Treating RMS with Switching Therapy

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to the anti-CD20 monoclonal antibody ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the antibody is used in patients who have been treated with a disease-modifying therapy other than ofatumumab. [Background technology]

[0002] 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. There is no cure for the disease, but a variety of disease-modifying therapies (DMTs) are available that usually slow disease progression.

[0003] DMT involves the administration of disease-modifying drugs (DMDs). Examples of drugs approved for the treatment of MS are glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate (DMF).

[0004] While these DMTs usually significantly reduce relapse rates and MRI disease activity, thereby delaying the time to disability progression, (severe) adverse events can generally be associated with each of these DMTs. For example, natalizumab can result in an increased risk of fatal opportunistic infections (i.e., progressive multifocal leukoencephalopathy or PML). Fingolimod can be associated with S1P-related safety risks, such as bradycardia, macular edema, hypertension, and increased hepatic transaminases at the time of treatment initiation.

[0005] Given that existing drugs for the treatment of MS are associated with risks, there remains a need to identify ways to reduce, minimize, or overcome these risks. In particular, there remains a need to address these and other risks that arise when a patient discontinues a previous therapy, e.g., when a patient transitions from a previous disease-modifying therapy (DMT), e.g., fingolimod or DMF, to another DMT.

[0006] This is because treatment for multiple sclerosis (MS) can span decades, often necessitating changes to treatment plans to adapt to changing conditions. Switching medications or discontinuing immunomodulators all together can leave patients vulnerable to relapse or disease progression. In some cases, severe MS disease activity is noted clinically and on MRI after withdrawal from treatment. When this disease activity is disproportionate to the pattern observed before treatment began, the patient is said to have experienced a rebound.

[0007] Planning a pregnancy is a common reason for discontinuing DMTs. DMTs have been associated with birth defects in animal studies, and stopping fingolimod before conception is recommended.

[0008] Several approved MS medications are associated with rebound, i.e., the reactivation of severe disease after withdrawal from the DMT that exceeds a patient's pre-DMT baseline levels. For example, rebound issues have 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, there is a need to reduce, minimize, or overcome the risk of rebound after discontinuation of a DMT, such as natalizumab or fingolimod.

[0009] Furthermore, rebound has been reported in patients who presented with breakthrough disease during treatment with DMTs such as fingolimod, so there is a need to improve treatment strategies for patients with breakthrough disease.

[0010] Therefore, the problem underlying the present invention is to provide an improved treatment strategy for MS patients who require treatment optimization. For example, the MS is relapsing-remitting MS (RRMS) and the treatment to be optimized is DMT. Reasons for treatment optimization can include adverse effects, treatment failure, breakthrough disease, disease progression, comorbidities, life cycle events such as pregnancy and lactation, and / or evolving patient preferences.

[0011] As a result, any interruption or change in treatment, for example, when switching therapies, leaves patients with active MS vulnerable to relapse.

[0012] Reasons for treatment interruption or change include adverse effects, treatment failure, disease progression, comorbidities, life cycle events such as pregnancy and lactation, and evolving patient preferences. Because fulminant MS rebound events similar to immune reconstitution inflammatory syndrome (IRIS) have been reported with withdrawal from MS treatment, it is important for clinicians to recognize situations that put patients at risk for severe disease reactivation.

[0013] Therefore, when treatment is interrupted or changed, it is necessary to reduce or minimize the likelihood of this effect.

[0014] Despite the existing need exemplified above, there are no reliable evidence-based recommendations for successful transitions between DMTs. When switching from an immune-active agent such as fingolimod or DMF, the risk of additional immune system effects must be considered and balanced against the risk of rebound or recurrent disease activity.

[0015] In the art, B-cell depletion using rituximab or ocrelizumab has been suggested as a therapeutic strategy to address relapse and rebound after discontinuation of DMT. Rituximab, in particular, has been suggested as a therapeutic strategy to address rebound after discontinuation of fingolimod. However, in a series published by Hatcher et al., one case was characterized by clinical deterioration one 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 persistent Gd-enhancing lesions despite treatment with steroids and rituximab.

[0016] In a separate report, two patients with rebound disease after cessation of fingolimod were noted to have clinical deterioration and new Gd-enhancing MRI lesions 1 week after initiation of ocrelizumab (Schmidt S, Schulten T. Severe rebound after cessation of fingolimod treated with ocrelizumab with coincidental transient aggravation: report of two cases. Ther Adv Neurol Disord. 2019;12:1-6.). Both patients showed significant progression of the Expanded Disability Status Scale (EDSS) after ocrelizumab administration, despite immune reconstitution more than 3 months after withdrawal from fingolimod. One of these patients' scores is shown in Figure 1.

[0017] Both patients with highly active RRMS showed breakthrough disease during fingolimod treatment, necessitating treatment optimization, and subsequently developed clinical and MRI features of severe rebound after fingolimod discontinuation. In both patients, rebound occurred as early as 4–6 weeks after fingolimod discontinuation. Schmidt and Schulten suggested that rebound could be explained by the release of T17 T cells trapped in secondary lymphoid organs that had infiltrated the central nervous system. Pharmacodynamic data showed a rapid recovery of lymphocyte counts beginning several days after treatment cessation. Ocrelizumab depletes pre-B cells as well as mature and memory B cells, thereby disrupting 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 certain B-cell subsets, it seems reasonable to assume that removal of these B cells from the peripheral immune system, even weeks after cessation of fingolimod treatment, could be responsible for secondary deterioration in both patients.

[0018] Thus, in light of the prior art, B cell depletion has not emerged as a promising means to address relapse and rebound after cessation of DMT (eg, natalizumab or fingolimod). Summary of the Invention

[0019] Despite this teaching in the prior art, the present invention surprisingly provides a treatment strategy that effectively reduces the risk of disease reactivation, relapse and rebound by administering an alternative B cell depleting agent.

[0020] In particular, we have surprisingly found that B-cell depletion with ofatumumab offers a powerful and effective treatment strategy for addressing severe relapse and rebound after cessation of DMTs (e.g., natalizumab or fingolimod). This treatment strategy is most efficient when ofatumumab therapy is initiated within 0–6 months.

[0021] As noted above, there is a need to reduce, minimize or overcome the risk of rebound after discontinuation of a DMT such as natalizumab or fingolimod. This need is surprisingly met by the present invention.

