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WO2025078463A1 - Régimes posologiques étendus pour l'administration d'anticorps anti-cd20 dans le traitement de la sclérose en plaques - Google Patents

Régimes posologiques étendus pour l'administration d'anticorps anti-cd20 dans le traitement de la sclérose en plaques 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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Prior art keywords
ofatumumab
antibody
multiple sclerosis
pharmaceutical composition
polysorbate
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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

L'invention concerne des régimes thérapeutique pour le traitement de la sclérose en plaques (SEP). Ces méthodes comprennent l'administration sous-cutanée d'anticorps anti-CD20 et assurent efficacité et sécurité à des intervalles de dosage sous-cutanés étendus.
PCT/EP2024/078440 2023-10-09 2024-10-09 Régimes posologiques étendus pour l'administration d'anticorps anti-cd20 dans le traitement de la sclérose en plaques Pending WO2025078463A1 (fr)

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