term ‘concomitant therapy’ includes administration of another agent (e.g., selected from the group consisting of a corticosteroid, an antihistamine, and an acetaminophen) before, during, or after administration of the anti-CD20 antibody (e.g., ofatumumab), e.g., before, during, or after administration of the first dose of the anti-CD20 antibody; or before, during, or after administration of one or more subsequent or each dose of the anti-CD20 antibody.
[0188] In some embodiments, the concomitant therapy is administered prior to the administration of the anti-CD20 antibody. In some embodiments, the concomitant therapy is administered 30 to 60 minutes prior to the administrations of the anti-CD20 antibody.
[0189] In some embodiments, the concomitant therapy is administered during the administration of the anti-CD20 antibody. In other embodiments, the concomitant therapy is administered following administration of the anti-CD20 antibody.
[0190] In some embodiments, no premedication is administered prior to administration of the anti-CD20 antibody.
[0191] In the above embodiments, a preferred anti-CD20 antibody is ofatumumab.
Subjects for treatment
[0192] In some embodiments, the subject is a mammal. In preferred embodiments, the subject is a human. In some embodiments, the subject is referred to as the patient.
[0193] In some embodiments, the anti-CD20 antibody is administered irrespective of body weight, sex, age, race or baseline B cell count of the subject. [0194] In some embodiments, the subject is an adult (e.g., a human adult). In some embodiments, the subject is aged 18 to 55 years (inclusive). In some embodiments, the subject is over 55 years old.
[0195] In some embodiments, the subject has been diagnosed with multiple sclerosis according to the 2017 Revised McDonald criteria (see Table 1 of Thompson AJ, Baranzini SE, Geurts J, et al (2018) Multiple sclerosis. Lancet; 391(10130): 1622-36). In some embodiments, the subject has a disability status with an (Expanded Disability Status Scale (EDSS) score of 0 to 5.5 (inclusive). In some embodiments, the subject’s B cells have already been depleted by any disease modifying MS therapy prior to initiation of the therapy disclosed herein, e.g., prior to administering ofatumumab Q2M (e.g., at about 135 mg s.c.). Thus, an MS subject to be treated by the methods disclosed herein may already have a B cell count < 10 cells/pL when administering the first dose of the anti-CD20 antibody (e.g., ofatumumab) according to the present disclosure (e.g., at about 135 mg s.c. and once every about two months thereafter).
[0196] In some embodiments, the patient is neurologically stable within one month prior to the first administration of the anti-CD20 antibody (e.g. ofatumumab). Neurologically stable refers to a clinical state characterized by lack of change in mental status or level of consciousness. This state may comprise control of seizures; absence of new neurologic defects, e.g. aphasia, ataxia, dysarthria, paresis, paralysis, visual field loss, or blindness, and is defined as neurologically stability.
[0197] In some embodiments, the subject is receiving or has received a disease modifying therapy for multiple sclerosis, such as ofatumumab, glatiramer acetate, ocrelizumab, ublituximab, cladribine, fmgolimod, natalizumab, teriflunomide, mitoxantrone or dimethyl fumarate.
[0198] In some embodiments, the subject is receiving or has received an anti-CD20 antibody therapy. In some embodiments, the anti-CD20 antibody is selected from ofatumumab, ocrelizumab, rituximab or ublituximab. In some embodiments, the subject has received at least 1 dose of the anti-CD20 antibody. In some embodiments, the subject has received at least 12 doses of the anti-CD20 antibody. In some embodiments, the subject has received at least between 1-12 doses and the anti-CD20 antibody.
[0199] In some embodiments, the subject is receiving or has received an anti-CD20 antibody (e.g., ofatumumab) once every month. In some embodiments, the subject has received an initial dose of an anti-CD20 antibody (e.g., ofatumumab) at weeks 0, 1 and 2, followed by one or more subsequent doses of the anti-CD20 antibody (e.g., ofatumumab) starting at week 4 and administered every month thereafter. In some embodiments, the subject has received at least 1 monthly dose of the anti-CD20 antibody (e.g., ofatumumab). In some embodiments, the subject has received at least 12 monthly doses of the anti-CD20 antibody (e.g., ofatumumab). In some embodiments, the subject has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 one monthly doses of the anti-CD20 antibody (e.g., ofatumumab).
[0200] In another embodiment, the patient is newly diagnosed. A newly diagnosed patient has not received any previous treatment (e.g. disease-modifying therapy) for multiple sclerosis.
[0201] In some embodiments, the subject has had at least 1 relapse during the year prior to treatment. In some embodiments, the subject has had at least 2 relapses during the 2 years prior to treatment. In some embodiments, the subject has had a positive Gd-enhancing MRI scan during the year prior to treatment. In some embodiments, the subject has active disease, meaning that they have relapses and/or signs of active inflammation on MRI scans.
[0202] In some embodiments, the patient has undergone screening for Hepatitis B virus (HB V) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment. Screening may include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing. This testing may be complemented with other appropriate markers as per local guidelines. In some embodiments, the patient does not have an active HBV infection. For instance, the patient does not have active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. Accordingly, the patient to be treated has undergone screening for Hepatitis B virus (HBV) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment and/or does not have an active HBV infection.
[0203] In some embodiments, the patient does not have a known IgE-mediated hypersensitivity to the anti-CD20 antibody (e.g. ofatumumab). In some embodiments, the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) or to any of one of the excipients in the anti-CD20 antibody (e.g. ofatumumab) formulation. For instance, the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) or to any ingredient in the formulation, including any non-medicinal ingredient, component or container.
[0204] In some embodiments, the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment. In some embodiments, the patient is not in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia). Accordingly, the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment and/or is not in a severely immunocompromised state.
[0205] Therefore, according to the invention, the patients to be treated can have any one or more of the above characteristics. For example, the patient could have one or more of the following characteristics: a) the patient has undergone screening for Hepatitis B virus (HBV) prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment; b) the patient does not have an active HBV infection; c) the patient has undergone quantitative serum immunoglobulin screening prior to initiation of anti-CD20 antibody (e.g. ofatumumab) treatment; d) the patient is not in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia); e) the patient does not have a known IgE-mediated hypersensitivity to the anti-CD20 antibody (e.g. ofatumumab); and/or f) the patient is not hypersensitive to the anti-CD20 antibody (e.g. ofatumumab) and/or to any of the excipients of the anti-CD20 antibody (e.g. ofatumumab) formulation, including any non-medicinal ingredient, component or container.
[0206] In some embodiments, a target level of B cell depletion is achieved following treatment according to the methods disclosed herein. Preferably, the methods provided herein deplete and/or maintain the subject’s B cell counts to < about 10 cells/pL (e.g., 10 cells/pL).
[0207] Low B cell counts have been observed to lead to inhibition of lesions and a decrease in risk of relapses. Thus, in some embodiments, a target level of Gd+Tl lesions rates per MRI scan is achieved.