[0022] Although natalizumab and fingolimod have distinct modes of action, the "anti-trafficking" strategy shared by both drugs reduces lymphocyte entry into the CNS, potentially explaining why rebound may occur upon discontinuation of these drugs. Although further research is needed, fingolimod has a more complex mechanism of action than simple anti-trafficking, likely increasing beneficial processes within the immune system while preventing adverse processes. For example, in a small-scale analysis of messenger RNA expression in peripheral blood CD4+ cells, fingolimod treatment was associated with changes in the transcription levels of 890 different genes. Many of these genes affect cytokine secretion, Toll-like receptor expression, and cell adhesion molecules, which may be involved in T cell function to suppress inflammation and autoimmunity. Surprisingly, ofatumumab was found to reduce the rebound phenomenon, but did not appear to directly affect the processes thought to cause it.

[0023] Unexpectedly, ofatumumab has the ability to reduce the risk of rebound in patients with breakthrough disease activity while being treated with fingolimod or another DMT different from ofatumumab.

[0024] Without being bound by theory, ofatumumab is thought to spare regulatory signals (e.g., those transmitted by B cells) and perhaps even spare regulatory T cells or B cells (subsets) themselves. This is evidenced by 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. Therefore, it is reasonable to assume that administration of ofatumumab after cessation of DMT treatment, e.g., fingolimod treatment, significantly reduces the risk of secondary deterioration (e.g., rebound after breakthrough disease activity).

[0025] Taken together, rebound after DMT discontinuation (e.g., fingolimod discontinuation) can be exacerbated by initiating treatment with another DMT, such as ocrelizumab. Thus, there are potential pitfalls and undesirable consequences of continuous administration of potent immunomodulatory and immunosuppressive drugs. In particular, ocrelizumab can complicate recovery from rebound after fingolimod cessation. Therefore, it was quite surprising that ofatumumab did not result in such complications or at least significantly reduced their risk.

[0026] Experimental withdrawal from fingolimod resulted in lymphoid overexpression of the S1P1 receptor, leading to increased lymphocyte exit from lymph nodes and increased severity of recurrent symptoms. Withdrawal from fingolimod may also result in astrocytic overexpression of S1P1 and downstream inflammatory responses, likely mediated by NF-κB activation and release of inflammatory cytokines and nitric oxide. Because overexpression of S1P and / or its receptor may also play a role in the pathogenesis of breakthrough disease, it is reasonable to consider ofatumumab as a potential treatment for breakthrough disease and recurrent syndromes, such as those resulting from rebound.

[0027] Furthermore, it is quite surprising that B-cell depletion with ofatumumab provides an effective strategy to avoid the unwanted risks of DMT therapy in pregnant or pre-pregnant women.

[0028] Thus, the subject of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, in patients who have been treated with a disease-modifying therapy (DMT) other than ofatumumab. DMT is defined as follows: All preferred embodiments exemplified below also apply to the use of the present invention.

[0029] A further object of the present invention is a method for treating or preventing relapsing multiple sclerosis, comprising 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 exemplified below also apply to the method of the present invention.

[0030] A further subject of the present invention is ofatumumab for producing a medicament for use in the treatment or prevention of relapsing multiple sclerosis, wherein the medicament is ofatumumab that has been used in patients who have been treated with a disease-modifying therapy other than ofatumumab. All preferred embodiments exemplified below also apply to this subject of the present invention.

[0031] In a preferred embodiment, the disease-modifying therapy other than ofatumumab is a previous DMT. This means that in a preferred embodiment, the patient is switching from a previous DMT to ofatumumab. In other words, the present invention relates to ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the ofatumumab is used in patients transitioning from a disease-modifying therapy.

[0032] In one embodiment of the present invention, ofatumumab is not administered to patients with active HBV infection.

[0033] In a preferred embodiment of the invention, disease-modifying therapy other than ofatumumab is discontinued before initiation of ofatumumab administration.

[0034] In a preferred embodiment of the invention, ofatumumab administration is initiated in a patient before the half-life of the drug used in the disease-modifying therapy other than ofatumumab is reached.

[0035] In a preferred embodiment of the invention, ofatumumab therapy is initiated immediately after discontinuation of the previous DMT (e.g., glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate). In this context, immediately means within one week, preferably three days, more preferably two days, more preferably one day, and most preferably within 12 hours after discontinuation of the previous DMT (e.g., glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate).

[0036] In another embodiment of the invention, ofatumumab therapy is initiated before discontinuation of a previous DMT (e.g., glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate). For example, the previous DMT may be continued until a loading dose regimen of ofatumumab is administered. The loading dose regimen may include subcutaneous (sc) injections of 20 mg ofatumumab on days 1, 7, and 14 of the dosing regimen; alternatively, the loading dose regimen may include sc injections of 20 mg ofatumumab on days 0, 7, and 14 of the dosing regimen.

[0037] Ofatumumab therapy and the previous DMT (e.g., glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate) can proceed in parallel. That is, ofatumumab administration is initiated before administration of the previous DMT is stopped. For example, the therapies can proceed in parallel for 1 day, 3 days, 1 week, 2 weeks, or 1 month.

[0038] In one embodiment of the present invention, ofatumumab therapy is initiated when a disease-modifying therapy other than ofatumumab (e.g., a previous DMT) has lost its effectiveness. For example, a drug used in the previous DMT can be washed out. Preferably, the drug is a DMD. Thus, ofatumumab therapy can be initiated when the previous DMT drug (e.g., a DMD) has been washed out. In this case, the previous DMT is the first DMT, and ofatumumab is the second DMT. In a preferred embodiment, the first DMT drug is considered to have been washed out if 25%, preferably 50%, more preferably 75%, even more preferably 85%, and most preferably 95% of the drug's half-life has elapsed until the final dose of the first DMT drug is administered before discontinuing the first DMT.

[0039] In an alternative embodiment, the first DMT drug is considered to be washed out when only 30%, preferably 20%, more preferably 10%, even more preferably 5%, and most preferably 2.5% or less of the amount administered as the final dose of the first DMT drug is detectable in a sample (e.g., blood or serum) from the patient. In a particularly preferred embodiment, the amount is max , i.e., the maximum (or peak) serum concentration that the first DMT drug achieves in serum after the final dose of the first DMT drug is administered prior to discontinuation of the first DMT.

