RU2849464C1 - Treating rms by changing therapy - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to the use of ofatumumab for the treatment of recurrent multiple sclerosis, where ofatumumab is used in a patient who has been treated with a disease-modifying therapy, different from ofatumumab, wherein said disease-modifying therapy is stopped before the administration of ofatumumab, where the disease-modifying therapy is selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate and where ofatumumab is administered subcutaneously, also relates to the use of ofatumumab for the manufacture of a medicament for the treatment of recurrent multiple sclerosis, where the drug is used in a patient who has been treated with a disease-modifying therapy different from ofatumumab, where said disease-modifying therapy is stopped before the administration of ofatumumab, where the disease-modifying therapy is selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate and where ofatumumab is administered subcutaneously, also relates to a method for treating recurrent multiple sclerosis, wherein the method comprises administering ofatumumab to a patient, suffering from recurrent multiple sclerosis, wherein the patient has been treated with a disease-modifying therapy, different from ofatumumab, wherein said disease-modifying therapy is terminated before the administration of ofatumumab, wherein the disease-modifying therapy is selected from teriflunomide, dimethylfumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate, and wherein ofatumumab is administered subcutaneously.

EFFECT: group of inventions provides successful treatment (particularly, a significant reduction in the number of recurrences and a decrease in disease activity according to MRI) of ofatumumab of patients previously treated with a disease-modifying therapy (DMT), selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate.

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Description

AREA OF TECHNOLOGY

The present invention relates to an anti-CD20 monoclonal antibody ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab is administered to a patient who has been treated with a disease-modifying therapy other than ofatumumab.

LEVEL OF TECHNOLOGY

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and axonal/neuronal destruction, ultimately leading to severe disability. Although there is no cure, various disease-modifying therapies (DMTs) are available, which typically slow the disease's progression.

DMT involves the administration of a disease-modifying drug (DMD). Examples of approved drugs for the treatment of MS include glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, and dimethyl fumarate (DMF).

Although these DMTs typically significantly reduce relapse rates and disease activity on MRI, thereby delaying the time to disability worsening, overall (severe) adverse events can be associated with each of these DMTs. For example, natalizumab may lead to an increased risk of fatal opportunistic infection (i.e., progressive multifocal leukoencephalopathy, or PML). Fingolimod may be associated with S1P-related safety risks, such as bradyarrhythmias at the start of treatment, macular edema, hypertension, and elevated liver transaminases.

Given that existing medications for the treatment of multiple sclerosis carry certain risks, there remains a need to find ways to reduce, minimize, or overcome these risks. In particular, there remains a need to address these and other risks that arise when patients discontinue their previous therapy, such as when switching from an earlier disease-modifying therapy (DMT), such as fingolimod or DMF, to another DMT.

This is because treatment for multiple sclerosis (MS) can last for decades, and therefore it is often necessary to modify the treatment plan to accommodate changing circumstances. Switching medications or completely discontinuing immunomodulatory drugs can leave patients vulnerable to relapse or disease progression. In some cases, significant MS activity is noted clinically and on MRI after treatment discontinuation. When such disease activity is disproportionate to the pattern observed before treatment, patients are said to have experienced a relapse of symptoms.

Planning a pregnancy is a common reason for discontinuing DMT. In animal studies, DMT has been linked to birth defects, leading to recommendations to discontinue fingolimod before conception.

Some approved MS medications cause symptom rebound, or reactivation of severe disease after DMT discontinuation, exceeding the patient's pre-DMT baseline. For example, the issue of symptom rebound has been discussed for natalizumab and fingolimod (Barry B. et al.: Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations. Neurol Ther (2019) 8:241–250). Therefore, the risk of symptom rebound after discontinuing DMTs such as natalizumab or fingolimod needs to be reduced, minimized, or overcome.

Since, in addition, recurrence of disease symptoms has been reported in patients with disease flares when treated with DMTs such as fingolimod, there is a need for improved treatment strategies for patients with disease flares.

Thus, the problem underlying the present invention is to provide improved treatment strategies for patients with MS requiring treatment optimization. For example, MS is a relapsing-remitting multiple sclerosis (RRMS), and the treatment being optimized is DMT. Reasons for treatment optimization may include adverse effects, treatment failure, disease exacerbation, disease progression, comorbidities, life-cycle events such as pregnancy and breastfeeding, and/or changing patient preferences.

As a consequence, any interruption or change in treatment, such as when switching therapies, makes a patient with active MS vulnerable to relapses.

Reasons for treatment interruption or modification include adverse events, treatment failure, disease progression, comorbidities, life-cycle events such as pregnancy and breastfeeding, and changing patient preferences. Because transient relapses of MS symptoms, resembling immune reconstitution inflammatory syndrome (IRIS), have been reported following treatment discontinuation for MS, it is important for clinicians to be aware of these circumstances, which put patients at risk of reactivation of severe disease.

Therefore, it is necessary to reduce or minimize this vulnerability if treatment is interrupted or changed.

Despite the existing need demonstrated above, reliable, evidence-based guidelines for successful transition between DMTs are unavailable. The risk of additive immune system effects when switching from medications with immunological effects, such as fingolimod or DMF, must be considered and weighed against the risk of symptom recurrence or recurrent disease activity.

In the art, B-cell depletion with rituximab or ocrelizumab has been proposed as a treatment strategy for relapses and symptom recurrence after DMT cessation. Specifically, rituximab has been proposed as a treatment strategy to control relapse after fingolimod cessation. However, in a series published by Hatcher et al., one case demonstrated clinical deterioration 1 day after rituximab infusion (Hatcher et al., Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment, JAMA Neurol. 2016;73(7):790-4). The other two cases were characterized by intractable Gd-enhancing lesions despite treatment with steroids and rituximab.

In a separate report, two patients with symptom recurrence after fingolimod discontinuation experienced clinical worsening and new Gd-enhancing MRI lesions 1 week after initiating ocrelizumab (Schmidt S, Schulten T, Severe rebound after cessation of fingolimod-treated ocrelizumab with coincidental transient aggravation: report of two cases. Ther Adv Neurol Disord. 2019;12:1-6). Two patients experienced significant progression of the Expanded Disability Status Scale (EDSS) after ocrelizumab administration, despite immune recovery more than 3 months after fingolimod discontinuation. This is shown for one of the patients in Fig. 1.

Both patients with highly active PRMS experienced a disease flare while receiving fingolimod, necessitating treatment optimization. They subsequently developed clinical and MRI evidence of severe symptom relapse after discontinuing fingolimod. Symptom relapse in both patients occurred within 4-6 weeks after discontinuing fingolimod. Schmidt and Schulten hypothesized that symptom relapse could be explained by the release of Th17 T cells confined to secondary lymphoid organs invading the central nervous system. Pharmacodynamic data showed a rapid recovery of lymphocyte counts within days of treatment cessation. Because ocrelizumab depletes pre-B cells, as well as mature and memory B cells, it disrupts regulatory signals transmitted by B cells. For example, B cells produce regulatory IL-10, which inhibits the differentiation of pathogenic Th1 and Th17 cells, and secrete IL-35,14,15, a recently discovered regulatory cytokine critical during autoimmune attacks. Regulatory B cells also secrete TGF-β. Given the regulatory function of some B cell subsets, it seems likely that the removal of these B cells from the peripheral immune system, even several weeks after cessation of fingolimod treatment, could have contributed to the secondary deterioration in both patients.

Thus, given the prior art, B cell depletion has not emerged as a promising treatment for relapses and recurrence of symptoms after discontinuation of DMTs (e.g., natalizumab or fingolimod).

ESSENCE OF THE INVENTION

Although this idea is absent from the prior art, the present invention unexpectedly provides a treatment strategy that effectively reduces the risk of disease reactivation, relapse, and symptom recurrence by administering another B-cell depleting agent.

In particular, it was unexpectedly discovered that B-cell depletion with ofatumumab provides a potent and effective treatment strategy for severe relapses and symptom recurrence after discontinuation of DMTs (e.g., natalizumab or fingolimod). This treatment strategy is most effective when ofatumumab therapy is initiated within 0-6 months.

As mentioned above, there is a need to reduce, minimize, or overcome the risk of symptom recurrence after discontinuing DMTs such as natalizumab or fingolimod. This need is unexpectedly met by the present invention.

Although the mechanisms of action of natalizumab and fingolimod differ, the "anti-migratory" strategy shared by both reduces lymphocyte infiltration into the central nervous system and may help explain why symptom relapse may occur upon discontinuation of these medications. Although further research is needed, fingolimod has a more complex mechanism of action than simple anti-migratory activity, likely enhancing beneficial processes and preventing detrimental ones in the immune system. For example, in a small analytical study of messenger RNA expression in CD4+ peripheral blood cells, fingolimod treatment was associated with changes in the transcription levels of 890 different genes. Many of these genes influence cytokine secretion, Toll-like receptor expression, and cell adhesion molecules, which may be involved in T-cell functions that suppress inflammation and autoimmunity. Unexpectedly, ofatumumab was found to reduce this symptom recurrence phenomenon, although it does not appear to have a direct effect on the processes thought to cause symptom recurrence.