[0208] In some embodiments, the methods provided herein (e.g., using ofatumumab as the anti-CD20 antibody) result in one or more of a) reduction in number of Gd+Tl lesions relative to baseline; b) reduction in number of new or enlarging T2 lesions relative to baselines; and/or c) reduction in annualized relapse rate (ARR) relative to baseline. [0209] In some embodiments, the methods provided herein (e.g., using a subsequent dosing regimen of 135 mg ofatumumab s.c. Q2M) are non-inferior to a reference maintenance regimen (e.g., a subsequent dosing regimen of 20 mg ofatumumab s.c. Q1M) in one or more of: a) reduction in number of Gd+Tl lesions; b) reduction in number of new or enlarging T2 lesions; c) reduction in ARR relative to a reference maintenance regimen; d) number and/or severity of injection-related reactions (IRRs); and/or e) immunogenicity (e.g., incidence of anti-drug antibodies (ADA)).
[0210] In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of - 0.25 or less. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of < 0.1. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of 0.01-0.05. In some embodiments, the methods provided herein Gd+Tl lesion rates of 0.005-0.05. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates < 0.005. In some embodiments, the methods provided herein achieve Gd+Tl lesion rates of < 0.02. In a preferred embodiment, the methods provided herein achieve Gd+ T1 lesion rates of < 0.03.
[0211] In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of 4 or less. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 2. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 1. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 0.9. In some embodiments, the methods provided herein achieve annualized new or enlarging T2 lesions rates of less than 0.8. In a preferred embodiment, the methods provided herein achieve annualized new or enlarging T2 lesions rates of < 0.72.
[0212] In some embodiments, the method provided herein achieved annual relapse rates (ARR) of less than 0.25. In some embodiments, the method provided herein achieve ARR of less than 0.22, less than 0.20, less than 0.15. or less than 0.12. In a preferred embodiment, the methods provided herein achieve an ARR of < 0.11.
[0213] Accordingly, the methods provided herein (e.g., using ofatumumab as the anti- CD20 antibody) may result in one or more of: a) Gd+ T1 lesion rates of < 0.03; b) annualized rates of new or enlarging T2 lesions of < 0.72; and/or c) annualized relapse rates (ARR) of < 0.11. [0214] In some embodiments, injection-related systemic reactions occur in less than 24.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein. In some embodiments, injection-related systemic reactions occur in less than 16.1% of subjects receiving a Q2M maintenance regimen (e.g., 135 mg ofatumumab s.c. Q2M) described herein.
[0215] In some embodiments, the methods provided herein deplete and/or maintain the subject’s B cell counts to < 10 cell/pL, and/or achieve Gd+Tl lesion rates of 0.01-0.05.
[0216] In some embodiments, the methods provided herein (e.g., using ocrelizumab or ublituximab as the anti-CD20 antibody) deplete and/or maintain the subject’s B cell count to < 10 cells/pL, < 8 cells/pL or < 5 cells/pL; and/or achieve Gd+Tl lesions rates (number of Gd+Tl lesions per MRI scan) of < 0.05, or < 0.02.
Unit dosages and Kits
[0217] Also provided herein is a fixed single unit dosage of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 100 to about 600 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 100 to about 170 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 135 mg of the anti-CD20 antibody. In some embodiments, the fixed single unit dosage comprises about 600 mg of the anti-CD20 antibody.
[0218] A preferred anti-CD20 antibody is ofatumumab (or a similar anti-CD20 antibody). Accordingly, in some embodiments, the fixed single unit dosage comprises about 110-160 mg ofatumumab each. In some embodiments, the fixed single unit dosage comprises about 120-150 mg ofatumumab each. In some embodiments, the fixed single unit dosage comprises about 130-140 mg ofatumumab each. In a preferred embodiment, the fixed single unit dosage comprises about 135 mg ofatumumab each. The fixed single unit dosage facilitates efficient depletion and maintenance of low B cell levels for up to 2 months.
[0219] In some embodiments, provided herein is a fixed single unit dosage of ocrelizumab (or a similar anti-CD20 antibody). In some embodiments, the fixed single unit dosage comprises about 135 mg ocrelizumab each. In some embodiments, the fixed single unit dosage comprises about 480-720 mg ocrelizumab each. In some embodiments, the fixed single unit dosage comprises about 540-660 mg ocrelizumab each. In some embodiments, the fixed single unit dosage comprises about 600 mg ocrelizumab each. In some embodiments, the fixed single unit dosage comprises about 730-1,110 mg ocrelizumab each. In some embodiments, the fixed single unit dosage comprises about 820-1,020 mg. In preferred embodiments, the fixed single unit dosage comprises about 920 mg ocrelizumab each.
[0220] In another embodiment, provided herein is a fixed single unit dosage of ublituximab (or a similar anti-CD20 antibody). In some embodiments, the fixed single unit dosage comprises about 100-170 mg ublituximab each. In some embodiments, the fixed single unit dosage comprises about 135 mg ublituximab each.
[0221] Also provided herein is a kit comprising an anti-CD20 antibody at one or more fixed single unit doses as described above. Also provided herein is a kit comprising one or more pre-filled pens, i.e., autoinjectors, or pre-filled syringes each containing a fixed single unit dose of the anti-CD20 antibody as described above. In some embodiments, the kit further comprises three pre-filled pens, i.e., autoinjectors or pre-filled syringes each containing a fixed single unit dose of about 20 mg of the anti-CD20 antibody (e.g., ofatumumab).
[0222] In some embodiments, each single fixed dose is provided in a total volume of about 0.4 mL. In a preferred embodiment, each single fixed dose is provided in a total volume of about 1.5 mL. In some embodiments, each single fixed dose is provided in a total volume of about 2 mL.
Neurofilament light chain
[0223] Neurofilament light chain (NFL) may be a useful biomarker of MS disease progression and responsiveness to treatment. In particular, higher levels of NFL have been found to correlate with an increase in T2 and Gd+Tl lesions as well as increased frequency of relapse. Accordingly, provided herein is the use of NFL as a prognostic biomarker for MS disease activity in subjects. In some embodiments, the subject is undergoing treatment with an anti-CD20 antibody.
[0224] Also provided herein is a method of predicting MS relapses of a subject, the method comprising detecting NFL levels (pg/mL). In some embodiments, the method comprises detecting NFL levels in the cerebrospinal fluid or the blood of the subject. In some embodiments, the subject is undergoing treatment with an anti-CD20 antibody.
[0225] Also provided herein is a method of treating MS in a subject in need thereof, the method comprising subcutaneously administering an anti-CD20 antibody to the subject, wherein the subject has elevated NFL levels, e.g., elevated NFL levels in the blood or cerebrospinal fluid. In preferred embodiments, the anti-CD20 antibody is ofatumumab. [0226] Also provided herein is a method of treating MS in a subject in need thereof, wherein the method comprises i) subcutaneously administering an anti-CD20 antibody to the subject and ii) monitoring the NFL levels of the subject. In preferred embodiments, the anti- CD20 antibody is ofatumumab.
Methods for monitoring disease progression
[0227] Methods for monitoring disease progression in MS are described below and can be combined with the methods of treatment disclosed herein.
[0228] Disease progression in a subject with MS may also be assessed using the Expanded Disability Status Scale (EDSS), the Symbol Digit Modalities Test (SDMT), the Rey Auditory Verbal Learning Test (RAVLT), Brief Visuospatial Memory Test-Revised (BVMT-R), the timed 25-foot walk test (T25-FW) and the 9-hole pegboard test (9-HPT).
[0229] Another method for monitoring disease progression in a subject with MS is oculomotor assessment. Oculomotor assessment may involve measuring eye movement parameters obtained from fixation, pro-saccade, anti-saccade, smooth pursuit visual and optokinetic nystagmus tasks. Oculomotor assessment may serve as an eye movement biomarker for disease progression, optionally a digital eye movement biomarker.