[0040] In one embodiment of the present invention, ofatumumab therapy is initiated within 0 to 6 months, more preferably within 1 to 5 months, more preferably within 2 to 4 months, and even more preferably within 3 months after discontinuing the previous 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, and more preferably about 10 weeks after discontinuing the previous DMT, e.g., fingolimod. Alternatively, ofatumumab therapy can be initiated more than 10 weeks, more preferably more than 9 weeks, more preferably more than 8 weeks, more preferably more than 7 weeks, more preferably more than 6 weeks, more preferably more than 5 weeks, or more preferably more than 4 weeks after discontinuing the previous DMT, e.g., fingolimod.

[0041] 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, and more preferably at about 10.5 weeks after stopping the previous DMT.

[0042] In a preferred embodiment of the invention, ofatumumab administration is initiated without a washout period.

[0043] In a preferred embodiment of the invention, the patient has been 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 has been treated with a DMT other than ofatumumab for, for example, up to 10 years, up to 8 years, up to 6 years, up to 4 years, or up to 2 years.

[0044] In particularly preferred embodiments, the use of ofatumumab according to the present invention prevents or reduces rebound, which is defined as follows: rebound may occur 0 to 6 months, or 1 to 5 months, or 2 to 4 months, and even more preferably within the third month, after discontinuing the other disease-modifying therapy (e.g., fingolimod). More specifically, rebound 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 discontinuing the other disease-modifying therapy (e.g., fingolimod). Alternatively, rebound 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 at about 10.5 weeks, after stopping other or previous disease-modifying therapy (e.g., fingolimod).

[0045] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab lacks efficacy. Lack of efficacy exists, for example, when a patient who has received a disease-modifying therapy (DMT) shows signs of disease activity, such as recurrence or lesions. Lack of efficacy can be defined as disease progression not being stopped or not adequately slowed. In other words, the present invention is directed to the use of ofatumumab to treat non-responders to previous DMTs.

[0046] In a preferred embodiment, ofatumumab is administered to patients with a suboptimal response to DMT therapy, e.g., anti-CD20 therapy. In a preferred embodiment, the suboptimal response has occurred within the past six months. In a preferred embodiment, the suboptimal response can be characterized by relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, and / or clinical deterioration.

[0047] In a preferred embodiment of the invention, ofatumumab is administered after detection of at least one Gd+ lesion, the term Gd+ lesion being defined below.

[0048] In a preferred embodiment of the invention, ofatumumab is administered after the detection of a new or enlarging T2 lesion, the term T2 lesion being defined below.

[0049] In one embodiment of the invention, the patient has developed breakthrough disease due to treatment with another disease-modifying therapy, for example, due to treatment with a previous DMT. In an alternative embodiment of the invention, rebound or recurrent disease activity is avoided.

[0050] Generally, breakthrough disease is evidenced by one or more clinically reported recurrences or one or more signs of MRI activity, including Gd+ enhancement and / or new or enlarging T2 lesions, with reference to the definition of breakthrough disease provided below.

[0051] Breakthrough disease may occur within 0 to 6 months, or within 1 to 5 months, or within 2 to 4 months, even more preferably within 3 months, before discontinuing the other disease-modifying therapy (e.g., fingolimod). More specifically, breakthrough disease may occur between 4 to 16 weeks, or between 5 to 15 weeks, or between 6 to 14 weeks, or between 7 to 13 weeks, or between 8 to 12 weeks, or between 9 to 11 weeks, or about 10 weeks before discontinuing the other disease-modifying therapy (e.g., fingolimod). Alternatively, breakthrough disease may occur between 3 to 18 weeks, or between 4 to 17 weeks, or between 5 to 16 weeks, or between 6 to 15 weeks, or between 7 to 14 weeks, or between 8 to 13 weeks, or between 9 to 12 weeks, or between 10 to 11 weeks, more preferably about 10.5 weeks, before discontinuing the other disease-modifying therapy (e.g., fingolimod).

[0052] In an alternative preferred embodiment of the invention, the patient lacks tolerance to other or previous disease-modifying therapies. Thus, in a preferred embodiment, ofatumumab is administered to patients who have discontinued a previous DMT due to an adverse event.

[0053] Preferably, the lack of tolerance relates to the presence of adverse events, such as headache, dizziness, nausea, infections (such as Zoster herpes), macular edema, infusion-related reactions or recurrent infections.

[0054] In one embodiment of the invention, the patient has had a history of one, two, or three disease-modifying therapies other than ofatumumab.

[0055] The term "two or three disease modifying therapies" preferably relates to two or three different drugs.

[0056] In a preferred embodiment of the invention, the patient is neurologically stable within one month prior to the first administration of ofatumumab. The term "neurologically stable" is defined below.

[0057] 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.

[0058] Furthermore, thalamic volume can serve as a marker associated with neurodegeneration. Azevedo et al. reported that thalamic atrophy is present early in the disease, reflects several aspects of MS pathology, including gray matter damage, and correlates well with physical disability and cognitive impairment. Therefore, thalamic volume has been proposed as a potentially interesting MRI metric related to the neurodegenerative features of MS. Azevedo et al. found that thalamic volume declined significantly faster in MS subjects compared with healthy controls (HCs), with a predicted decline of -0.71% per year (95% confidence interval [CI] = -0.77% to -0.64%) compared with -0.28% per year (95% CI = -0.58% to 0.02%) in HCs (p = 0.007 for the difference). The rate of decline was consistent across 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.

[0059] In the present invention, it has been unexpectedly found that administration of ofatumumab results in a beneficial reduction in thalamic volume loss, as referenced in the experimental section below.

[0060] Therefore, in a preferred embodiment of the present invention, ofatumumab is administered when thalamic volume loss has not been sufficiently reduced by previous disease-modifying treatment.Compared to the untreated baseline, a reduction of thalamic volume loss of less than 30%, less than 25%, or less than 20% is not considered to be a sufficient reduction.In this context, the untreated baseline loss can be considered to be 0.71% per year.

[0061] For example, ofatumumab can be administered if administration of a prior disease-modifying therapy did not reduce thalamic volume loss by less than 0.70% per year, or less than 0.65% per year, or less than 0.60% per year. Alternatively, ofatumumab can be administered if administration of a prior disease-modifying therapy did not reduce thalamic volume loss by less than 1.40%, or less than 1.3%, or less than 1.2% within 24 months.