Unexpectedly, ofatumumab has the potential to reduce the risk of symptom recurrence in patients with disease flare while taking fingolimod or another DMT other than ofatumumab.

Without being bound by theory, ofatumumab is thought to deplete regulatory signals (e.g., those transmitted by B cells), possibly even (a subset of) regulatory T or B cells themselves. This is supported by data from Theil et al., 2019, Imaging Mass Cytometry and Single-Cell Genomics Reveal Differential Depletion and Repletion of B-Cell Populations Following Ofatumumab Treatment in Cynomolgus Monkeys. Frontiers in Immunology (2019), Volume 10: 1–11. Thus, it is likely that administering ofatumumab after discontinuing DMT treatment, such as fingolimod, significantly reduces the risk of secondary deterioration (e.g., relapse after a flare-up of disease activity).

Taken together, symptom recurrence after DMT discontinuation (e.g., fingolimod) may be exacerbated by initiating treatment with another DMT, such as ocrelizumab. Thus, pitfalls and undesirable consequences of sequential use of potent immunomodulatory and immunosuppressant medications are possible. In particular, ocrelizumab may complicate symptom recurrence after fingolimod discontinuation. Therefore, it was entirely unexpected that ofatumumab does not cause such complications, or at least significantly reduces their risk.

Experimental discontinuation of fingolimod resulted in overexpression of lymphocyte S1P1 receptors, leading to lymphocyte leakage from lymph nodes and increased symptom severity during relapse. Fingolimod discontinuation may also lead to astrocytic overexpression of S1P1 and a subsequent inflammatory response, possibly mediated by NF-κB activation and the release of inflammatory cytokines and nitric oxide. Because overexpression of S1P and/or its receptor may also play a role in the etiology of disease relapse, it is likely that ofatumumab is suitable for the treatment of both disease relapse and relapse syndromes, such as those resulting from symptom relapse.

Furthermore, it was entirely unexpected that B-cell depletion with ofatumumab provides an effective strategy to avoid the unwanted risks of DMT therapy in pregnant women or before pregnancy.

The present invention therefore provides ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab is administered to a patient who has been treated with a disease-modifying therapy (DMT) other than ofatumumab. A definition of DMT is provided below. All preferred embodiments illustrated below are also applicable to the use of the invention.

Another object of the invention is a method for the treatment or prevention of relapsing multiple sclerosis, which method comprises administering ofatumumab to a patient suffering from relapsing multiple sclerosis, wherein said patient has received a disease-modifying therapy other than ofatumumab. All preferred embodiments illustrated below are also applicable to the method of the invention.

Another aspect of the invention is ofatumumab for the manufacture of a medicament for the treatment or prevention of relapsing multiple sclerosis, wherein the medicament is administered to a patient who has received a disease-modifying therapy other than ofatumumab. All preferred embodiments illustrated below also apply to this aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment, the disease-modifying therapy other than ofatumumab is the early administration of DMT. This means that, in a preferred embodiment, the patient is switched from an earlier DMT to ofatumumab. In other words, the invention relates to the use of ofatumumab for the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab is administered to a patient switching from disease-modifying therapy.

In an embodiment of the invention, ofatumumab is not administered to patients with active HBV infection.

In a preferred embodiment of the invention, disease-modifying therapy other than ofatumumab is discontinued prior to the initiation of ofatumumab administration.

In a preferred embodiment of the invention, administration of ofatumumab is initiated before the patient reaches the half-life of the drug used in the disease-modifying therapy other than ofatumumab.

In a preferred embodiment of the present invention, ofatumumab therapy is initiated immediately after discontinuation of an earlier DMT (such as glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate). In this context, immediately means one week, preferably three days, more preferably two days, more preferably one day, most preferably within 12 hours after discontinuation of an earlier DMT (such as glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate).

In another embodiment of the present invention, ofatumumab therapy is initiated before discontinuing an earlier DMT (such as glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate). For example, the earlier DMT may be continued until the ofatumumab loading dose regimen is administered. The loading dose regimen may include subcutaneous (SC) injections of 20 mg ofatumumab on day 1, day 7, and day 14 of the dosing regimen; alternatively, the loading dose regimen may include SC injections of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen.

Ofatumumab therapy and an earlier DMT (e.g., glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate) can be administered concurrently. That is, ofatumumab is initiated before the earlier DMT is discontinued. For example, these therapies can be administered concurrently for 1 day, 3 days, 1 week, 2 weeks, or 1 month.

In an embodiment of the present invention, ofatumumab therapy is initiated when a disease-modifying therapy other than ofatumumab (e.g., an earlier DMT) loses efficacy. For example, the drug used in the earlier DMT may be washed out. Preferably, the drug is a DMD. Thus, ofatumumab therapy may be initiated when the earlier DMT drug (e.g., DMD) is washed out. In this case, the earlier DMT is the first DMT, and ofatumumab is the second DMT. In a preferred embodiment, the first DMT drug is considered washed out when 25%, preferably 50%, more preferably 75%, even more preferably 85%, most preferably 95% of the drug's half-life has elapsed, until the last dose of the first DMT drug is administered before the first DMT is discontinued.

In an alternative embodiment, the first DMT preparation is considered to be washed out if only 30%, preferably 20%, more preferably 10%, even more preferably 5%, most preferably 2.5% or less of the amount administered as the last dose of the first DMT preparation can be detected in samples (e.g., blood or serum) from the patient. In a particularly preferred embodiment, said amount can be replaced by _Cmax , i.e., the maximum (or peak) serum concentration that the first DMT preparation reaches in serum after administration of the last dose of the first DMT preparation before discontinuation of the first DMT.

In an embodiment of the present invention, ofatumumab therapy is initiated within 0-6 months, more preferably within 1-5 months, more preferably within 2-4 months, and even more preferably within the third month after discontinuation of an earlier disease-modifying therapy (e.g., fingolimod). More specifically, ofatumumab therapy can be initiated between 4 and 16 weeks, more preferably between 5 and 15 weeks, more preferably between 6 and 14 weeks, more preferably between 7 and 13 weeks, more preferably between 8 and 12 weeks, more preferably between 9 and 11 weeks, more preferably about 10 weeks after discontinuation of an earlier DMT, for example, fingolimod. Alternatively, ofatumumab therapy may be initiated up to 10 weeks, more preferably up to 9 weeks, more preferably up to 8 weeks, more preferably up to 7 weeks, more preferably up to 6 weeks, more preferably up to 5 weeks, more preferably up to 4 weeks after discontinuation of an earlier DMT, such as fingolimod.

Alternatively, ofatumumab therapy is initiated between 3 and 18 weeks, more preferably between 4 and 17 weeks, more preferably between 5 and 16 weeks, more preferably between 6 and 15 weeks, more preferably between 7 and 14 weeks, more preferably between 8 and 13 weeks, more preferably between 9 and 12 weeks, more preferably between 10 and 11 weeks, more preferably about 10.5 weeks after cessation of early DMT.

In a preferred embodiment of the present invention, administration of ofatumumab is initiated without a washout period.

In a preferred embodiment of the present invention, the patient is treated with a disease-modifying therapy other than ofatumumab for at least 6 months, more preferably at least 7 months, more preferably at least 8 months, more preferably at least 9 months, more preferably at least 10 months, more preferably at least 11 months, more preferably at least 12 months. The patient can be treated with a DMT other than ofatumumab, for example, up to 10 years, up to 8 years, up to 6 years, up to 4 years, or up to 2 years.

In a particularly preferred embodiment, the use of ofatumumab according to the invention prevents or reduces the recurrence of symptoms. Recurrence of symptoms is defined below. The recurrence of symptoms may occur within 0-6 months, or 1-5 months, or within 2-4 months, and even more preferably, within the third month after cessation of another disease-modifying therapy (e.g., fingolimod). More specifically, the recurrence of symptoms may occur between 4 and 16 weeks, or between 5 and 15 weeks, or between 6 and 14 weeks, or between 7 and 13 weeks, or between 8 and 12 weeks, or between 9 and 11 weeks, or about 10 weeks after cessation of another disease-modifying therapy (e.g., fingolimod). Alternatively, recurrence of symptoms may occur between 3 and 18 weeks, or between 4 and 17 weeks, or between 5 and 16 weeks, or between 6 and 15 weeks, or between 7 and 14 weeks, or between 8 and 13 weeks, or between 9 and 12 weeks, or between 10 and 11 weeks, more preferably approximately 10.5 weeks after discontinuation of other or earlier disease-modifying therapy (e.g., fingolimod).

In a preferred embodiment of the present invention, a disease-modifying therapy other than ofatumumab is ineffective. This lack of effectiveness is observed, for example, if a patient receiving disease-modifying therapy (DMT) exhibits signs of disease activity, such as relapses or lesions. This lack of effectiveness can be defined as a failure to halt or adequately slow disease progression. In other words, the present invention is directed to the use of ofatumumab for the treatment of patients who have failed to respond to an earlier DMT.

In a preferred embodiment, ofatumumab is administered to patients with a suboptimal response to DMT therapy, such as anti-CD20 therapy. In a preferred embodiment, the suboptimal response has been observed within the previous 6 months. In a preferred embodiment, the suboptimal response may be characterized by relapse, ≥2 active gadolinium-enhancing lesions [Gd+], any new/enlarging T2 lesions, and/or clinical worsening.