[0230] The method for monitoring disease progression in a subject with MS using oculomotor assessment may comprise tracking eye movement. Suitable methods and systems for tracking eye movement have been described in W02019161503, WO2022232935 (Innodem Neurosciences), US20170276934 (ICSPI Corp.), US20180342066 (Sony Interactive Entertainment), WO2021028858, W02007076479 (Alcon), all of which are incorporated herein in full by reference.
[0231] Thus, disclosed herein is a method wherein the subject may have been treated or is currently being treated with an anti-CD20 antibody (e.g., ofatumumab, e.g. administered during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by a subsequent dosing regimen of 20 mg once monthly or 135 mg once every 2 months) and the method comprises oculomotor assessment as described above. In some embodiments, the anti-CD20 antibody is ofatumumab, ocrelizumab, rituximab or ublituximab. In a preferred embodiment, the anti-CD20 antibody is ofatumumab. General
[0232] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of those in the art.
[0233] The term “about” in relation to a numerical value x is optional and means, for example, x ± 10%, unless the context dictates otherwise.
[0234] As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
[0235] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”.
[0236] As used in this specification, the term “day 1” is equivalent to the term “week 0”, the term “day 7” is equivalent to “week 1”, the term “day 14” is equivalent to “week 2”, the term “4 weeks” is equivalent to “1 month”, the term “12 weeks” is equivalent to “3 months”, the term “24 weeks” is equivalent to “6 months”, unless specifically stated or obvious from context.
[0237] The skilled person would understand that the term “baseline” refers to the baseline measurement recorded prior to the start of treatment, such as baseline numbers of Gd+Tl lesions.
[0238] As used herein, the terms “subject” and “patient” are used interchangeably and refer to a human (e.g., an adult human of at least 18 years of age).
[0239] As used in this specification, an “anti-CD20 antibody” is an antibody that specifically binds to the human CD20 antigen expressed on B cells. CD20 is expressed on late pre-B cells, mature B cells, and memory B cells, while not expressed on lymphoid stem or plasma cells. Examples of anti-CD20 antibodies include, but are not limited to, ofatumumab, rituximab, tositumomab, ublituximab, ocrelizumab (2H7.vl6), 11B8 or 7D8 (disclosed in W02004/035607), an anti-CD20 antibody disclosed in WO 2005/103081 such as C6, an anti- CD20 antibody disclosed in WO2003/68821 such as IMMU-106 (from Immunomedics), an anti-CD20 antibody disclosed in W02004/103404 such as AME-133 (from Applied Molecular Evolution/Lilly), and anti-CD20 antibody disclosed in US 2003/0118592 such as TRU-015 (from Trubion Pharmaceuticals Inc). [0240] The terms “treating” and “treatment” refer to both therapeutic treatment and prophylactic or preventative therapies.
[0241] All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs and as commonly used in the art to which this application belongs. The publications and other reference materials referenced herein to describe the background of the disclosure and to provide additional detail regarding its practice are hereby incorporated by reference.
Further Exemplary Embodiments
1. A method of treating multiple sclerosis in a subject in need thereof, the method comprising administering to the subject an anti-CD20 antibody once every two months.
2. The method of any one of the preceding embodiments, wherein the anti-CD20 antibody is selected from the group consisting of ofatumumab (e.g., KESIMPTA® /BONSPRI®), ocrelizumab (e.g., OCREVUS®), rituximab (e.g., RITUXAN®/M AB THERA®) and ublituximab (e g., BRIUMVI®).
3. The method of any one of the preceding embodiments, wherein the anti-CD20 antibody is ofatumumab.
4. The method of any one of the preceding embodiments, wherein the anti-CD20 antibody (e.g. ofatumumab) is administered at a dose of about 130 to about 140 mg once every 2 months, e.g., 130 to 140 mg (e.g., about 135 mg, e.g., 135 mg) every two months.
5. The method of any one of the preceding embodiments, wherein the subject is receiving, or has received, an anti-CD20 antibody, e.g., ofatumumab (e.g., KESIMPTA® /BONSPRI®), ocrelizumab (e.g., OCREVUS®), rituximab (e.g.,
RITUXAN®/MAB THERA®) or ublituximab (e.g., BRIUMVI®), e.g., ofatumumab (e.g., KESIMPTA®/BONSPRI®).
6. The method of any one of the preceding embodiments, wherein the subject is receiving, or has received, ofatumumab (e.g., KESIMPTA®/BONSPRI®) once monthly.
7. The method of any one of the preceding embodiments, wherein the subject has received, ofatumumab (e.g., KESIMPTA®/BONSPRI®) at weeks 0, 1, and 2.
8. The method of any one of the preceding embodiments, wherein the subject has received an initial dose, e.g., a loading dose, of an anti-CD20 antibody, e.g., ofatumumab (e.g., KESIMPTA®/BONSPRI®), at weeks 0, 1, and 2, followed by one or more subsequent (e.g., maintenance) dose(s) of an anti-CD20 antibody, e.g., ofatumumab (e.g., KESIMPTA®/BONSPRI®), once monthly.
9. The method of any one of the preceding embodiments, wherein the subject has received at least between 1 and 12 once monthly doses of an anti-CD20 antibody, e.g., ofatumumab (e.g., KESIMPTA®/BONSPRI®).
10. A solution for injection comprising about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., pH about 5.5.
11. The solution for injection of embodiment 10 comprising about 90 mg/mL ofatumumab (e.g., 90 mg/mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5). For example, the pH may be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4- 5.6), in particular pH 5.3-5.8, or pH 5.3-5.7.
12. A solution for injection consisting of about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5% to 5% (w/v)) arginine free base (e.g. L-arginine), about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5 (e.g. with hydrochloric acid).
13. The solution for injection of embodiment 12 consisting of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g. L-arginine), about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid). For example, the pH may be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3- 5.7.
14. A pharmaceutical composition comprising about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5.
15. The pharmaceutical composition of embodiment 14 comprising about 90 mg/mL ofatumumab (e.g., 90 mg/mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5). For example, the pH may be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3-5.7.
16. A pharmaceutical composition consisting of about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5% to 5% (w/v)) arginine free base (e.g. L- arginine), about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5 (e.g. with hydrochloric acid).
17. The pharmaceutical composition of embodiment 16 consisting of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g. L-arginine), about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid). For example, the pH may be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), in particular pH 5.3-5.8, or pH 5.3- 5.7.
EXAMPLES
[0242] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.
Example 1: B cell profiles and PK exposure
Methods
[0243] The inventors discovered that a Q2M administration interval is particularly suitable for the s.c. treatment of MS with ofatumumab. It provides the convenience of less frequent dosing while maintaining effective B cell level control but without extending the interval too long so as to require such a high dose of ofatumumab that it cannot comfortably be delivered subcutaneously.
[0244] Pharmacokinetics (PK)-B cell profiles for different dosing regimens were simulated using the PK-B cell model established with extensive data obtained in RMS patients from completed Phase 2 and Phase 3 studies as described (Yu H, Graham G, David OJ, et al (2022) Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis. CNS Drugs; 36(3):283-300). The PK profiles for all dosing regimens in the RMS patient population were estimated based on simulations of individual PK profiles using characteristics of all the patients who received subcutaneous administration in the OMS112831, COMB157G2102, COMB157G2301 and COMB157G2302 studies, which corresponds to 1461 patients per simulation. This was considered a good representation of the adult RMS population given similar inclusion/ exclusion criteria for a future phase 3 trial.