[0062] In this regard, a further subject of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the ofatumumab reduces thalamic volume loss, preferably by less than 0.70% per year, or less than 0.65% per year, or less than 0.60% per year. For example, loss can be reduced to 0.30% to 0.70% per year, or 0.40% to 0.65% per year, or 0.45% to 0.60% per year. Alternatively, the present invention relates to ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the ofatumumab reduces thalamic volume loss by less than 1.40%, or less than 1.3%, or less than 1.2% within 24 months. For example, loss can be reduced to 0.6% to 1.40%, or 0.8% to 1.3%, or 0.9% to 1.2% within 24 months.

[0063] The MSIS-29 (see definition below) is a clinically useful and scientifically sound measure of the impact of MS from the patient's perspective, suitable for clinical studies and epidemiological experiments. The MSIS-29 is considered a reliable, valid, and responsive PRO (patient-reported outcome) measure that complements other indicators of disease severity and is being used to improve our understanding of the impact of MS.

[0064] In the present invention, it has been unexpectedly found that administration of ofatumumab results in a beneficial reduction in the MS Impact Scale MSIS-29, as defined below, with reference to the Experimental Section below.

[0065] Thus, in a preferred embodiment of the invention, ofatumumab is administered if an insufficient reduction in MSIS-29 score has been achieved under previous disease-modifying therapy: a reduction in MSIS-29 score of less than 2.5, or less than 2.0, or less than 1.5 cannot be considered an adequate reduction.

[0066] For example, ofatumumab can be administered if the administration of a previous disease-modifying therapy has not achieved a 1.5 or 2.0 or 2.5 reduction in MSIS-29 score within 24 months.

[0067] In this regard, a further subject of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the ofatumumab reduces the MSIS-29 score. Preferably, the ofatumumab reduces the MSIS-29 score by at least 1.5, more preferably by at least 2.0, and even more preferably by at least 2.5 within 24 months. The reduction may be up to 3.0, 3.5, or 4.0.

[0068] In a preferred embodiment of the invention, the patient has an EDSS score of 1 to 4 before the first dose of ofatumumab. EDSS stands for Expanded Disability Status Scale and is defined below.

[0069] In a preferred embodiment, ofatumumab can be administered regardless of body weight, sex, age, race, or baseline B-cell count. For example, a 35-year-old woman weighing 60 kg preferably receives the same dose as a 50-year-old man weighing 90 kg. In particular, body weight, sex, age, race, or baseline B-cell count have no clinically significant effect on the pharmacokinetics of ofatumumab.

[0070] In a preferred embodiment, ofatumumab is administered to patients who have discontinued a previous DMT, e.g., anti-CD20 therapy, due to side effects such as severe infusion-related reactions or recurrent infections.

[0071] In general, the term DMT is known in the art and is defined below. In the context of the present invention, examples of suitable DMTs are treatments with the following drugs: teriflunomide, leflunomide, dimethyl fumarate, fingolimod, natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab, glatirameracetat, and laquinimod.

[0072] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is administered orally. Examples of suitable DMTs are teriflunomide, leflunomide, laquinimod, dimethyl fumarate, and fingolimod.

[0073] In certain preferred embodiments 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. In alternative embodiments, fingolimod is administered at a daily dose of 0.1 mg to 2.5 mg, for example 0.25 mg.

[0074] In certain preferred embodiments of the invention, the disease-modifying therapy other than ofatumumab is dimethyl fumarate (DMF). Preferably, DMF is administered in a daily dose of 120 mg to 480 mg, particularly 480 mg.

[0075] In certain preferred embodiments of the 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.

[0076] In certain preferred embodiments of the invention, the disease-modifying therapy other than ofatumumab is teriflunomide. Preferably, teriflunomide is administered in a daily dose of 6 to 18 mg, preferably 14 mg.

[0077] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is administered by injection. Examples of suitable DMTs are natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab, and glatiramer acetate.

[0078] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is natalizumab. Preferably, natalizumab is administered intravenously at a dose of 100 to 500 mg, preferably 300 mg, every four weeks.

[0079] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is daclizumab. Preferably, daclizumab is administered at a dose of 50-250 mg, preferably 150 mg s.c., once monthly.

[0080] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is glatiramer acetate. Preferably, the glatiramer acetate is administered in a regimen of once daily sc injections at a dose of 20 mg / mL or three times weekly sc injections at a dose of 40 mg / mL.

[0081] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is rituximab, preferably administered at a dose of 500 or 1,000 mg, especially intravenously, every 6 to 12 months.

[0082] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is ocrelizumab. Preferably, ocrelizumab is administered at a dose of 600 mg every 6 months, particularly intravenously.

[0083] Preferably, the patient has been previously treated with at least two, e.g., two to five, consecutive courses of intravenous ocrelizumab or rituximab, the last dose of which may be administered, e.g., four to nine months before administration of ofatumumab.

[0084] According to the present invention, the efficacy of ofatumumab is maintained in patients with RMS who have transitioned from intravenous anti-CD20 therapy.

[0085] In a preferred embodiment, ofatumumab is administered to patients who have had a suboptimal response to anti-CD20 therapy in the past 6 months (e.g., relapse, ≧2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, clinical deterioration) and / or who have discontinued anti-CD20 therapy due to adverse events, such as, for example, severe infusion-related reactions or recurrent infections.

[0086] In a preferred embodiment of the invention, the disease-modifying therapy other than ofatumumab is alemtuzumab. Preferably, alemtuzumab is administered at a dose of 12 mg / day and is administered as an infusion.

[0087] In a preferred embodiment of the invention, ofatumumab is administered at a dose of 10-30 mg every 4 weeks, preferably at a dose of 20 mg every 4 weeks. Preferably, ofatumumab is administered by subcutaneous injection (sc).

[0088] In a preferred embodiment of the present invention, ofatumumab is administered as a loading dose. The term loading dose is defined below. In a preferred embodiment, three loading doses are administered, preferably at week 0, week 1, and week 2 after initiating ofatumumab therapy. This means that the first loading dose at week 0 constitutes the start of therapy. In an alternative preferred embodiment, three loading doses are administered on day 1, and days 5-9, preferably day 7, and days 12-16, preferably day 14, after initiating ofatumumab therapy. This means that the first loading dose on day 1 constitutes the start of therapy.

[0089] In a preferred embodiment of the invention, the loading dose is 10-30 mg, preferably 20 mg, ofatumumab.

[0090] The preferred dose of ofatumumab is: Initial dose of 20 mg by subcutaneous injection at weeks 0, 1, and 2, followed by Subsequent doses of 20 mg subcutaneously once monthly, starting on week 4.