In a preferred embodiment of the present invention, atumumab is administered after detection of at least one Gd+ lesion. The term "Gd+ lesion" is defined below.

In a preferred embodiment of the present invention, ofatumumab is administered after the detection of new or enlarging T2 lesions. The term T2 lesion is defined below.

In an embodiment of the present invention, the patient has experienced a disease exacerbation following treatment with another disease-modifying therapy, such as treatment with a previous DMT. In an alternative embodiment of the present invention, recurrence of symptoms or relapse of disease activity is avoided.

Typically, disease exacerbation is confirmed by one or more clinically documented relapses or one or more MRI activity features, where MRI activity includes Gd+ enhancement and/or new or enlarging T2 lesions. Reference is made to the definition of disease exacerbation below.

A disease flare may occur within 0-6 months, 1-5 months, 2-4 months, and even more preferably, within the third month before discontinuing another disease-modifying therapy (e.g., fingolimod). More specifically, a disease flare may occur between 4 and 16 weeks, or between 5 and 15 weeks, or between 6 and 14 weeks, or between 7 and 13 weeks, or between 8 and 12 weeks, or between 9 and 11 weeks, or approximately 10 weeks before discontinuing another disease-modifying therapy (e.g., fingolimod). Alternatively, the disease flare may occur between 3 and 18 weeks, or between 4 and 17 weeks, or between 5 and 16 weeks, or between 6 and 15 weeks, or between 7 and 14 weeks, or between 8 and 13 weeks, or between 9 and 12 weeks, or between 10 and 11 weeks, more preferably approximately 10.5 weeks before discontinuation of other disease-modifying therapy (e.g., fingolimod).

In an alternative preferred embodiment of the present invention, the patient is intolerant to another or prior disease-modifying therapy. Thus, in a preferred embodiment, ofatumumab is administered to a patient who previously discontinued DMT due to adverse events.

Preferably, intolerance is due to the presence of side effects such as headache, dizziness, nausea, infections (such as herpes zoster), macular oedema, infusion-related reactions, or recurrent infections.

In an embodiment of the present invention, the patient has a history of one, two, or three disease-modifying therapies other than ofatumumab.

The terms "two or three disease-modifying therapies" preferably refer to two or three different drugs.

In a preferred embodiment, the patient is neurologically stable for one month prior to the first administration of ofatumumab. The term "neurologically stable" is defined below.

In a preferred embodiment of the invention, ofatumumab is administered after a relapse, which may also be referred to as an "acute relapse." The term "relapse" is defined below.

Furthermore, thalamic volume may act as a marker associated with neurodegeneration. Azevedo et al. reported that thalamic atrophy present in the early stages of the disease reflects several aspects of MS pathology, including gray matter damage, and correlates well with physical and cognitive impairment. Therefore, thalamic volume has been proposed as a potentially attractive MRI parameter associated with the neurodegenerative features of multiple sclerosis. Azevedo et al. found that thalamic volume decreased significantly faster in subjects with MS compared to healthy controls (HC), with an estimated decrease of -0.71% per year (95% confidence interval [CI] = -0.77% to -0.64%) in subjects with MS and -0.28% per year (95% CI = -0.58% to 0.02%) in HC (p for difference = 0.007). The rate of decline was constant throughout the MS disease duration and across MS clinical subtypes, see “Thalamic Atrophy in Multiple Sclerosis: A Magnetic Resonance Imaging Marker of Neurodegeneration throughout Disease,” Ann Neurol. 2018 February; 83(2): 223-234. doi:10.1002/ana.25150.

In the present invention, it was unexpectedly discovered that administration of ofatumumab leads to a beneficial reduction in thalamic volume loss. Reference is made to the experimental section below.

Therefore, in a preferred embodiment of the present invention, ofatumumab is administered when thalamic volume loss has not been sufficiently reduced by prior disease-modifying therapy. A reduction in thalamic volume loss of less than 30%, less than 25%, or less than 20% compared to baseline without treatment can be considered insufficient. Therefore, the untreated baseline loss can be estimated as 0.71% per year.

For example, ofatumumab may be administered if prior disease-modifying therapy has not reduced thalamic volume loss to below 0.70% per year, or below 0.65% per year, or below 0.60% per year. Alternatively, ofatumumab may be administered if prior disease-modifying therapy has not reduced thalamic volume loss to below 1.40%, below 1.3%, or below 1.2% over 24 months.

In this regard, another object of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab reduces the loss of thalamic volume, preferably, below 0.70% per year, or below 0.65% per year, or below 0.60% per year. For example, the losses can be reduced to 0.30% - 0.70% per year, or 0.40% - 0.65% per year, or 0.45% - 0.60% per year. Alternatively, the present invention relates to ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab reduces the loss of thalamic volume below 1.40%, or below 1.3%, or below 1.2% over 24 months. For example, the loss can be reduced to 0.6% - 1.40%, or to 0.8% - 1.3%, or to 0.9% - 1.2% over 24 months.

The MSIS-29 (see definition below) is a clinically useful and evidence-based assessment of the impact of MS from the patient's perspective, suitable for clinical trials and epidemiological studies. It is considered a reliable, valid, and sensitive PRO (patient-reported outcomes) measure that complements other disease severity measures used to improve our understanding of the impact of MS.

In the present invention, it was unexpectedly discovered that administration of ofatumumab results in a favorable reduction in the MSIS-29 MS impact score, as defined below. Reference is made to the experimental section below.

Therefore, in a preferred embodiment of the present invention, ofatumumab is administered when a sufficient reduction in the MSIS-29 score with prior disease-modifying therapy has not been achieved. A reduction in the MSIS-29 score of less than 2.5, or less than 2.0, or less than 1.5 may be considered insufficient.

For example, ofatumumab may be administered if the administration of an earlier disease-modifying therapy did not result in a decrease in the MSIS-29 score of 1.5, 2.0, or 2.5 points at 24 months.

In this regard, another object of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab reduces the MSIS-29 score. Preferably, ofatumumab reduces the MSIS-29 score by at least 1.5, more preferably by at least 2.0, even more preferably by at least 2.5 over 24 months. The reduction may be to 3.0, 3.5, or 4.0.

In a preferred embodiment, the patient has an EDSS score of 1 to 4 prior to the first administration of ofatumumab. EDSS stands for Expanded Disability Status Scale, which is defined below.

In a preferred embodiment, ofatumumab can be administered regardless of body weight, gender, age, race, or baseline B-cell count. For example, it is preferred that a 35-year-old woman weighing 60 kg receive the same dose as a 50-year-old man weighing 90 kg. In particular, weight, gender, age, race, or baseline B-cell count do not have a clinically significant effect on the pharmacokinetics of ofatumumab.

In a preferred embodiment, ofatumumab is administered to patients who have previously discontinued a DMT, such as anti-CD20 therapy, due to adverse events such as severe infusion-related reactions or recurrent infections.

The term DMT is generally known in the art and is defined below. For the present invention, examples of suitable DMTs include treatment with the following drugs: teriflunomide, leflunomide, dimethyl fumarate, fingolimod, natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab, glatiramer acetate, and laquinimod.

In a preferred embodiment of the present invention, a disease-modifying therapy other than ofatumumab is administered orally. Examples of suitable DMTs include teriflunomide, leflunomide, laquinimod, dimethyl fumarate, and fingolimod.

In a particularly preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is fingolimod. Preferably, fingolimod is administered at a dose of 0.5 mg once daily. Alternatively, fingolimod is administered at a daily dose of 0.1 mg to 2.5 mg, such as 0.25 mg.

In a particularly preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is dimethyl fumarate (DMF). Preferably, DMF is administered at a daily dose of 120 to 480 mg, in particular 480 mg.

In a particularly preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is laquinimod. Preferably, laquinimod is administered at a daily dose of 0.2 to 1.0 mg, preferably 0.6 mg.

In a particularly preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is teriflunomide. Preferably, teriflunomide is administered at a daily dose of 6 to 18 mg, preferably 14 mg.

In a preferred embodiment of the present invention, a disease-modifying therapy other than ofatumumab is administered by injection. Examples of suitable DMTs include natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab, and glatiramer acetate.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is natalizumab. Preferably, natalizumab is administered intravenously every four weeks at a dose of 100 to 500 mg, preferably 300 mg.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is daclizumab. Preferably, daclizumab is administered at a dose of 50 to 250 mg, preferably 150 mg subcutaneously once monthly.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is glatiramer acetate. Preferably, glatiramer acetate is administered at a dose of 20 mg/mL by subcutaneous injection once daily or 40 mg/mL by subcutaneous injection 3 times weekly.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is rituximab. Preferably, rituximab is administered at a dose of 500 or 1000 mg every 6 to 12 months, in particular intravenously.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is ocrelizumab. Preferably, ocrelizumab is administered at a dose of 600 mg every 6 months, in particular intravenously.

Preferably, patients have previously received at least two, for example, two to five, consecutive courses of intravenous ocrelizumab or rituximab. The last dose can be administered, for example, 4 to 9 months before ofatumumab.

According to the present invention, the efficacy of ofatumumab is maintained in patients with RMS switching from intravenous anti-CD20 therapies.