[0245] PK and B cell profiles were simulated for a wide range of potential dosing regimens identified by the inventors. In all simulations presented here, the s.c. autoinjector parameter estimates were used in the PK-B cell model. However, the results are not limited to an autoinjector presentation and apply also to other forms of administration, e.g., by pre-filled syringe. In all simulations, an initial dosing regimen of 20 mg at weeks 0, 1 and 2 was used with the subsequent dosing regimen starting at week 4. The PK and B cell profiles were simulated over 52 weeks of dosing. The PK and B cell profiles present the median, 5th and 95th percentiles of the data. Results
40 mg ofatumumab s.c. Q2M regimen
[0246] PK and B cell profiles of an extended dosing regimen comprising subsequent dosing of 40 mg ofatumumab s.c. Q2M were simulated (i.e., twice the Q1M dose of 20 mg ofatumumab).
[0247] Figure 1 shows the B cell depletion profile of the 40 mg s.c. Q2M regimen in comparison to the approved 20 mg s.c. Q1M regimen. The B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen (at week 0, 1 and 2). After week 4, both regimens also demonstrate a fast initial depletion of B cells. At week 8, however, the subsequent dosing regimen of 40 mg s.c. Q2M begins to deviate from the B cell depletion profile of the 20 mg s.c. Q1M regimen, in terms of median B cell profile and distribution of the B cells across the population.
[0248] Both the 20 mg s.c. Q1M and the 40 mg s.c. Q2M regimens are estimated to achieve a median CD19+ B cell count < 10 cells/pL. However, the estimated median B cell count for 40 mg s.c. Q2M regimen is higher than the median B cell count achieved by the 20 mg s.c. Q1M regimen. This is because the median B cell count for the 40 mg s.c. Q2M regimen fluctuates during the two-month dosing interval, while the median B cell count for the 20 mg s.c. Q1M regimen remains relatively stable between monthly doses.
[0249] Indeed, the median B cell count for the 40 mg s.c. Q2M regimen begins rising about 4 weeks after each subsequent dose is administered and peaks just before the administration of the next subsequent dose. In the first 28 weeks of treatment, the median B cell count for the 40 mg s.c. Q2M regimen rises from around 1 cell/pL to between about 3 and 2 cells/pL between doses, while the median B cell count for the 20 mg s.c. Q1M regimen consistently remains around 1 cell/pL. The 40 mg s.c. Q2M regimen thus demonstrates higher levels of B cell repletion between doses than the 20 mg s.c Q1M regimen.
[0250] Moreover, the 95th percentile (the upper boundary of the light grey shaded interval in Figure 1) for the 40 mg s.c. Q2M regimen exhibits a higher B cell count than the 95th percentile (upper boundary of the dark grey shaded interval in Figure 1) for the 20 mg Q1M regimen. The 95th percentile B cell count for the 40 mg s.c. Q2M regimen peaks above 30 cells/pL between doses, while the 95th percentile B cell count for the 20 mg s.c. Q1M regimen remains < 10 cells/pL. As explained above, B cell counts of < 10 cells/pL are associated with lower Gd+Tl lesion rates and higher treatment efficacy. The 40 mg s.c. Q2M regimen is thus not expected to achieve the same level of B cell depletion (and consequently treatment efficacy) as the 20 mg s.c. Q1M regimen across the patient population.
[0251] As shown in Figure 2, the 40 mg s.c. Q2M dosing regimen also exhibits a less favourable pharmacokinetic profile. The median concentration of ofatumumab in the 40 mg s.c. Q2M regimen drops to below 0.1 mg/L between doses, suggesting a risk of underexposure in the two-month dosing interval. Thus, the exposure provided by the 40 mg s.c. Q2M dosing regimen is inferior to the currently approved 20 mg s.c. Q1M dosing regimen.
[0252] The pharmacokinetic profile and the B cell profile estimated for the 40 mg s.c. Q2M regimen indicate that this extended dosing regimen is clinically inferior to the approved 20 mg s.c. Q1M regimen.
80 mg ofatumumab s.c. Q2M regimen
[0253] A subsequent dosing regimen of 80 mg ofatumumab s.c. Q2M was simulated (i.e., four-fold the approved Q1M 20 mg dose).
[0254] Figure 3 shows the B cell depletion profile of the 80 mg s.c. Q2M regimen in comparison to the approved 20 mg s.c. Q1M regimen. As explained above, the B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen. After week 4, the subsequent dosing regimen of 80 mg s.c. Q2M shows good agreement to the 20 mg s.c. Q1M profile, in terms of fast initial depletion and the median B cell profile. In particular, the 80 mg s.c. Q2M regimen shows a similar median B cell count to the 20 mg s.c. Q1M regimen, which is sustained throughout the two- month dosing interval. Similar to the 20 mg s.c. Q1M regimen, the 80 mg s.c. Q2M regimen is estimated to achieve the desired median CD19+ B cell count of < 10 cells/pL.
[0255] However, the 80 mg s.c. Q2M regimen demonstrates an inferior distribution of B cells across the population compared to the 20 mg s.c. Q1M regimen. The 95th percentile (the upper boundary of the light grey shaded interval in Figure 3) for the 80 mg s.c. Q2M regimen exhibits a higher B cell count than the 95th percentile (upper boundary of the dark grey shaded interval in Figure 3) for the 20 mg s.c. Q1M regimen. In particular, the 95th percentile B cell count for the 80 mg s.c. Q2M regimen remains above 10 cells/pL over the simulated 52 weeks of treatment. The inability of the 80 mg s.c. regimen to achieve a B cell count of < 10 cells/pL for all patients indicates that this extended dosing regimen is likely to be clinically inferior to the approved 20 mg s.c. Q1M regimen. [0256] As shown in Figure 4, the pharmacokinetic profile of the 80 mg s.c. Q2M regimen is also inferior to the 20 mg s.c. Q1M regimen. In particular, the median Cmin (mg/mL) estimated for the 80 mg s.c. Q2M regimen is lower than the median Cmin for the 20 mg s.c. Q1M regimen. Thus, the 80 mg s.c. Q2M regimen is predicted to provide lower exposure levels than the approved monthly regimen.
[0257] Based on the simulated pharmacokinetic and B cell depletion profiles described above, the 80 mg s.c. Q2M regimen provides inferior clinical efficacy to the previously approved regimen.
135 mg ofatumumab s.c. Q2M regimen
[0258] Of all the tested extended subsequent dosing regimens, the 135 mg s.c. Q2M regimen produced a surprisingly favourable B cell profile. Figure 5 shows the B cell depletion profile of the 135 mg s.c. Q2M regimen compared to the 20 mg s.c. Q1M regimen. The B cell depletion profiles up to week 4 are the same for the two regimens as they both use the same 20 mg initial dosing regimen. After week 4, the subsequent dosing regimen of 135 mg s.c. Q2M shows good agreement to the 20 mg Q1M profile in terms of fast initial depletion, the median B cell profile and distribution of the B cells across the population. In particular, the 135 mg Q2M dosing regimen shows a similar, or even lower, median B cell count which is sustained throughout the two-month dosing interval. The 135 mg regimen is estimated to achieve a median CD19+ B cell count < 10 cells/pL, similar to the B cell count achieved by the monthly dosing regimen. As explained previously, B cell counts of < 10 cells/pL are associated with lower Gd+Tl lesion rates and higher treatment efficacy.