[0091] If an ofatumumab injection is missed, it should be administered as soon as possible, preferably without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

[0092] In an alternative embodiment of the invention, ofatumumab is administered without a loading dose.

[0093] In a preferred embodiment of the present invention, a premedication is administered to a patient before the first dose of ofatumumab is administered. Preferably, the premedication includes acetaminophen, an antihistamine, and / or a steroid. Methylprednisolone may be a preferred steroid. 100 mg IV may be a preferred dose. Preferably, the premedication is administered 30 to 60 minutes before the ofatumumab injection.

[0094] In certain preferred embodiments, no prior administration is administered prior to the first dose of ofatumumab.

[0095] 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.

[0096] In a preferred embodiment of the invention, the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), in particular RRMS, as these terms are defined below.

[0097] In an alternative embodiment of the invention, the patient to be treated does not meet one or more of the following criteria: - Have no active disease and have been diagnosed with primary progressive multiple sclerosis or secondary progressive multiple sclerosis Meets criteria for neuromyelitis optica Breastfeeding - Have an active, chronic immune system disease other than multiple sclerosis, or have an immunodeficiency syndrome Have neurological findings consistent with or confirmed progressive multifocal leukoencephalopathy (PML) Have an active systemic infection or AIDS, or test positive for human immunodeficiency virus antibodies during screening - at risk of developing or reactivating hepatitis, syphilis, or tuberculosis -Has received any live or live attenuated vaccine within 2 months prior to starting therapy.

[0098] Preferably, ofatumumab is administered parenterally, for example, by epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion. The preferred route of administration is subcutaneous injection.

[0099] In one embodiment of the present invention, the ofatumumab composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If appropriate, the composition may also contain a solubilizing agent and a local anesthetic, such as lignocaine, to alleviate pain at the injection site. Generally, the components of the formulation are supplied individually or together in unit dosage form in a hermetically sealed container, such as an ampoule or sachet, indicating the active agent content, e.g., as a lyophilized powder or a water-free concentrate.

[0100] Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.

[0101] Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0102] In one embodiment, the formulation of ofatumumab can be formulated according to the formulations disclosed in WO 2009 / 009407.

[0103] In one embodiment, ofatumumab is formulated into an antibody formulation in which 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.

[0104] In one embodiment, ofatumumab is formulated into an antibody formulation comprising 10-100 mM sodium acetate, 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0.2 mM EDTA, and 0.01-0.2% polysorbate 80, and adjusted to a pH of 5.0-7.0. Preferably, the ofatumumab formulation comprises 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, and 0.02% polysorbate 80, and adjusted to a pH of 5.5.

[0105] In one embodiment, the ofatumumab formulation is provided in a pre-filled syringe or auto-injector. Preferably, a pre-filled auto-injector intended for sc administration is used.

[0106] In a preferred embodiment, ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each 20 mg / 0.4 mL pre-filled pen or pre-filled syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg ofatumumab and arginine (4 mg), edetate disodium (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 can be added to adjust the pH.

[0107] In a preferred embodiment, the ofatumumab formulation is intended for patient self-administration, preferably by subcutaneous injection.

[0108] In a preferred embodiment, the formulation is administered subcutaneously to the abdomen, thigh, or outer upper arm. In a preferred embodiment, the formulation is not administered to bruises, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

[0109] In one embodiment, the first injection of the ofatumumab formulation can be administered under the guidance of a healthcare professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Prior to administration, the pen or prefilled syringe is preferably removed from the refrigerator and allowed to return to room temperature, for example, for about 15 to 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, single-dose pre-filled pen, e.g., Sensoready® pen · Injection: 20 mg / 0.4 mL, single-dose prefilled syringe.

[0110] In a preferred embodiment, a 20 mg subcutaneous ofatumumab dose every 4 weeks provides a mean AUC tau about 400-550, more preferably 450-500, e.g., 483 mcg h / mL, and / or a mean C maxIn a preferred embodiment, after repeated subcutaneous administration of ofatumumab 20 mg doses, the steady-state volume of distribution may be 4.5 to 6.5, more preferably 5.0 to 6.0, e.g., 5.42 L.

[0111] After subcutaneous administration, ofatumumab can be absorbed through the lymphatic system. [Brief explanation of the drawings]

[0112] [Figure 1] FIG. 1 shows patients who showed significant Expanded Disability Status Scale (EDSS) progression after ocrelizumab administration despite immune reconstitution more than 3 months after weaning from fingolimod. [Figure 2] FIG. 2 shows ofatumumab-induced CDC of freshly isolated primary human B cells. [Figure 3] FIG. 3 shows that ofatumumab potently induces CDC after the subsequent addition of complement. DETAILED DESCRIPTION OF THE INVENTION

[0113] definition antibody: The term "antibody," as used herein, refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either, which has the ability to specifically bind to an antigen. Binding preferably occurs for a significant period of time under typical physiological conditions. The term "antigen-binding portion" of an antibody, as used herein, refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., CD20). For further definitions, reference is made to WO 2018 / 033841, particularly pages 9-13.

[0114] Breakthrough Diseases For purposes of this invention, breakthrough diseases are defined as follows: At least one recorded relapse in the past year or two recorded relapses in the past two years the presence of at least one Gd+ lesion on an MRI scan within the past 12 months, and / or Presence of new or enlarging T2 lesions within the past 12 months.

[0115] CD20: The CD20 molecule (also known as human B-lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. CD20 is found on the surface of more than 90% of B cells from peripheral blood or lymphoid organs, where it is expressed during early pre-B cell development and persists until plasma cell differentiation. CD20 is present on both normal and malignant B cells. The 85-amino acid carboxyl-terminal region of the CD20 protein is located in the cytoplasm. Reference is made to the description in GenBank, accession number NP_690605.

[0116] Disease Modifying Therapy (DMT) The term "disease-modifying therapy" is used because there is still no curative treatment for multiple sclerosis (MS), but several disease-modifying drugs (DMDs) have been approved for MS. Generally, DMTs for RMS reduce the frequency and / or severity of relapses. Thus, while DMTs are not a cure for RMS patients, patients can reduce the number and severity of their relapses.

[0117] EEDS The Expanded Disability Status Scale (EDSS) is a method for quantifying disability in multiple sclerosis and monitoring changes in disability level over time.