In a preferred embodiment, ofatumumab is administered to patients with a suboptimal response to anti-CD20 therapy within the previous 6 months (e.g., relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new/enlarging T2 lesions, clinical worsening) and/or to patients or those who have discontinued anti-CD20 therapy due to adverse events, such as severe infusion-related reactions or recurrent infections.

In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is alemtuzumab. Preferably, alemtuzumab is administered at a dose of 12 mg/day as an intravenous infusion.

In a preferred embodiment of the present invention, ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks. Preferably, ofatumumab is administered by subcutaneous injection (s.c.).

In a preferred embodiment of the present invention, ofatumumab is administered in a loading dose. The term "loading dose" is defined below. In a preferred embodiment, three loading doses are administered. Preferably, at week 0 and at weeks 1 and 2 after the start of ofatumumab therapy. This means that the first loading dose at week 0 is the start of therapy. In an alternative preferred embodiment, three loading doses are administered on day 1 and on days 5-9, preferably on day 7, and on days 12-16, preferably on day 14, after the start of ofatumumab therapy. This means that the first loading dose on day 1 is the start of therapy.

In a preferred embodiment of the present invention, the loading dose is 10-30 mg, preferably 20 mg ofatumumab.

The preferred dosage of ofatumumab is:

- initial dose of 20 mg by subcutaneous injection at 0, 1 and 2 weeks, followed by administration

- subsequent administration of 20 mg subcutaneously once a month, starting from the 4th week.

If an ofatumumab injection is missed, it is recommended to administer it as soon as possible, without waiting for the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

In an alternative embodiment of the present invention, ofatumumab is administered without a loading dose.

In a preferred embodiment of the present invention, premedication is administered to the patient prior to the first dose of ofatumumab. Premedication preferably includes acetaminophen, antihistamines, and/or steroids. Methylprednisolone may be a preferred steroid. 100 mg IV may be a preferred dose. Preferably, premedication is administered 30-60 minutes prior to the ofatumumab injection.

In a particularly preferred embodiment, premedication is not administered prior to the first dose of ofatumumab.

In a preferred embodiment of the invention, ofatumumab is administered for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, preferably in adults.

In a preferred embodiment of the present invention, the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), in particular RRMS. These terms are defined below.

In an alternative embodiment of the present invention, the patient to be treated does not meet one or more of the following criteria:

- diagnosis of primary progressive multiple sclerosis or secondary progressive multiple sclerosis without disease activity

- compliance with neuromyelitis optica criteria

- breastfeeding

- the presence of an active chronic disease of the immune system, other than multiple sclerosis or immunodeficiency syndrome

- presence of neurological symptoms consistent with progressive multifocal leukoencephalopathy (PML) or confirmed PML

- presence of active systemic infections or acquired immunodeficiency syndrome or a positive test result for antibodies to the human immunodeficiency virus during screening

- a risk group for the development or reactivation of hepatitis, syphilis or tuberculosis

- received any live or live attenuated vaccines within 2 months prior to the start of therapy.

Ofatumumab is preferably administered parenterally, such as by epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion. The preferred route of administration is subcutaneous injection.

In one embodiment of the invention, the ofatumumab composition is formulated according to conventional procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If desired, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to relieve pain at the injection site. Typically, the ingredients are supplied either separately or mixed together in a unit dosage form, such as a dry lyophilized powder or anhydrous concentrate, in a hermetically sealed container such as an ampoule or sachet, indicating the amount of active substance.

If the composition is to be administered by infusion, it may be administered in an infusion bottle containing sterile water or pharmaceutical grade saline.

If the composition is administered by injection, an ampoule containing sterile water for injection or saline may be provided to allow mixing of the ingredients before administration.

In one embodiment, the formulation for ofatumumab may be formulated in accordance with the formulation described in WO 2009/009407.

In one embodiment, ofatumumab is administered in an antibody formulation, wherein ofatumumab is present in an amount of about 20-300 mg/ml, 50-300 mg/ml, 100-300 mg/ml, 150-300 mg/ml, 200-300 mg/ml, or 250-300 mg/ml, preferably 50 mg/ml.

In one embodiment, ofatumumab is administered in an antibody formulation, wherein the formulation comprises 10 to 100 mM sodium acetate, 25 to 100 mM sodium chloride, 0.5 to 5% arginine free base, 0.02 to 0.2 mM EDTA, 0.01 to 0.2% polysorbate 80, and adjusted to a pH of 5.0 to 7.0. Preferably, the ofatumumab formulation comprises 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, 0.02% polysorbate 80, and adjusted to a pH of 5.5.

In one embodiment, the ofatumumab formulation is presented in a prefilled syringe or auto-injector. A prefilled auto-injector intended for subcutaneous administration is preferably used.

In a preferred embodiment, the ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each 20 mg/0.4 ml prefilled pen or prefilled syringe delivers 0.4 ml of solution. Preferably, each 0.4 ml contains 20 mg ofatumumab and arginine (4 mg), disodium edetate (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg), and water for injection, USP at pH 5.5. Hydrochloric acid may be added to adjust the pH.

In a preferred embodiment, the dosage form of ofatumumab is intended for self-administration by the patient, preferably by subcutaneous injection.

In a preferred embodiment, the composition is administered subcutaneously to the abdomen, thigh, or outer upper arm. In a preferred embodiment, the composition is not administered to moles, scars, or areas where the skin is tender, bruised, red, hard, or damaged.

In one embodiment, the first injection of the ofatumumab formulation may be administered under the guidance of a healthcare professional. Symptomatic treatment is recommended if injection-related reactions occur. Prior to administration, the pen or prefilled syringe should preferably be removed from the refrigerator and allowed to warm to room temperature, for example, for approximately 15-30 minutes. In a preferred embodiment, the ofatumumab formulation of the present invention is a clear to slightly opalescent, colorless to slightly brownish-yellow solution, available as follows:

- Injection: 20 mg/0.4 ml in a disposable pen, such as the Sensoready® pen.

- Injection: 20 mg/0.4 ml in a pre-filled syringe per dose.

In a preferred embodiment, subcutaneous administration of ofatumumab at a dose of 20 mg every 4 weeks results in a mean AUC _tau of about 400 to 550, more preferably 450 to 500, such as 483 μg h/mL, and/or a mean C _max of 1.0 to 2.5, more preferably 1.2 to 1.7, such as 1.43 μg/mL at steady state. In a preferred embodiment, the volume of distribution at steady state may be 4.5 to 6.5, more preferably 5.0 to 6.0, such as 5.42 L after subcutaneous administration of repeated doses of ofatumumab 20 mg.

Following subcutaneous administration, ofatumumab can be absorbed through the lymphatic system.

BRIEF DESCRIPTION OF DRAWINGS

FIGURE 1 shows significant progression of the patient's Expanded Disability Status Scale (EDSS) score after ocrelizumab administration, despite immune recovery more than 3 months after discontinuation of fingolimod.

FIGURE 2 shows ofatumumab-induced CDCs of freshly isolated primary human B cells.

FIGURE 3 shows that ofatumumab effectively induces CDC after delayed complement addition.

Definitions

Antibody:

The term "antibody," as used herein, refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of any of these that has the ability to specifically bind to an antigen. Binding preferably occurs under typical physiological conditions over a significant period of time. The term "antigen-binding portion" of an antibody, as used herein, refers to fragments of the antibody that retain the ability to specifically bind to an antigen (e.g., CD20). For further definitions, reference is made to WO 2018/033841, in particular pages 9-13.

Exacerbation of the disease

For the purposes of this invention, an exacerbation of a disease is defined as:

at least one documented relapse within the previous year OR two relapses within the previous two years,

the presence of at least one Gd+ lesion on MRI within the last 12 months and/or

presence of new or enlarging T2 lesions within the past 12 months.

CD20:

The CD20 molecule (also known as human B-lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein with a molecular mass of approximately 35 kDa localized on pre-B and mature B lymphocytes. CD20 is found on the surface of more than 90% of B cells in peripheral blood or lymphoid organs, is expressed during early pre-B cell development, and remains expressed until plasma cell differentiation. CD20 is present on both normal B cells and malignant B cells. The carboxyl-terminal region of 85 amino acids of the CD20 protein is located in the cytoplasm. Reference is made to the description in GenBank, accession no. NP_690605.

Disease-modifying therapy (DMT)

The term "disease-modifying therapy" is used because there is currently no curative treatment for multiple sclerosis (MS), but several disease-modifying drugs (DMDs) have been approved for the treatment of MS. DMTs for RMS typically reduce the frequency and/or severity of relapses. Thus, DMTs are not a cure for patients with RMS, but they can reduce the number and severity of relapses.

EDSS

The Expanded Disability Status Scale (EDSS) is a way to quantify disability in multiple sclerosis and track changes in disability status over time.

The EDSS scale ranges from 0 to 10 in 0.5 unit increments, indicating a higher level of impairment. The assessment is based on a neurologist's examination.

EDSS steps 1.0 through 4.5 apply to people with MS who can walk without assistance and are based on measures of impairment in eight functional systems (FS):

- pyramidal - muscle weakness or difficulty moving the limbs

- cerebellar - ataxia, loss of balance, coordination, or tremor

- brainstem - problems with speech, swallowing and nystagmus

- sensory - numbness or loss of sensation

- bowel and bladder function

- visual function - vision problems

- brain functions - problems with thinking and memory

- other.