[0259] The 95th percentile (the upper boundary of the dark grey shaded interval in Figure 5) for the 135 mg s.c. Q2M regimen also exhibits a lower B cell count that the 95th percentile (upper boundary of the light grey shaded interval in Figure 5) for the 20 mg Q1M regimen. The 95th percentile B cell count is lower for the 135 mg s.c. Q2M regimen than for the 20 mg s.c. Q1M count during the intervals between subsequent dose administration. Furthermore, after week 12 (i.e., after the second 135 mg subsequent dose is administered), the 95th percentile for the 135 mg Q2M regimen shows a B cell count that remains below 10 cells/pL and below that of the 20 mg Q1M regimen, even at the end of each 2M interval immediately prior to the administration of the next subsequent dose.
[0260] The 135 mg s.c. Q2M regimen also leads to less frequent repletion in B cell count, with B cell depletion levels peaking every two months prior to dose administration as opposed to every month, while allowing for a sufficiently quick repletion, if necessary (e.g., in the event of an infection, etc.).
[0261] As shown in Figure 6, the 135 mg s.c. Q2M dosing regimen also exhibits an appropriate pharmacokinetic profile. Cmin was selected as the most sensitive and clinically relevant target metric to demonstrate non-inferiority of the new regimen throughout the entire Q2M dosing interval compared to the 20 mg s.c. Q1M regimen. As shown in Table 1 below, the lower 5th percentile of Cmin for 135 mg s.c. Q2M and 20 mg s.c. Q1M are comparable, therefore minimizing the risk of underexposure. Thus, the 135 mg s.c. Q2M dosing regimen is expected to provide exposure throughout the dosing interval that is at least non-inferior to the approved 20 mg s.c. Q1M dosing regimen.
Table 1: Median and (5th, 95th) quantiles of the PK metrics AUCtau (weeks 4-12), Cmax (week 5) and Cmin (pre-dose Week 12) from the PK simulation in an RMS population receiving ofatumumab
Dosing AUCtau (weeks 4-12) Cmax (week 5) Cmin (pre-dose regimen (mg.day/L) (mg/L) week 12)
Figure imgf000062_0001
[0262] Based on pharmacokinetics and B cell profile modelling, the 135 mg s.c. Q2M regimen is expected to also show a similar safety profile as the 20 mg s.c. Q1M dose regimen. In particular, the inventors have discovered that including the 20 mg s.c. initial regimen at weeks 0, 1 and 2 prior to starting the higher-dose 135 mg s.c. Q2M subsequent regimen at week 4, further reduces the risk of any systemic injection-related reactions (IRRs), the severity of which is likely related to dose and B cell count. The initial regimen ensures effective depletion of B cells by week 4 (overall proportion of ofatumumab treated patients with a B cell count < 10 cells/pL was 81.9% at Week 2 and 91.8% by Week 4, as determined in COMB157G2301 and COMB157G2302), i.e., prior to administration of the first 135 mg subsequent dose, thereby mitigating against the potential risk of an increase in systemic IRRs with higher dose.
[0263] Thus, in comparison to the approved 20 mg s.c. Q1M dosing regimen, the 135 mg s.c. Q2M dosing regimen demonstrates an at least non-inferior pharmacokinetics profile and is estimated to lead to at least similar, or even more pronounced, B cell depletion sustained throughout the two-month dosing interval, with fewer patients showings signs of B cell repletion before each subsequent dose administration, while retaining the ability to sufficiently quickly replete B cell levels by interrupting treatment when desired, for example in the event of an infection, etc.
[0264] In addition, the 135 mg s.c. Q2M dosing regimen exhibited superior pharmacokinetic and B cell depletion profiles compared to the other tested dosing regimens, including 40 mg s.c. Q2M and 80 mg s.c. Q2M. Increasing the approved monthly ofatumumab dose (i.e., 20 mg) by a factor of two (i.e., 40 mg), or even by a factor of four (i.e., 80 mg) was not sufficient to provide an effective dosing regimen wherein ofatumumab is administered at half the frequency of the approved regimen (Q2M).
Example 2: Stable high-concentration antibody formulations
[0265] Ofatumumab may be provided in a high-concentration antibody formulation, preferably an antibody formulation comprising 90 mg/mL ofatumumab (e.g. 135 mg in 1.5 mL). As explained above, such high-concentration antibody formulations may be difficult to produce due to long-term stability issues. Often, significant optimization is required to develop a high-concentration antibody formulation that facilitates long-term storage and pain- free delivery to patients.
[0266] For this reason, the physico-chemical drug stability of ofatumumab at a concentration of 90 mg/ mL was tested in three alternative formulations (A, B, and C) as shown in Table 2 below.
Table 2: Exemplary ofatumumab formulations
Figure imgf000063_0001
Figure imgf000064_0001
[0267] Formulation A contained 50 mM sodium acetate, 51 mM sodium chloride, 1% (w/v) arginine free base, 0.02% (w/v) polysorbate 80, 0.05 mM EDTA adjusted to pH 5.5. Formulation A thus corresponded to the formulation used for the approved 20 mg/0.4 mL dosage form of ofatumumab. In formulation B, the polysorbate 80 (PS80) concentration was doubled to 0.04% (w/v) in view of the tendency of high-concentration antibody formulations to form aggregates. Methionine was added to formulation C at a concentration of 5 mM to account for the aggregation, particle formation and oxidative stress that may be observed in high-concentration antibody formulations.
[0268] The long-term stability of ofatumumab in these three alternative formulations was tested for up to six months in three different storage conditions: i) intended condition (5°C ± 3°C); ii) accelerated condition (25°C ± 2°C and 60 ± 5% relative humidity); and iii) stress condition (40°C ± 2°C and 75 ± 5% relative humidity).
All three formulations were stored in the same injection device for the duration of the study.
[0269] The formulations were assessed for purity, aggregates and relative potency.
Purity measured by size exclusion chromatography (SEC)
[0270] The purity of the three different ofatumumab formulations was measured by size exclusion chromatography (SEC) over a storage period of six months. Table 3 shows the purity percentage over time for each formulation at the intended condition, the accelerated condition and the stress condition.
Table 3 - Purity as measured by SEC
Figure imgf000065_0001
[0271] As demonstrated in Table 3, the purity of all three formulations was well preserved over six months of storage. In particular, all three formulations had:
• a purity, when measured by size exclusion chromatography, of at least 99% at time point 0, and of: (a) at least 99% after being stored for 1.5 months at 5°C ± 3°C; and/or (b) at least 99% after being stored for six months at 5°C ± 3°C; • a purity, when measured by size exclusion chromatography, of at least 99% at time point 0, and of: (a) at least 98% after being stored for 1.5 months at 25°C ± 2°C and 60 ± 5% relative humidity; and/or (b) at least 96% after being stored for six months at 25°C ± 2°C and 60 ± 5% relative humidity; and
• a purity, when measured by size exclusion chromatography, of at least 99% at time point 0, and of: (a) at least 96% after being stored for 1.5 months at 40°C ± 2°C and 60 ± 5% relative humidity; and/or (b) at least 87% after being stored for six months at 40°C ± 2°C and 60 ± 5% relative humidity.