[0118] The EDSS scale ranges from 0 to 10 in 0.5 increments, with higher values ​​representing greater levels of disability. Scoring is based on an examination by a neurologist.

[0119] EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any assistance and are based on eight functional disability scales (FS): Pyramidal function - muscle weakness or difficulty moving the limbs Cerebellar function - ataxia, loss of balance, coordination or tremors Brainstem function - problems with speech, swallowing and nystagmus Sensory function – numbness or loss of sensation Bowel and bladder function Visual function - problems with vision Brain function - thinking and memory problems ·others.

[0120] Functional systems (FS) represent neuronal networks in the brain responsible for specific tasks. Each FS is scored on a scale from 0 (no impairment) to 5 or 6 (more severe impairment). Adapted from Kurtzke JF. Rating Neurologic Impairment in Multiple Sclerosis: An Expanded Disability Status Scalae (EDSS). Neurology. 1983, Nov;33(11):1444-52.

[0121] Gd+ lesions Gadolinium ("contrast") is a chemical compound that is injected into a person's veins during an MRI scan. Gadolinium is normally prevented from passing from the bloodstream into the brain or spinal cord by the blood-brain barrier. However, during active inflammation in the brain or spinal cord, such as during an MS relapse, the blood-brain barrier breaks down, allowing gadolinium to pass through. Gadolinium can then enter the brain or spinal cord and leak into MS lesions, emitting light and creating highlighted spots on the MRI. Such MS lesions are called gadolinium-enhancing lesions or Gd+ lesions.

[0122] Half-life The half-life of a biological substance (e.g., a DMT drug) is the time it takes for half of the substance to be eliminated by biological processes. This concept is used when the rate of elimination is approximately exponential. In the medical context, half-life explicitly describes the time it takes for the plasma concentration of a substance to fall to half of its steady-state value while circulating in the whole blood of an organism (plasma half-life).

[0123] loading dose A loading dose is an initial dose of drug, preferably an initial higher dose that may be given at the beginning of a treatment course (e.g., DMT), before stepping down to a maintenance dose, preferably a lower maintenance dose.

[0124] Neurologically stable A clinical state characterized by no change in mental status or level of consciousness, which may include seizure control; absence of new neurological deficits, such as aphasia, ataxia, dysarthria, paresis, motor paralysis, visual field loss, or blindness, and is defined as neurological stability.

[0125] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 Version 2 is a 29-item self-administered questionnaire covering two domains: physical and psychological. Responses are recorded on a 4-point ordinal scale ranging from 1 (not at all true) to 4 (extremely true), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete, and the questions are designed to assess patients' views of the impact of MS on their daily lives over the past 2 weeks. [The text is based on 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.]

[0126] Ofatumumab: Ofatumumab is a human monoclonal antibody directed against the CD20 protein. It can specifically bind to both the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab can bind to the CD20 molecule, and the Fc domain mediates immune effector function, resulting in B cell lysis in vitro. In particular, ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed on B cells, for example. Ofatumumab is produced in a murine NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains, with a molecular weight of approximately 146 kDa.

[0127] Ofatumumab is described in EP 1 558 648 and EP 3 284 753. Further reference is made to drugbank.ca, accession number DB06650, and WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the protein formula is C 6480 H 10022 N 1742 O 2020 S 44 and the average protein weight is approximately 146,100 Da.

[0128] The metabolic pathway of ofatumumab may be degradation into small peptides and amino acids by ubiquitous proteolytic enzymes. Ofatumumab may be eliminated in two ways: a target-independent pathway, as is the case for other IgG molecules, and a target-mediated pathway associated with binding to B cells.

[0129] The half-life of ofatumumab at steady state can be approximately 16 days, particularly after repeated subcutaneous administration of a 20 mg dose.

[0130] Ofatumumab preferably does not share common clearance pathways with chemical drugs metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. Preferably, ofatumumab is not involved in regulating the expression of drug-metabolizing enzymes.

[0131] patient The term "patient" preferably refers to a human patient, preferably an adult.

[0132] rebound A reactivation of severe disease above a patient's pre-DMT baseline after withdrawal from DMT is considered a rebound 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.

[0133] recurrence A relapse can be defined as a new episode of neurological deficit or deterioration, preferably lasting longer than 24 hours. In other words, a relapse can be considered a discrete episode of neurological dysfunction (also referred to in the art as an "attack," "outbreak," or "exacerbation"), preferably lasting at least 24 hours. Typically, a relapse is followed by a period of complete or partial recovery and no progression of symptoms or accumulation of disability (remission).

[0134] Relapses are presumed to be caused by new or expanding demyelinating plaques at the site of the inflammatory event within the central nervous system (CNS).

[0135] Revised McDonald's Criteria (Thompson et al 2018) Under the revised McDonald criteria, MS can be diagnosed if there is spatially dispersed myelin damage (DIS), as seen on MRI: - At least one T2-bright lesion in at least two or four CNS locations: the paracortical, periventricular, and subtentorial regions of the brain, and the spinal cord. (T2 is the most common MRI scan used to diagnose MS and detect areas of old and new myelin damage in the brain and spinal cord.) -These lesions do not necessarily have to be gadolinium-enhancing (contrast material).

[0136] Regarding temporal myelin damage (DIT), MRI evidence is as follows: - New T2 and / or gadolinium-enhancing lesions on the follow-up MRI compared with the baseline scan (regardless of time since baseline). The 2005 revision required at least 30 days between the initial and first episode. -At any time, asymptomatic gadolinium enhancement and non-enhancing lesions are present simultaneously.

[0137] Primary progressive MS (PPMS) has special diagnostic requirements. Specifically, the revised McDonald criteria require at least one year of documented progression (either prospectively or retrospectively) plus two of the following three findings: - Demonstration of intracerebral DIS, observed in at least one T2 lesion in the three major brain regions (periventricular, paracortical, or subtentorial) -Demonstration of DIS within the spinal cord, based on at least two T2 lesion DIS (≥2 T2 lesions); - Positive CSF involvement, again observed in the presence of oligoclonal bands and / or a high IgG index.

[0138] RRMS Relapsing-remitting multiple sclerosis (MS) is characterized by a relapse, defined as an episode of new neurological deficit or neurological deterioration lasting longer than 24 hours, often in the absence of fever or infection.