A functional system (FS) is a network of neurons in the brain responsible for specific tasks. Each FS is rated on a scale from 0 (no functional impairment) to 5 or 6 (more severe functional impairment). Reference is made to Kurtzke JF. Rating Neurologic Impairment in Multiple Sclerosis: An Expanded Disability Status Sclale (EDSS). Neurology. 1983, Nov;33(11):1444–52.

Gd+ lesion

Gadolinium (a "contrast agent") is a chemical compound injected into a vein during an MRI. Gadolinium is typically prevented from entering the brain or spinal cord from the bloodstream due to the blood-brain barrier. However, during active inflammation in the brain or spinal cord, such as during a multiple sclerosis relapse, the blood-brain barrier is disrupted, allowing gadolinium to pass through. Gadolinium can then enter the brain or spinal cord and leak into the MS lesion, illuminating it and creating a distinctive spot on the MRI. This MS lesion is called a gadolinium-enhanced lesion, or Gd+ lesion.

Half-life

The half-life of a biological substance (e.g., the drug DMT) is the time it takes for half of the substance to be eliminated by biological processes. This concept is used when the elimination rate is approximately exponential. In a medical context, the half-life explicitly describes the time required for the plasma concentration of the substance to halve (the plasma half-life) to reach its steady state in circulation in the body's whole blood.

Loading dose

A loading dose is an initial dose of a drug, preferably a higher initial dose, that may be administered at the beginning of a course of treatment (e.g., DMT) before a subsequent maintenance dose, preferably tapering off to a lower maintenance dose.

Neurologically stable

A clinical condition characterized by the absence of changes in mental status or level of consciousness. This condition may include seizure control; the absence of new neurological deficits, such as aphasia, ataxia, dysarthria, paresis, paralysis, scotoma, or blindness; and is defined as neurological stability.

Multiple Sclerosis Impact Scale (MSIS-29)

The MSIS-29, version 2, is a 29-item self-administered questionnaire that includes two domains: physical and psychological. Responses are rated on a 4-point ordinal scale from 1 (not at all) to 4 (very much), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete, and the questions are designed to determine the patient's perception of the impact of MS on their daily life over the past 2 weeks. Reference is made to Hobart J and Cano S (2009), "Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods," Health Technol Assess; 13(12):iii, ix-x, 1-177. NS RO to Hobart J, Lamping D, Fitzpatrick R, et al (2001), “The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure,” Brain; 124(Pt 5):962-73.

Ofatumumab:

Ofatumumab is a human monoclonal antibody to the CD20 protein. Ofatumumab can specifically bind to both the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab can bind to CD20, and the Fc domain mediates immune effector functions, leading to B-cell lysis in vitro. Specifically, ofatumumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that binds to human CD20, expressed, for example, on B cells. Ofatumumab is produced in the murine NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains with a molecular weight of approximately 146 kDa.

Ofatumumab is described in EP 1 558 648 B1 and EP 3 284 753 B1. Additional references are made to the description in drugbank.ca, registration number DB06650, and to WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the chemical formula of the protein is C ₆₄₈₀ H ₁₀₀₂₂ N ₁₇₄₂ O ₂₀₂₀ S ₄₄ , and the average mass of the protein is about 146100 Da.

Ofatumumab's metabolic pathway may involve degradation into small peptides and amino acids by ubiquitous proteolytic enzymes. Ofatumumab may be eliminated via two pathways: a target-independent pathway, as with other IgG molecules, and a target-mediated pathway associated with B-cell binding.

The steady-state half-life of ofatumumab may be approximately 16 days, particularly following subcutaneous administration of repeated 20 mg doses.

Ofatumumab preferably does not share a clearance pathway with chemical drugs metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. Preferably, ofatumumab is not involved in the regulation of the expression of drug-metabolizing enzymes.

Patient

The term "patient" preferably refers to a human patient, preferably an adult.

Recurrence of symptoms

Reactivation of severe disease after DMT withdrawal, exceeding the patient's pre-DMT baseline, is considered a symptom relapse event. Reference is made to Barry et al., "Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations." Neurol Ther (2019) 8:241–250.

Relapse

Relapses can be defined as a new neurological deficit or episode of neurological deterioration, preferably lasting more than 24 hours. In other words, relapses can be considered discrete episodes (also referred to in the art as "attacks," "flares," or "exacerbations") of neurological dysfunction, preferably lasting at least 24 hours. Relapses are typically followed by complete or partial recovery and a period during which no progression of symptoms or accumulation of impairment is observed (remission).

Relapses are thought to be caused by new or expanding demyelinating plaques at the site of inflammation in the central nervous system (CNS).

Revised McDonald criteria (Thompson et al 2018)

According to the revised McDonald criteria, a diagnosis of multiple sclerosis is probable if myelin damage is disseminated in space (DIS), as seen on MRI as:

- At least one bright T2 lesion in at least two of four CNS locations: the juxtacortical, periventricular, and infratentorial regions of the brain and spinal cord. (T2 is the most common MRI scan used to diagnose MS and detect areas of myelin damage, old and new, in the brain and spinal cord.)

- These lesions do not require enhancement with gadolinium (contrast agent).

Regarding dissemination of myelin injury over time (DIT), MRI evidence is considered to be:

- New T2 and/or gadolinium-enhancing lesion on the follow-up MRI compared to the baseline scan (regardless of the time elapsed since baseline). The 2005 revision required at least 30 days between the baseline and first seizure.

- Concomitant presence of asymptomatic gadolinium-enhancing and non-gadolinium-enhancing lesions at any time.

Progressive primary MS (PPMS) has unique diagnostic requirements. Specifically, the revised McDonald criteria require at least one year of demonstrated progress (prospectively or retrospectively) plus two of the following three findings:

- Evidence of DIS in the brain based on at least one T2 lesion in three key brain regions (periventricular, juxtacortical, or infratentorial)

- Evidence of DIS in the spinal cord based on at least two T2 DIS lesions (≥2 T2 lesions);

- Positive involvement of CFS, again by the presence of oligoclonal bands and/or a high IgG index.

RRMS

Relapsing-remitting multiple sclerosis (MS) is characterized by relapses, defined as a new neurological deficit or an episode of neurological deterioration lasting more than 24 hours in the absence of fever or infection.

During periods of remission, no significant disease progression is observed. At different time points, RRMS can be further characterized as active (with relapses and/or evidence of new MRI activity) or inactive, and also worsening (confirmed increase in functional impairment over a period of time after a relapse) or not worsening. Referenced to Lublin 2014, Neurology. 2014 Jul 15; 83(3): 278–286.

RMS

The term RMS (relapsing multiple sclerosis) covers RRMS, SPMS and clinically isolated syndrome (CIS).

Primary progressive MS (PPMS)

PPMS is characterized by deterioration of neurological function (accumulation of functional impairment) from the onset of symptoms without early relapses or remissions. PPMS can be further characterized at different time points as active (with occasional relapse and/or evidence of new MRI activity) or inactive, and as progressive (evidence of disease worsening as measured by an objective measure of change over time, with or without relapse or new MRI activity) or non-progressive. References are made to Lublin 2014.

Each person's experience with PPMS will be unique. PPMS can have short periods of disease stability, with or without relapses or new MRI activity, as well as periods of increasing functional impairment, with or without new relapses or MRI lesions.

Secondary progressive MS (SPMS)

SPMS has an initial relapsing-remitting course. Most people diagnosed with RRMS eventually develop a secondary progressive course, characterized by progressive deterioration of neurological function (accumulation of impairment) over time. SPMS can be further characterized at different time points as active (with relapses and/or evidence of new activity on MRI) or inactive, and as progressive (evidence of worsening disease as measured by an objective measure of change over time, with or without relapses) or non-progressive. Reference is made to Lublin 2014.

Each person's experience with SPMS will be unique. SPMS follows relapsing-remitting multiple sclerosis. Functional impairment gradually worsens over time, with or without signs of disease activity (relapses or MRI changes). SPMS can experience episodic relapses as well as periods of stability.

Clinically isolated syndrome (CIS):

Clinically isolated syndrome (CIS) can refer to a single clinical attack of the central nervous system (CNS) with inflammatory demyelinating symptoms that are suggestive of multiple sclerosis (MS). CIS manifestations can be unifocal or multifocal and typically involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral hemispheres. Reference is made to Miller et al., Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169.

T1 and T2 lesions

T1 and T2 refer to different MRI techniques used to obtain magnetic resonance images. Specifically, T1 and T2 refer to the time between the magnetic pulses and the image recording. These different techniques are used to detect various structures or chemicals in the central nervous system. T1 and T2 lesions refer to whether the lesions were detected using the T1 or T2 technique. A T1 MRI image provides information about the current disease activity, highlighting areas of active inflammation. A T2 MRI image provides information about the disease burden or lesion load (the total area of the lesion, both old and new).