Aggregation measured by size exclusion chromatography (SEC)
[0272] The formation of aggregates in the three ofatumumab formulations was assessed by SEC over six months of storage. Table 4 shows the sum of aggregates over time for each formulation at the intended condition, the accelerated condition and the stress condition.
Table 4 - Sum of aggregates as measured by SEC
Figure imgf000066_0001
Figure imgf000067_0001
[0273] All three formulations prevented significant aggregate formation over six months of storage under the intended and accelerated conditions. The size variant profile after six months of storage at the intended condition showed a very minor increase of the sum aggregates compared to time point 0. At the accelerated condition, the sum of aggregates increased by only -0.5% over six months of storage.
Relative complement-dependent cytotoxicity (CDC) potency
[0274] The potency of the three formulations over six months of storage was tested by a complement-dependent cytotoxicity assay on Raji cells expressing CD20. Table 5 shows the relative potency of all three batches over six months of storage under the intended condition, the accelerated condition and the stress condition.
Table 5 - Relative complement-dependent cytotoxicity (CDC)
Figure imgf000067_0002
Figure imgf000068_0001
[0275] Table 5 demonstrates that the relative potency remained stable for all three formulations for at least six months at the intended condition and at the accelerated condition. In particular, the three formulations demonstrated a relative CDC potency of at least 90% after six months of storage at 5°C ± 3°C.
Sub-Visible particles by Light Obscuration
[0276] Particle formation in the three alternative formulations was tested by lightobscuration. The number of sub-visible particles per mL was measured at the intended storage condition, the accelerated storage condition, and the stress storage condition. Table 6 below shows the number of sub-visible particles observed in each formulation per mL over time.
Table 6 - number of sub-visible particles per mL
Figure imgf000068_0002
Figure imgf000069_0001
[0277] United States Pharmacopeia, Chapter 787 ‘Subvisible Particulate Matter in Therapeutic Protein Injections’ (‘USP 787’) requires that a container has <6000 particles >10pm in size, and <600 particles >25pm in size. Formulations A, B and C all met the requirements of USP 787 at all conditions and times. There was no significant change in the number of subvisible particles per mL in either of the three formulations over 6 months of storage at the intended condition (5°C ± 3°C), and only minor changes were observed at the accelerated condition (25°C ± 2°C).
Conclusion
[0278] The results above demonstrate that the formulation comprising 90 mg/mL ofatumumab, 50 mM sodium acetate, 51 mM sodium chloride, 1% (w/v) arginine free base, 0.02% (w/v) polysorbate 80, 0.05 mM EDTA adjusted to pH 5.5 is a stable antibody formulation. As shown above, this formulation displays stable properties for at least six months under the intended storage condition (5°C ± 3°C).
[0279] Surprisingly, this formulation was stable without requiring the methionine and the increased surfactant concentration. Indeed, the results presented here show that neither the addition of 5 mM methionine (C), nor the increase of the PS80 concentration from 0.02% to 0.04% (B) had a detectable impact on long-term stability compared to the formulation (A) used for the approved 20 mg/0.4 mL dosage form of ofatumumab, despite the concentration of ofatumumab in the tested formulations (i.e., 90 mg/mL) being 180% the concentration of ofatumumab in the approved dosage form (i.e. 50 mg/mL).
[0280] These studies indicate that a 135 mg s.c. Q2M ofatumumab regimen yields a PK/PD profile that is at least clinically non-inferior to the previously approved 20 mg s.c. Q1M regimen. Moreover, this extended dosing regimen supported by Applicant’s reformulation of ofatumumab at a concentration of 90 mg/mL to provide the full 135 mg ofatumumab in a volume suitable for subcutaneous administration. The 135 mg s.c ofatumumab Q2M dosage regimen therefore strikes an effective balance between PK/PD and formulation considerations. Example 3: A phase III, non-inferiority, randomized, open-label, parallel group study of ofatumumab subcutaneous 135 mg Q2M versus 20 mg 0 IM subsequent dose
[0281] The primary objective and purpose of this Phase 3 study is to confirm noninferior PK (Cmin) profile at week 12 (pre-administration) concentration of the new 135 mg s.c. Q2M versus the approved subsequent regimen of 20 mg s.c. Q1M. Cmin was selected as the most sensitive and clinically relevant target metric to demonstrate non-inferiority of the new regimen throughout entire Q2M dosing interval. The non-inferior PK profile (exposure), along with pharmacodynamic profile (B cell depletion) consistent with the approved regimen, will further support the demonstration of comparability of the less-frequent subsequent dosing regimen. Other objectives of this study are described below (Table 7).
Table 7: Study objectives and related endpoints
Figure imgf000070_0001
Figure imgf000071_0001
s.c. = subcutaneous; RMS = Relapsing Multiple sclerosis, IRR = Incidence Rate Ratio Study design
[0282] This is a Phase III, open label, parallel-group, multicenter study in approximately 180 study participants with RMS. The study consists of two parts - core part (up to 52 weeks) and extension part (an additional up to 2 years) (see Figure 7).
[0283] The core study includes a screening period, a treatment period and a safety follow up period. The first approximately 100 study participants enrolled will be randomized 1 : 1 (50 per arm) to either the 135mg Q2M or 20 mg Q1M arm in the 12-week parallel-group part of the study. The primary (PK) non-inferiority (NI) endpoint is based on Cmin plasma levels observed at week 12. At the end of the parallel group part, patients in the 20 mg Q1M arm will switch to receive 135 mg Q2M starting at week 12. Patients randomized to the 135 mg Q2M arm will continue on this regimen through week 52. Once approximately 100 patients have been randomized, an additional approximately 80 patients (for a total of 180 study participants) will be enrolled in the 135 mg Q2M arm dosing regimen and followed for safety up to 52 weeks. All study participants (regardless of initial teatment assignment) will initiate treatment with an initial dosing regimen of three doses of 20 mg s.c. (on week 0, 1 and 2) with first subsequent dose (135 mg Q2M or 20 mg Q1M) starting at week 4. Safety in all study participants will be evaluated for the duration of the 52-week study core part. [0284] Study participants completing the treatment period core part of study (duration up to 52 weeks) will have the option to participate in the long-term extension part of the study and continue to receive ofatumumab 135 mg Q2M for an additional up to around 2 years.
Study population
[0285] The study will involve 180 adult patients with relapsing Multiple Sclerosis, age 18-55 (inclusive), male or female, and an EDSS score of 0-5.5 (inclusive).
[0286] Key inclusion criteria for patient enrollment in the study include: written informed consent must be obtained before any assessment is performed; male or female patients aged 18 to 55 years (inclusive) at screening; diagnosis of MS according to the 2017 Revised McDonald criteria (Thompson AJ, Baranzini SE, Geurts J, et al (2018) Multiple sclerosis. Lancet; 391(10130): 1622-36); relapsing MS: relapsing-remitting course (RRMS), or Secondary progressive (SPMS) course with disease activity; disability status at Screening with an EDSS score of 0 to 5.5 (inclusive); documentation of at least: 1 relapse during the previous year OR 2 relapses during the previous 2 years prior to Screening OR a positive Gd- enhancing MRI scan during the year prior to randomization; and neurologically stable within 1 month prior to randomization.