[0139] There is no apparent progression of the disease during periods of remission. RRMS can be further characterized at different time points as either active (there is evidence of relapses and / or new MRI activity) or inactive, and as worsening (there is a confirmed increase in disability over a specified period of time after a relapse) or not worsening. Reference is made to Lublin 2014, Neurology. 2014 Jul 15; 83(3): 278-286.

[0140] RMS The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS and clinically isolated syndrome (CIS).

[0141] Primary progressive MS (PPMS) PPMS is characterized by a worsening of neurological function (accumulating disability) from symptom onset without early relapses or remissions. PPMS can be further characterized at different time points as either active (with evidence of occasional relapses and / or new MRI activity) or inactive, and as progressive (with evidence of worsening disease on objective measures of change over time, with or without relapses or new MRI activity) or not. Reference Lublin 2014.

[0142] Each person's experience with PPMS is unique: PPMS can have brief periods of stable disease, with or without relapses or new activity on MRI, as well as periods of increased disability, with or without new relapses or lesions on MRI.

[0143] Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive deterioration of neurological function over time (accumulation of disability). SPMS can be further characterized at different time points as being active (there is evidence of relapses and / or new MRI activity) or inactive, and as being progressive (there is evidence of worsening disease on objective measures of change over time, with or without relapses) or not progressing. Reference Lublin 2014.

[0144] The experience of each person with SPMS is unique. SPMS follows the relapsing-remitting form of MS. Disability gradually increases over time, with or without evidence of disease activity (relapses or changes on MRI). In SPMS, occasional relapses can occur during stable periods as well.

[0145] Clinically isolated syndrome (CIS): Clinically isolated syndrome (CIS) can refer to a single clinical attack of inflammatory demyelinating symptoms in the central nervous system (CNS) that are suggestive of multiple sclerosis (MS). CIS symptoms can be solitary or multiple and typically involve the optic nerves, brainstem, cerebellum, spinal cord, or hemispheres of the brain. Reference is made to Miller et al., Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169.

[0146] T1 and T2 lesions T1 and T2 refer to different MRI methods used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time elapsed between the magnetic pulse and the recording of the image. These different methods are used to detect different structures or chemicals in the central nervous system. T1 and T2 lesion refers to whether a lesion was detected using either the T1 or T2 method. T1 MRI images provide information about current disease activity by highlighting areas of active inflammation. T2 MRI images provide information about disease burden or lesion load (the total amount of old and new lesion areas).

[0147] Washout The term washout refers to the period between clinical treatments (preferably between different DMTs) that allows any drug delivered as a first treatment (e.g., a first DMT) to be washed out—partially or completely—from the patient before the second treatment (e.g., a second DMT) is initiated. During the washout period, the patient preferably does not receive any other drug (e.g., a DMT for the treatment of MS). Preferably, the drug is a disease-modifying drug (DMD).

[0148] In a preferred embodiment, the first DMT drug is considered to be washed out if 25%, preferably 50%, more preferably 75%, even more preferably 85%, and most preferably 95% of the drug half-life has elapsed until the final dose of the first DMT drug is administered before discontinuation of the first DMT.

[0149] In an alternative embodiment, the first DMT drug is considered to be washed out when only 30%, preferably 20%, more preferably 10%, even more preferably 5%, and most preferably 2.5% or less of the amount administered as the final dose of the first DMT drug is detectable in a sample (e.g., blood or serum) from the patient. In a particularly preferred embodiment, the amount is max , i.e., the maximum (or peak) serum concentration that the first DMT drug achieves in serum after the final dose of the first DMT drug is administered prior to discontinuation of the first DMT.

[0150] Detection of the first DMT can be performed by one or more of PAGE, Western blotting, ELISA, HPLC and mass spectrometry, capillary electrophoresis, Fourier transform infrared spectroscopy, circular dichroism, DLS, thermal shift assay, NMR, X-ray, chromatography, and fluorescence spectroscopy. [Example]

[0151] [Example 1] In vitro data reveal differences between anti-CD20 antibodies in the induction of complement-dependent cytotoxicity (CDC) In vivo, anti-CD20 antibodies can mediate B-cell killing by cellular and / or complement-dependent mechanisms, and CDC is an important mechanism of ofatumumab-induced B-cell lysis.

[0152] PBMCs (peripheral blood mononuclear cells) were prepared by collecting human primary B cells by centrifugation and dissolving them at 2 × 10 in assay medium (RPMI 1640 + Glutamax supplemented with 0.1% BSA and 20 mM HEPES). 5 B cells were then simultaneously incubated with 3-fold serial dilutions of antibodies and human serum (30%) as a source of complement in a V-bottom 96-well plate for 1 hour at 37°C and 5% CO2. Cells were washed, stained with SYTOX Blue (0.25 μM), and then analyzed for B cell lysis by flow cytometry on a FACS Fortessa. Cell death was assessed by SYTOX Blue. + The results, shown in Figure 2, demonstrate a strong concentration-dependent induction of CDC in primary human B cells by ofatumumab compared to ocrelizumab and rituximab.

[0153] In a second experiment, B cells were incubated with the previously described antibodies, but in the absence of a complement source. Cells were washed as previously described. After 6 hours, a complement source was added. Only antibodies with low off rates remained bound to the cells and bound complement, but after this delayed addition of complement, ofatumumab potently induced CDC. 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.

[0154] Thus, surprisingly, ofatumumab offers the ability to activate complement components and induce CDC, which clearly distinguishes it from ocrelizumab in terms of potency and efficacy.

[0155] [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 was investigated as described below.

[0156] 1. Ofatumumab Ofatumumab was provided in prefilled syringes containing 20 mg ofatumumab (50 mg / ml, 0.4 ml content) for subcutaneous administration. Matching placebo prefilled syringes had the same appearance as the study drug.

[0157] Control treatment can be teriflunomide (Aubagio®) 14 mg.

[0158] Ofatumumab treatment group: ofatumumab 20 mg s.c. injections on days 1, 7, 14, week 4 (study month 1), and every 4 weeks thereafter plus teriflunomide-matching placebo capsules given orally once daily.

[0159] Eligible patients were randomized 1:1 to receive either active ofatumumab 20 mg or active teriflunomide 14 mg. Randomization was stratified by geographic region and MS subtype (RRMS, SPMS).

[0160] 2. Patient population Patients eligible to participate in this study had to meet the following criteria: Diagnosis of MS according to the 2010 revised McDonald criteria (Polman et al. 2011).