Washing out

The term "washout" refers to the period between clinical treatments (preferably, the periods between different DMTs) during which any drug administered as the first treatment (e.g., the first DMT) can be partially or completely cleared from the patient's system before the start of a second treatment (e.g., the second DMT). During the washout period, the patient preferably does not receive any other medications (e.g., DMTs for MS). Preferably, the medication is a disease-modifying drug (DMD).

In a preferred embodiment, the drug of the first DMT is considered to be washed out if 25%, preferably 50%, more preferably 75%, even more preferably 85%, most preferably 95% of the drug half-life has passed from the administration of the last dose of the first DMT drug until the first DMT is discontinued.

In an alternative embodiment, the first DMT preparation is considered to be washed out if only 30%, preferably 20%, more preferably 10%, even more preferably 5%, most preferably 2.5% or less of the amount administered as the last dose of the first DMT preparation can be detected in samples (e.g., blood or serum) from the patient. In a particularly preferred embodiment, said amount can be replaced by _Cmax , i.e., the maximum (or peak) serum concentration that the first DMT preparation reaches in serum after administration of the last dose of the first DMT preparation before discontinuation of the first DMT.

Detection of the first DMT can be accomplished by one or more of PAGE, Western blotting, ELISA, HPLC and mass spectrometry, capillary electrophoresis, Fourier transform infrared spectroscopy, circular dichroism, DLS, thermal shift analysis, NMR, X-ray spectroscopy, chromatography, and fluorescence.

EXAMPLES

Example 1:

In vitro data show differences between anti-CD20 antibodies with respect to the induction of complement-dependent cytotoxicity (CDC).

In vivo, anti-CD20 antibodies can mediate B-cell killing via cellular and/or complement-dependent mechanisms. CDC is an important mechanism of ofatumumab-induced B-cell lysis.

PBMCs (peripheral blood mononuclear cells) are prepared, and primary human B cells are collected by centrifugation and resuspended at a concentration of 2 x 10 ⁵ cells/mL in assay medium (RPMI 1640 + Glutamax supplemented with 0.1% BSA and 20 mM HEPES). B cells are then incubated in v-bottom 96-well plates simultaneously with antibodies in 3-fold serial dilutions and human serum (30%) as a source of complement at 37°C, 5% CO ₂ for 1 h. Cells are washed, stained with SYTOX Blue (0.25 μM), and then B cell lysis is analyzed by flow cytometry on a FACS Fortessa. Cell death is defined as SYTOX Blue ⁺ cells. The results are shown in Figure 2, demonstrating a strong concentration-dependent induction of CDC by ofatumumab in primary human B cells compared with ocrelizumab and rituximab.

In the second experiment, B cells were incubated with the antibody as described above, albeit in the absence of a complement source. The cells were washed as described previously. After 6 hours, a complement source was added. Although only antibodies with a slow off-rate remain bound to cells and bind complement, ofatumumab strongly induces CDC after this delayed addition of complement. This is shown in Figure 3.

Figure 2: Ofatumumab-induced CDC of freshly isolated primary human B cells

Figure 3. Ofatumumab potently induces CDC after delayed complement addition.

Thus, ofatumumab unexpectedly demonstrated the ability to activate complement factors and induce CDC. In terms of activity and efficacy, ofatumumab clearly differs from ocrelizumab in this regard.

Example 2:

Patient data showing reduction in recurrence and Gd+ lesions after switching

The effect of ofatumumab administered to patients treated with DMTs other than ofatumumab is investigated as described below.

1. Ofatumumab

Ofatumumab is supplied in prefilled syringes for subcutaneous administration containing 20 mg ofatumumab (50 mg/ml, 0.4 ml volume). The matching placebo for the ofatumumab prefilled syringe is the same appearance as the study drug.

Control treatment may be teriflunomide (Aubagio®) 14 mg.

Ofatumumab group: ofatumumab 20 mg SC injections on days 1, 7, 14, week 4 (study month 1) and every 4 weeks thereafter + teriflunomide-matched placebo capsule orally once daily.

Eligible patients can be randomly assigned in a 1:1 ratio to either the active ofatumumab 20 mg group or the active teriflunomide 14 mg group. Random assignment is based on geographic region and MS subtype (RRMS, SPMS).

2. Patient population

Patients eligible for inclusion in this study had to meet the following criteria:

Diagnosis of multiple sclerosis according to the revised McDonald criteria of 2010 (Polman et al., 2011).

Relapsing MS: relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) with disease activity as defined by Lublin et al., 2014.

Disability status on screening with an EDSS score of 0 to 5.5 (inclusive).

Patients previously treated with DMT were selected from a group including glatiramer acetate, dimethyl fumarate (DMF), daclizumab, fingolimod, natalizumab, and laquinimod.

At least one recurrence in the previous 1 year is documented, OR two recurrences in the previous 2 years before screening, OR a positive Gd-enhancing MRI in the year before random assignment. Note: Screening MRI may be used if there were no positive Gd-enhancing scans in the previous year.

Neurologically stable for 1 month prior to randomization

3. Results

3.1 Outcomes for patients receiving fingolimod as a prior DMT

a) Unexpected reduction in relapses

The following table shows the results of the first study on the number of relapses before and after inclusion in the study (at 12 and 24 months of the study).

Medicine Observation variable N Average OMV NURLP12 39 1.26 NURLP24a 39 2.28 NCFRLP12 39 0.23 NCFRLP24 39 0.31

The following abbreviations are used in the table above:

Reduction Explanation N N: number of patients evaluated NURLP12 number of relapses in the last 12 months (screening) NURLP24a number of relapses in the last 24 months (screening) NCFRLP12 number of relapses up to 12 months after the first dose NCFRLP24 number of relapses up to 24 months after the first dose

The table shows that among patients randomly assigned to receive ofatumumab (Study 1), 27 patients were assessed at each visit, i.e., at baseline, 12 months, and 24 months. The relapse rate was approximately 1.26 per patient in the 12 months prior to screening. This rate dropped unexpectedly to approximately 0.23 in the 12 months following treatment switching and to approximately 0.30 over the 24-month period.

The decline in the ofatumumab group was unexpectedly large. The decline was greater than in the comparison group.

b) Unexpected reduction in T1 lesions enhancing Gd

The following results are obtained for the amount of damage Gd.

Medicine Analytical visit N Average OMV INITIAL LEVEL 37 2.95 Week 48 36 0.03 Week 96 27 0

The table shows that among patients randomly assigned to receive ofatumumab, there was an unexpected reduction in the number of Gd+ lesions.

3.2 Outcomes for patients receiving DMF instead of earlier DMT

Medicine Observation variable N Average OMV NURLP12 56 1.11 NURLP24a 56 2 NCFRLP12 56 0.21 NCFRLP24 56 0.39

Medicine Analytical visit N Average OMV INITIAL LEVEL 55 2.02 Week 48 52 0 Week 96 33 0

3.3 Outcomes for patients receiving daclizumab as an earlier DMT

Medicine Observation variable N Average OMB NURLP12 11 1 NURLP24a 11 1.18 NCFRLP12 11 0 NCFRLP24 11 0

Medicine Analytical visit N Average OMV INITIAL LEVEL 11 0.18 Week 48 10 0 Week 96 2 0

3.4 Outcomes for patients receiving natalizumab as an earlier DMT

Medicine Observation variable N Average OMV NURLP12 30 1.2 NURLP24a 30 2.37 NCFRLP12 30 0.13 NCFRLP24 30 0.2

Medicine Analytical visit N Average OMV INITIAL LEVEL 28 2.5 Week 48 27 0.04 Week 96 20 0

4.5. Outcomes for patients receiving glatiramer acetate as an earlier DMT.

Medicine Observation variable N Average OMV NURLP12 156 1.21 NURLP24a 156 2.13 NCFRLP12 156 0.10 NCFRLP24 156 0.17

Medicine Analytical visit N Average OMV INITIAL LEVEL 154 1.52 Week 48 147 0.02 Week 96 128 0.02

Example 3:

Clinical trial

The results described above in Example 2 are confirmed in a clinical trial as described below.

1. Population

The study population consists of adults with RMS. The study is being conducted in approximately 120-170 centers worldwide.

Subjects eligible for inclusion in this study must meet all of the following criteria:

1. Diagnosis of multiple sclerosis according to the revised McDonald criteria of 2017

2. Relapsing MS: relapsing forms of MS (RMS), including RMS and secondary progressive MS (SPMS).

3. Disability status on screening with an EDSS score from 0 to 4 (inclusive).

4. History of treatment for multiple sclerosis with a maximum of 3 DMT.

5. The subject switches from fingolimod or dimethyl fumarate, which have been administered for at least 6 months, as the last DMT before the first administration of study drug.

6. Worsening of disease activity when the participant was adequately using fingolimod or dimethyl fumarate prior to switching, as evidenced by one or more clinically documented relapses or one or more signs of activity on MRI (e.g., Gd+ enhancement, new or enlarging T2 lesions).

7. Neurologically stable for one month prior to the first administration of study drug.

2. Medicinal product, treatment groups, duration of treatment

Ofatumumab is supplied in an auto-injector (AI) for subcutaneous administration containing 20 mg ofatumumab (50 mg/mL, contents 0.4 mL). Ofatumumab is a clear to opalescent, colorless to pale yellow liquid, essentially free of particles.

This is an open-label, single-arm treatment study.