Exclusion criteria
[0287] Patients are excluded from the study if they meet any of the following key exclusion criteria: patients with primary progressive MS (PPMS) or secondary progressive multiple sclerosis (SPMS) without disease activity (however, the disclosed therapy is expected to be useful also for these forms of MS and other anti-CD20 antibodies such as ocrelizumab are authorized to treat these forms of MS as well as RMS); patients meeting criteria for neuromyelitis optica; disease duration of more than 10 years in patients with an EDSS score of 2 or less; pregnant or nursing (lactating) women; women of child-bearing potential unless using highly effective methods of contraception during study drug dosing and for 12 months post-dosing; sexually active males unless they agree to use condom during intercourse while on study drug; patients with an active chronic disease of the immune system other than MS; patients with neurological findings consistent with progressive multifocal leukoencephalopathy (PML) or confirmed PML; patients at risk of developing or having reactivation of hepatitis: positive results at Screening for serology markers for hepatitis A, B, C and E (HA, HB, HC, and HE) indicating acute or chronic infection; patients with active systemic infections or known to have AIDS or to test positive for HIV antibody at Screening; patients at risk of developing or having reactivation of syphilis or tuberculosis; patients who received any live or live-attenuated vaccines within 2 months prior to randomization; patients who have been treated with medications as specified or within timeframes specified (e.g. corticosteroids, ofatumumab, rituximab, ocrelizumab, alemtuzumab, natalizumab, cyclophosphamide, teriflunomide, leflunomide, etc.); any other disease or condition that could interfere with participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures; and/or patients with prespecified neurological/psychiatric disorder prior to randomization (e.g. suicidality, substance abuse, or clinically significant CNS disease or neurological disorders that mimic MS).
Study treatments
Investigational and comparator drugs
[0288] The investigational drug will be provided in an autoinjector containing 135 mg ofatumumab for subcutaneous administration. The comparator drug will be provided in an autoinjector containing 20 mg ofatumumab for subcutaneous administration.
[0289] All patients will start with an initial dosing regimen of 20 mg ofatumumab at Day 1 (week 0), Day 7 (week 1), and Day 14 (week 2) followed by 135 mg ofatumumab subsequent dose once every 2 months or 20 mg ofatumumab subsequent dose every month, starting at Month 1 (week 4), depending on randomization arm.
Table 8: Details of the investigational and comparator drug regimens
Figure imgf000073_0001
Treatment arms/groups
[0290] Eligible patients will be randomized at visit Day 1 to one of the following 2 treatment arms in a 1 : 1 randomization ratio:
• Initial dosing regimen with ofatumumab 20 mg s.c. injection on day 1 (week 0), day 7 (week 1) and day 14 (week 2) followed by a subsequent regimen with ofatumumab 135 mg s.c injection every two months starting at week 4.
• Initial dosing regimen with ofatumumab 20 mg s.c. injection on day 1 (week 0), day 7 (week 1) and day 14 (week 2) followed by a subsequent regimen with ofatumumab 20 mg s.c. injection every month starting at week 4 up till week 12.
[0291] At the week 12 visit, study participants in the second treatment arm, after completion of primary endpoint assessments prior to week 12 dosing, will switch to a subsequent regimen with ofatumumab 135 mg s.c. injection every two months.
[0292] Study participants who complete 52 weeks of core part on treatment will be offered to continue ofatumumab 135 mg s.c. every two months for an additional around 24 months (~ 2 years).
Concomitant therapy
[0293] Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen has been observed in RMS clinical studies. Therefore, premedication with corticosteroids, acetaminophen and/or antihistamines (or equivalent) is optional and may be administered at the discretion of the investigator. If the investigator chooses to administer premedication, it should be administered 30 to 60 min prior to study drug injection.
[0294] Patients will remain at the site under observation for approximately 5 hours following the first dose of 135 mg.
[0295] The decision to treat MS relapses should be based on the Investigator’s judgement and or local clinical practices. If MS relapses require treatment, the standard treatment should consist of a short course of corticosteroids of 3-5 days and up to 1,000 mg methylprednisolone/day or equivalent on an inpatient or outpatient basis. Standard of care will be followed during treatment. Prohibited medications
[0296] The following medications are prohibited for the duration of the study: systemic corticosteroids (except for when given for MS relapse treatment) and, as a precaution, administration of any live or live-attenuated vaccine (including for measles) is prohibited while patients are exposed to study drug (long-lasting effects of the study drugs should be taken into consideration).
Sample size and Data analysis
[0297] The overall number of participants planned to be enrolled in the study is 180. The core part of the study will randomize the first approximately 100 study participants in a 1 : 1 ratio (50 per arm) to either the 135 mg Q2M or 20mg Q1M arms for the primary analysis purpose.
[0298] This sample size of 100 will have more than 90% power to test the noninferiority on PK parameter Cmin at week 12 of 135mg Q2M regimen versus the 20mg Q1M regimen, using an NI margin of log (0.8) and one-sided false positive rate of 2.5%.
[0299] In each arm, study participants will have a drug concentration sample taken at week 12 prior to administration of the next (week 12) subsequent dose. The primary analysis based on the PK endpoint (Cmin) will be to demonstrate that the lower bound of the 95% confidence interval of the difference in the mean log-transformed concentrations between the 135 mg Q2M and 20 mg Q1M dose regimens is not lower than log (0.8).
[0300] Exposure to 135 mg Q2M will be increased by an additional approximately 80 participants who will be enrolled in the 135 mg Q2M arm (once recruitment of approximately 100 participants is completed for the parallel -group part) and by patients in the 20 mg Q1M arm who will switch to the 135 mg Q2M regimen at week 12.
[0301] This overall sample size of 180 participants (assuming a drop-out rate over 1 year of 10%) will have a 5% margin of error to estimate the incidence of any adverse event (AE) with 10% incidence rate over 52 weeks of exposure.
[0302] Positive results from this study would confirm that administering ofatumumab in a dosage regimen comprising a) an initial dosing regimen, wherein the initial dosing regimen comprises administering 20 mg ofatumumab at weeks 0, 1 and 2, followed by b) administering ofatumumab during a subsequent dosing regimen, wherein the subsequent dosing regimen comprises administering 135 mg ofatumumab at week four and once every 2 months thereafter, is as effective, or even more effective, at treating multiple sclerosis, compared to the established dosage regimen comprising the same initial dosing regimen followed by 20 mg ofatumumab monthly subsequent dosing regimen.
Example 4: Subcutaneous dosing of ocrelizumab
[0303] Ocrelizumab (OCREVUS®) is approved in the treatment of MS by intravenous infusion. An initial 600 mg dose is administered as two separate intravenous infusions (300 mg followed 2 weeks later by a second 300 mg infusion), followed by single 600 mg intravenous infusion every 6 months, with the first dose of 600 mg administered 6 months after the first infusion of the initial dose.
[0304] Ocrelizumab can be administered subcutaneously every 6 months, for example at a dose of 600 mg. A particularly useful ocrelizumab dosing regimen is 920 mg administered subcutaneously once every 6 months. However, as the dose requirement for ocrelizumab is higher compared to ofatumumab, the inventors propose the use of a particular formulation to enable the subcutaneous administration of ocrelizumab at 6-monthly intervals as described herein. An exemplary such formulation comprises, in addition to ocrelizumab, 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w/v) polysorbate 20, and 1,500-12,000 U/mL rHuPH20, pH 5.3. Thus, a particularly useful formulation for subcutaneous administration of ocrelizumab comprises 40 mg/mL ocrelizumab (e.g., 920 mg in 23 mL), 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w/v) polysorbate 20, and 1,500-12,000 U/mL rHuPH20, pH 5.3.
[0305] Ocrelizumab administered as described herein is expected to achieve B cell count to <10 cells/pL (e.g., <5 cells/pL) or and Gd+Tl lesions rates of <0.05 (e.g., <0.02).
Table 9: Sequences
Figure imgf000077_0001
Figure imgf000078_0001
HCDR = heavy chain complementarity determining region, LCDR = light chain complementarity determining region; (K) indicates that the C-terminal lysine residues of the heavy chains (Lys452) may be removed by the action of basic carboxypeptidases during the cell culture process. HCDR and LCDRs are recited in the Kabat format.

Claims

1. A method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering ofatumumab to the subject at a dose of about 130 mg to about 140 mg once every 2 months, e.g., 130 to 140 mg every 2 months.
2. The method according to claim 1, the method comprising subcutaneously administering ofatumumab to the subject at a dose of about 135 mg once every 2 months, e.g., 135 mg every 2 months.
3. The method according to claim 1 or claim 2, comprising: a) subcutaneously administering ofatumumab to the subject during an initial dosing regimen of 3 separate 19-21 mg doses at weeks 0, 1 and 2, followed by b) subcutaneously administering ofatumumab to the subject during a subsequent dosing regimen of 130-140 mg at week 4 and once every 2 months thereafter.
4. The method according to any one of claims 1-3, comprising: a) subcutaneously administering ofatumumab to the subject during an initial dosing regimen of 3 separate 20 mg doses at weeks 0, 1 and 2, followed by b) subcutaneously administering ofatumumab to the subject during a subsequent dosing regimen of 135 mg at week 4 and once every 2 months thereafter.
5. The method according to any one of the preceding claims, wherein the method depletes and/or maintains the subject’s (e.g., mean) B cell count to <10 cells/pL.
6. The method according to any one of the preceding claims, wherein ofatumumab is administered in a pharmaceutical composition further comprising arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), e.g., about pH 5.5, optionally wherein the pharmaceutical composition further comprises EDTA.
7. The method according to claim 6, wherein the pharmaceutical composition comprises about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine, about 10 to about 100 mM e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to about pH 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), e.g., about pH 5.5, optionally wherein the pharmaceutical composition further comprises about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA.
8. The method according to claim 7, wherein the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), adjusted to about pH 5.5 (e.g., pH 5.5), optionally wherein the pharmaceutical composition further comprises about 0.05 mM (e.g., 0.05 mM) EDTA.
9. The method according to any one of the preceding claims, wherein the subsequent doses of ofatumumab are administered in a pharmaceutical composition that comprises ofatumumab at a concentration of about 80-100 mg/mL (e.g., 80-100 mg/mL), e.g., about 90 mg/mL (e.g., 90 mg/mL).
10. The method according to claim 9, wherein ofatumumab is administered in a pharmaceutical composition that does not comprise hyaluronidase.
11. The method according to any one of the preceding claims, wherein ofatumumab is administered using a pre-filled pen (autoinjector).
12. The method according to claim 11, wherein the pre-filled pen contains a fixed single unit dose of about 135 mg (e.g., 135 mg) ofatumumab.
13. The method according to any one of the preceding claims, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).
14. The method according to claim 13, wherein the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) with disease activity, or clinically isolated syndrome (CIS).
15. The method according to any one of claims 1-12, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS).
16. The method according to any one of the preceding claims, wherein the method results in one or more of: a. reduction in number of Gd+Tl lesions relative to baseline; b. reduction in number of new or enlarging T2 lesions relative to baseline; and/or c. reduction in annualized relapse rate (ARR) relative to baseline.
17. The method according to any one of the preceding claims, wherein the method further comprises administering a concomitant therapy, for example selected from the group of a corticosteroid, an antihistamine, and acetaminophen.
18. The method according to claim 17, wherein the concomitant therapy is administered before administration of ofatumumab, e.g., about 30 to about 60 minutes before administration of ofatumumab.
19. A solution for injection containing about 135 mg (e.g., 135 mg) ofatumumab, e.g., in a pharmaceutical composition as defined in any one of claims 6-10.
20. The method according to any one of claims 1-18, wherein the subsequent doses of ofatumumab are administered in a solution for injection as defined in claim 19.
21. A pre-filled syringe or pre-filled pen (autoinjector) containing the solution as defined in claim 19, e.g., in a total volume of around 1.5 mL, for subcutaneous administration.
22. A kit comprising ofatumumab at one or more fixed single unit doses of about 135 mg (e.g., 135 mg) each.
23. A kit comprising one or more pre-filled syringes or pre-filled pens (autoinjectors) each containing a fixed single unit dose of about 135 mg (e.g., 135 mg) ofatumumab, optionally wherein the kit further comprises three pre-filled syringes or pre-filled pens (autoinjectors) or each containing a fixed single unit dose of about 20 mg (e.g., 20 mg) ofatumumab.
24. The kit according to claim 22 or claim 23, wherein each fixed single unit dose of about 135 mg (e.g., 135 mg) ofatumumab is provided in a pre-filled syringe or pre-filled pen (autoinjector), e.g., in a total volume of around 1.5 mL per pre-filled syringe or pre-filled pen (autoinjector).
25. A pharmaceutical composition comprising about 80 to about 100 mg/mL (e.g., 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base, about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5.
26. The pharmaceutical composition of claim 25, comprising about 90 mg/mL ofatumumab (e.g., 90 mg/mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base, about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to pH about 5.5 (e.g., pH 5.5).
27. A pharmaceutical composition consisting of about 80 to about 100 mg/mL (e.g. 80 to 100 mg/mL) ofatumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate (e.g. sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w/v) (e.g., 0.5 to 5% (w/v)) arginine free base (e.g. L- arginine), about 0.01 to about 0.2% (w/v) (e.g., 0.01 to 0.2% (w/v)) polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to pH about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) e.g., about pH 5.5 (e.g. with hydrochloric acid).
28. The pharmaceutical composition of claim 27 consisting of about 90 mg/mL (e.g., 90 mg/mL) ofatumumab, about 50 mM (e.g., 50 mM) sodium acetate (e.g. sodium acetate trihydrate), about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w/v) (e.g., 1% (w/v)) arginine free base (e.g. L-arginine), about 0.02% (w/v) (e.g., 0.02% (w/v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g. with hydrochloric acid).
29. A pharmaceutical composition comprising about 80-100 mg/mL (e.g., 80-100 mg/mL) (e.g. about 90 mg/mL, e.g., 90 mg/mL) ofatumumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).
30. A method of treating multiple sclerosis in a subject in need thereof, the method comprising subcutaneously administering to the patient the pharmaceutical composition of any one of claims 25 to 29.
31. The method according to claim 30, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).
32. The method according to claim 31, wherein the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) with disease activity, or clinically isolated syndrome (CIS).
PCT/EP2024/078440 2023-10-09 2024-10-09 Extended dosing regimens for anti-cd20 antibodies in the treatment of multiple sclerosis Pending WO2025078463A1 (en)

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