The planned duration of treatment is 96 weeks.

3. A transition period, preferably including washout from the previous DMT.

For the purposes of this study, we define the transition period as the time between discontinuation of current treatment (fingolimod or DMF) and initiation of ofatumumab treatment. The exact timing of the transition is based on the investigator's clinical judgment.

During the washout period, the subject may not take any other DMT for the treatment of MS.

4. Instructions for prescribing and taking the study drug

The study medication (ofatumumab injections) is administered beginning at Visit 1. The medication is then administered at scheduled visits throughout the treatment period. Beginning at Week 4, subcutaneous injections should be administered at intervals of 4 weeks (+/- 3 days).

To assess tolerability of the initial dose of study drug, subjects are closely monitored after administration for any reactions, including injection-related reactions.

At Visit 1, subjects receive a subcutaneous injection on-site. The subject or a caregiver administers the study medication under the supervision of study staff.

After Visit 1, subjects may administer the study medication at home or have a caregiver trained by study staff in proper technique and precautions administer the study medication. Ability to self-administer injections must be demonstrated and documented before home administration is permitted. Injection 2 (Day 7) is monitored remotely by designated on-site staff to support self-administration/home administration and provide additional training as needed. Subjects return to the study site at Weeks 2 and 4.

Example 4: Clinical trials showing reduced thalamic volume loss and improvement in MSIS-29

State of the art

Ofatumumab demonstrated superior efficacy compared with teriflunomide in the phase 3 ASCLEPIOS I/II trials, see ECTRIMS Online Library, Hauser S et al. 09/13/19; 279581; 336. MS patients treated with ofatumumab experienced a 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) reduction in annualized relapse rate (ARR) compared with Aubagio®* (teriflunomide) (both p<0.001) in the ASCLEPIOS I and II trials, respectively. Ofatumumab demonstrated highly significant suppression of gadolinium (Gd) T1 lesions compared with Aubagio®, demonstrating profound suppression of new inflammatory activity. Ofatumumab demonstrated a 34.4% relative risk reduction in 3-month confirmed disability progression (CDP) (p=0.002) and 32.5% 6-month CDP (p=0.012) compared with Aubagio® in pre-specified pooled analyses.

Objectives and methods

In the ASCLEPIOS I study, patients were randomly assigned (1:1) to receive ofatumumab 20 mg subcutaneously every 4 weeks (after an initial loading regimen of 20 mg subcutaneously on days 1, 7, and 14) or teriflunomide 14 mg orally once daily for up to 30 months. Patients were 18-55 years old with an Expanded Disability Status Scale (EDSS) score (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444-52) of 0-5.5 at screening, had ≥1 relapse in the past year or ≥2 relapses in the past 2 years, or had a positive gadolinium-enhancing (Gd+) MRI within the year prior to randomization.

Results

(i) Loss of thalamic volume

Ofatumumab, compared with teriflunomide, significantly reduced thalamic volume loss between 24 months and baseline (mean percentage change -1.00 to -1.40, mean difference 0.40, p=0.002).

(ii) MSIS-29

A higher MSIS-29 score indicates greater impact of MS on daily life from the patient's perspective. Treatment with ofatumumab reduced the impact of MS on patient’s daily life compared with teriflunomide: the mean change from baseline in the MSIS-29 physical impact score was significantly greater in the ofatumumab group than in the teriflunomide group at all time points, i.e., month 6 (-2.75 to -0.44, mean difference -2.30, p=0.017), month 12 (-2.43 to 0.17, mean difference -2.59, p=0.009), month 18 (-2.37 to 0.67, mean difference -3.05, p=0.005), month 24 (-2.6 to 0.59, mean difference -3.19, p=0.008), and month 30 (-3.21 to 0.55, mean difference -3.76, p=0.026) (Table 14.2-7.1).

Treatment with ofatumumab was associated with a greater reduction in the impact of MS on patients' daily lives compared with the teriflunomide group, as measured by the MSIS-29 Psychological Impact Scale. However, the difference between treatment groups only reached statistical significance after 12 months.

Conclusions

(i)

Thalamic volume is an MRI-based marker associated with neurodegeneration, facilitating the development of neuroprotective treatments. According to prior art, thalamic volume decreased in subjects with MS with an estimated decline of -0.71% per year and -0.28% per year in healthy individuals (see Azevedo 2018). Treatment with teriflunomide (-1.4% over 2 years) does not appear to have a beneficial effect on thalamic volume loss compared to prior art data. Conversely, switching to ofatumumab as a disease-modifying therapy has shown promising results.

(ii)

Analysis of the proportion of patients without clinical and MRI disease activity (i.e., patients with NEDA-4) and the MSIS-29 health-related quality of life assessment showed a positive effect and confirmed the durability of the therapeutic effect of ofatumumab.

Example 5: Maintenance of efficacy of ofatumumab in patients with relapsing MS switching from intravenous anti-CD20 therapy

State of the art: B-cell depletion in patients with relapsing multiple sclerosis (RMS) using anti-CD20 monoclonal antibodies (mAbs) reduces the annual relapse rate and inflammatory lesion activity on magnetic resonance imaging and delays the time to confirmed disability worsening. Ocrelizumab and rituximab, monoclonal anti-CD20 antibodies, are administered intravenously in the outpatient setting; ofatumumab is administered subcutaneously using a prefilled syringe or auto-injector (AI), facilitating self-administration.

Objectives: A 12-month prospective, single-arm, multicenter clinical study confirming the maintenance of efficacy of ofatumumab in patients with RMS switching from intravenous anti-CD20 monoclonal antibody therapy.

Methods: Approximately 100 adults with RMS were enrolled at 10-20 centers in the United States. Eligible patients had previously received 2-5 consecutive courses of intravenous ocrelizumab or rituximab (other anti-CD20 mAbs are excluded), with the last dose 4-9 months before baseline. Other inclusion criteria include an Expanded Functional Worsening Scale score of 5.5 or less at screening and CD19 B-cell depletion to less than 1% of baseline anti-CD20 therapy. Patients with a suboptimal response to anti-CD20 therapy within the previous 6 months (relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new/enlarged T2 lesions, clinical worsening) or who discontinued anti-CD20 therapy due to severe infusion-related reactions, recurrent infections, or progressive disease were excluded. All participants receive ofatumumab 20 mg subcutaneously via a pen on days 1, 7, and 14, and then monthly during months 1–12. The primary endpoint is no change or a reduction in the number of Gd+ lesions at month 12. Secondary endpoints include participant retention and changes in immune biomarkers, treatment satisfaction, safety, and tolerability at months 6 and 12. There is a 6-month interim analysis.

Results: The study complements the Phase 3 program of ofatumumab in RMS by providing data on maintained efficacy, retention, and satisfaction based on monthly subcutaneous administration of the drug using a pen in patients previously treated with ocrelizumab or rituximab.

Conclusions: The study provided important data on the maintenance of ofatumumab efficacy in patients with RMS who switched from intravenous anti-CD20 therapy.

Claims (87)

1. Use of ofatumumab for the treatment of relapsing multiple sclerosis, wherein ofatumumab is administered to a patient who has been treated with a disease-modifying therapy other than ofatumumab, wherein said disease-modifying therapy is discontinued prior to the initiation of ofatumumab, wherein the disease-modifying therapy is selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate, and wherein ofatumumab is administered subcutaneously. 2. The use of ofatumumab according to paragraph 1, where disease-modifying therapy is ineffective. 3. Use of ofatumumab according to paragraph 1 or 2, where the patient develops an exacerbation of the disease as a result of treatment with disease-modifying therapy. 4. The use of ofatumumab according to paragraph 3, characterized in that an exacerbation of the disease is indicated by one or more clinically registered relapses or one or more signs of activity on MRI. 5. The use of ofatumumab according to claim 4, wherein MRI activity includes Gd+ enhancement and/or new or enlarging T2 lesions. 6. The use of ofatumumab according to any of paragraphs 1-5, where the patient is intolerant of disease-modifying therapy. 7. The use of ofatumumab according to any of paragraphs 1-6, where the patient has a history of no more than 1, 2, or 3 disease-modifying therapies. 8. The use of ofatumumab according to any one of claims 1-7, characterized in that the disease-modifying therapy was administered for at least 6 months prior to the first administration of ofatumumab. 9. The use of ofatumumab according to any of claims 1-8, wherein the patient is neurologically stable for one month prior to the first administration of ofatumumab. 10. The use of ofatumumab according to any of claims 1-9, wherein the patient has an EDSS score of 1 to 4 prior to the first administration of ofatumumab. 11. The use of ofatumumab according to any one of claims 1-10, wherein the disease-modifying therapy is selected from fingolimod, dimethyl fumarate (DMF), glatiramer acetate and natalizumab. 12. The use of ofatumumab according to any one of claims 1-11, wherein the disease-modifying therapy is administered orally. 13. The use of ofatumumab according to any one of claims 1-10 or 12, wherein the disease-modifying therapy drug is selected from fingolimod, dimethyl fumarate and teriflunomide. 14. Use of ofatumumab according to paragraph 12 or 13, where: (a) the disease-modifying therapy is fingolimod; or (b) disease-modifying therapy is dimethyl fumarate. 15. The use of ofatumumab according to claim 14, wherein the disease-modifying therapy is fingolimod and wherein fingolimod was administered at a daily dose of 0.5 mg. 16. The use of ofatumumab according to any one of claims 1-10, wherein the disease-modifying therapy drug is selected from natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate. 17. The use of ofatumumab according to any one of claims 1-10 and 16, wherein the disease-modifying therapy is ocrelizumab. 18. Use of ofatumumab according to claim 17, where the patient has previously received at least two consecutive courses of intravenous administration of ocrelizumab. 19. Use of ofatumumab according to item 17 or 18, where the last dose was administered 4-9 months before the administration of ofatumumab. 20. The use of ofatumumab according to any of claims 1-19, wherein ofatumumab is administered after a relapse. 21. The use of ofatumumab according to any one of claims 1-20, characterized in that ofatumumab is administered after detection of at least one Gd+ lesion. 22. The use of ofatumumab according to any one of paragraphs 1-21, characterized in that ofatumumab is administered after detection of new or enlarging T2 lesions. 23. The use of ofatumumab according to any one of paragraphs 1-22, characterized in that the cessation of the previous disease-modifying therapy results in a recurrence of symptoms. 24. The use of ofatumumab according to any one of paragraphs 1-23, characterized in that the administration of ofatumumab is started before the patient reaches the half-life of the drug used in disease-modifying therapy. 25. The use of ofatumumab according to any of claims 1-24, wherein the administration of ofatumumab is started after a washout period of 1 day to 3 weeks. 26. The use of ofatumumab according to any of paragraphs 1-24, wherein the administration of ofatumumab is started without a washout period. 27. The use of ofatumumab according to any one of claims 1-26, wherein ofatumumab is administered if the loss of thalamic volume has not been sufficiently reduced as a result of disease-modifying therapy. 28. The use of ofatumumab according to any one of claims 1-27, wherein ofatumumab is administered if a sufficient reduction in the MSIS-29 score has not been achieved as a result of disease-modifying therapy. 29. The use of ofatumumab according to claim 28, wherein the MSIS-29 score was reduced by less than 2.5 as a result of disease-modifying therapy. 30. The use of ofatumumab according to any of paragraphs 1-29, wherein ofatumumab is administered at a dose of 10 to 30 mg monthly. 31. The use of ofatumumab according to paragraph 30, where ofatumumab is administered at a dose of 20 mg monthly. 32. The use of ofatumumab according to any one of claims 1-31, wherein ofatumumab is administered as a loading dose. 33. The use of ofatumumab according to claim 32, wherein 20 mg of ofatumumab at week 0, week 1 and week 2 is administered as a loading dose. 34. The use of ofatumumab according to any one of claims 1-31, wherein ofatumumab is administered without a loading dose. 35. The use of ofatumumab according to any one of claims 1-34, wherein the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome. 36. The use of ofatumumab according to any of paragraphs 1-35, wherein the patient is additionally given premedication before the first dose of ofatumumab is administered. 37. The use of ofatumumab according to claim 36, wherein premedication includes acetaminophen, antihistamines and/or steroids. 38. The use of ofatumumab according to paragraph 36 or 37, where premedication is administered 30-60 minutes before the injection of ofatumumab. 39. The use of ofatumumab according to any of paragraphs 1-35, wherein premedication is not administered before the first dose of ofatumumab. 40. The use of ofatumumab according to any of paragraphs 1-39, which avoids the recurrence of symptoms or relapse of disease activity. 41. The use of ofatumumab according to claim 2, wherein the lack of efficacy is defined as the failure to stop or adequately slow down the progression of the disease. 42. Use of ofatumumab for the manufacture of a medicinal product for the treatment of relapsing multiple sclerosis, wherein the medicinal product is administered to a patient who has been treated with a disease-modifying therapy other than ofatumumab, wherein said disease-modifying therapy is discontinued prior to the start of administration of ofatumumab, wherein the disease-modifying therapy is selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate, and wherein ofatumumab is administered subcutaneously. 43. A method for treating relapsing multiple sclerosis, wherein the method comprises administering ofatumumab to a patient suffering from relapsing multiple sclerosis, wherein the patient has been treated with a disease-modifying therapy other than ofatumumab, wherein said disease-modifying therapy is discontinued prior to the initiation of administration of ofatumumab, wherein the disease-modifying therapy is selected from teriflunomide, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate, and wherein ofatumumab is administered subcutaneously. 44. The method of claim 43, wherein the disease-modifying therapy is ineffective. 45. The method according to claim 43 or 44, wherein the patient develops an exacerbation of the disease as a result of treatment with disease-modifying therapy. 46. The method according to paragraph 45, characterized in that an exacerbation of the disease is indicated by one or more clinically registered relapses or one or more signs of activity on MRI. 47. The method of claim 46, wherein MRI activity comprises Gd+ enhancement and/or new or enlarging T2 lesions. 48. The method according to any one of paragraphs 43-47, wherein the patient is intolerant to disease-modifying therapy. 49. The method according to any one of paragraphs 43-48, wherein the patient has a history of no more than 1, 2, or 3 disease-modifying therapies. 50. The method according to any one of claims 43-49, characterized in that the disease-modifying therapy was administered for at least 6 months prior to the first administration of ofatumumab. 51. The method according to any one of claims 43-50, wherein the patient is neurologically stable for one month prior to the first administration of ofatumumab. 52. The method according to any one of claims 43-51, wherein the patient has an EDSS score of 1 to 4 prior to the first administration of ofatumumab. 53. The method according to any one of claims 43-52, wherein the disease-modifying therapy is selected from fingolimod, dimethyl fumarate (DMF), glatiramer acetate and natalizumab. 54. The method according to any one of claims 43-53, wherein the disease-modifying therapy is administered orally. 55. The method according to any one of claims 43-52 or 54, wherein the disease-modifying therapy drug is selected from fingolimod, dimethyl fumarate and teriflunomide. 56. The method according to paragraph 54 or 55, wherein: (a) the disease-modifying therapy is fingolimod; or (b) disease-modifying therapy is dimethyl fumarate. 57. The method of claim 56, wherein the disease-modifying therapy is fingolimod and wherein fingolimod was administered at a daily dose of 0.5 mg. 58. The method according to any one of claims 43-52, wherein the disease-modifying therapy drug is selected from natalizumab, ocrelizumab, alemtuzumab and glatiramer acetate. 59. The method according to any one of claims 43-52 or 58, wherein the disease-modifying therapy is ocrelizumab. 60. The method of claim 59, wherein the patient has previously received at least two consecutive courses of intravenous administration of ocrelizumab. 61. The method according to claim 59 or 60, wherein the last dose was administered 4-9 months before the administration of ofatumumab. 62. The method according to any one of claims 43-61, wherein ofatumumab is administered after a relapse. 63. The method according to any one of claims 43-62, wherein ofatumumab is administered after detection of at least one Gd+ lesion. 64. The method according to any one of claims 43-63, wherein ofatumumab is administered after detection of new or enlarging T2 lesions. 65. The method according to any one of paragraphs 43-64, characterized in that cessation of disease-modifying therapy results in recurrence of symptoms. 66. The method according to any one of claims 43-65, wherein the administration of ofatumumab is started before the patient has reached the half-life of the drug used in disease-modifying therapy. 67. The method according to any one of claims 43-66, wherein the administration of ofatumumab is started after a washout period of from 1 day to 3 weeks. 68. The method according to any one of claims 43-66, wherein the administration of ofatumumab is started without a washout period. 69. The method according to any one of claims 43-68, wherein ofatumumab is administered if the loss of thalamic volume has not been sufficiently reduced as a result of disease-modifying therapy. 70. The method according to any one of claims 43-69, wherein ofatumumab is administered if a sufficient reduction in the MSIS-29 score has not been achieved as a result of disease-modifying therapy. 71. The method of claim 70, wherein the MSIS-29 score was reduced by less than 2.5 as a result of disease-modifying therapy. 72. The method according to any one of paragraphs 43-71, wherein ofatumumab is administered at a dose of 10 to 30 mg monthly. 73. The method according to claim 72, wherein ofatumumab is administered at a dose of 20 mg monthly. 74. The method according to any one of claims 43-73, wherein ofatumumab is administered with a loading dose. 75. The method of claim 74, wherein 20 mg ofatumumab at week 0, week 1, and week 2 is administered as a loading dose. 76. The method according to any one of claims 43-73, wherein ofatumumab is administered without a loading dose. 77. The method according to any one of claims 43-76, wherein the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome. 78. The method according to any one of paragraphs 43-77, wherein the patient is additionally administered premedication before the administration of the first dose of ofatumumab. 79. The method of claim 78, wherein the premedication comprises acetaminophen, antihistamines and/or steroids. 80. The method according to claim 78 or 79, wherein the premedication is administered 30-60 minutes before the injection of ofatumumab. 81. The method according to any one of paragraphs 43-77, characterized in that no premedication is administered before the administration of the first dose of ofatumumab. 82. The method according to any one of paragraphs 43-81, which avoids the recurrence of symptoms or relapse of disease activity. 83. The method of claim 44, wherein the lack of effectiveness is defined as a failure to stop or adequately slow down the progression of the disease.