[0161] Relapsing MS: Relapsing-remitting course (RRMS) or secondary progressive (SPMS) course with disease activity, as defined by Lublin et al., 2014.

[0162] Disability status at screening, EDSS score 0–5.5 (inclusive).

[0163] The patient had previously been treated with DMTs selected from glatiramer acetate, dimethyl fumarate (DMF), daclizumab, fingolimod, natalizumab, and laquinimod.

[0164] Documentation of at least the following: one recurrence in the past year or two recurrences in the past two years prior to screening, or a positive Gd-enhanced MRI scan one year prior to randomization. Note: If no positive Gd-enhanced scan is present from the previous year, the screening MRI scan may be used.

[0165] Neurologically stable within 1 month prior to randomization

[0166] 3.Results 3.1 Outcomes for patients receiving fingolimod as a previous DMT a) Unexpected drop in recurrence The table below shows the results of the first study on the number of relapses before and after joining the study (results from the study up to 12 and 24 months).

[0167] [Table 1]

[0168] In the table above, the following abbreviations are used:

[0169] [Table 2]

[0170] The table shows that among patients randomized to ofatumumab (Study 1), 27 patients were evaluated at each visit: baseline, 12 months, and 24 months. Twelve months before screening, the number of relapses per patient was approximately 1.26. This rate unexpectedly dropped to approximately 0.23 12 months after treatment switching and to approximately 0.30 at 24 months.

[0171] The decline in the ofatumumab group was unexpectedly large: it was greater than in the comparator group.

[0172] b) Unexpected decrease in Gd-enhancing T1 lesions The following results were obtained for Gd lesion counts:

[0173] [Table 3]

[0174] The table shows that among patients randomized to ofatumumab, there was a striking reduction in the number of Gd+ lesions.

[0175] 3.2 Outcomes for patients treated with DMF as a previous DMT

[0176] [Table 4]

[0177] 3.3 Outcomes for patients treated with daclizumab as a previous DMT

[0178] [Table 5]

[0179] 3.4 Outcomes for patients treated with natalizumab as a previous DMT

[0180] [Table 6]

[0181] 4.5 Outcomes for patients treated with glatiramer acetate as a previous DMT

[0182] [Table 7]

[0183] [Example 3] clinical trials The results as described above in Example 2 were confirmed in clinical trials as described below.

[0184] 1. Group The study population will consist of adult subjects with RMS. Studies will be conducted at approximately 120-170 centers worldwide.

[0185] Subjects eligible for inclusion in this study must meet all of the following criteria: 1. Diagnosis of MS according to the 2017 revised McDonald criteria 2. Relapsing MS: Relapsing forms of MS (RMS), including RMS and secondary progressive MS (SPMS). 3. Disability status at screening with an EDSS score of 0-4 (inclusive). 4. MS treatment history with up to three DMTs 5. Subjects transitioning from fingolimod or dimethyl fumarate administered as their final DMT for a period of at least 6 months prior to administration of the first study drug 6. Breakthrough disease activity occurred while the participant was appropriately using fingolimod or dimethyl fumarate prior to transition, as evidenced by one or more clinically reported relapses or one or more signs of activity on MRI (e.g., Gd+ enhancement, new or enlarging T2 lesions) 7. Neurologically stable within 1 month prior to administration of the first study drug.

[0186] 2.Treatment drugs, treatment groups, and treatment duration Ofatumumab is provided in an autoinjector (AI) containing 20 mg ofatumumab (50 mg / ml, 0.4 ml volume) for subcutaneous administration. Ofatumumab is a clear to milky white, colorless to pale yellow, essentially particle-free liquid.

[0187] This is an open-label treatment study with one treatment arm.

[0188] The planned treatment duration is 96 weeks.

[0189] 3. The transition period preferably includes 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 will be based on the investigator's clinical judgment.

[0190] During the washout period, subjects cannot receive any other DMT for the treatment of MS.

[0191] 4. Instructions for prescribing and taking the study treatment Study drug (ofatumumab injections) will be administered beginning at Visit 1. Drug will then be administered at scheduled visits throughout the treatment period. Beginning at Week 4, subcutaneous injections will be administered at 4-week intervals (+ / - 3 days).

[0192] To assess the tolerability of the initial dose of study medication, subjects were closely monitored for any reactions after administration, including those related to the injection.

[0193] At Visit 1, subjects will receive an sc injection at the site. The subject or caregiver will inject the study drug under the supervision of study staff.

[0194] After Visit 1, subjects may self-inject the study medication at home or have a caregiver trained in proper technique and safety precautions by study staff inject the experimental medication. Ability to self-inject must be demonstrated and documented before home administration is permitted. Injection 2 (Day 7) will be monitored remotely by personnel in a designated location to support self / home administration and provide additional training as needed. Subjects will return to the site for Week 2 and Week 4 administrations.

[0195] [Example 4] Clinical trial shows reduced thalamic volume loss and improvement in MSIS-29 background Ofatumumab demonstrated superior efficacy versus teriflunomide in the ASCLEPIOS I / II Phase 3 trial, 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) (p<0.001 in both studies) in the ASCLEPIOS I and II studies, respectively. Ofatumumab showed highly significant suppression of gadolinium (Gd)T1 lesions compared with Aubagio®, demonstrating robust suppression of de novo inflammatory activity. Ofatumumab demonstrated a 34.4% relative reduction in confirmed disability progression (CDP) at 3 months (p=0.002) and a 32.5% relative risk reduction at 6 months (p=0.012) compared to Aubagio® in a pre-specified pooled analysis.

[0196] Objectives and Methods In ASCLEPIOS I, patients were randomized (1:1) to receive either ofatumumab 20 mg sc injections every 4 weeks (followed by a 20 mg sc loading regimen on days 1, 7, and 14) or teriflunomide 14 mg orally once daily for up to 30 months. Patients were included if they were 18 to 55 years of age, had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at screening (according to Kurtzke, Neurology. 1983, Nov;33(11):1444-52), had experienced ≥1 relapse within the past year or ≥2 relapses in the past 2 years, or had a positive gadolinium-enhanced (Gd+) MRI scan during the year prior to randomization.

[0197] result (i) Thalamic volume loss Ofatumumab significantly reduced thalamic volume loss between month 24 and baseline compared with teriflunomide (mean percentage change -1.00 vs. -1.40, mean difference 0.40, p=0.002).

[0198] (ii) MSIS-29 Higher scores on the MSIS-29 indicate a greater impact of MS on daily life from the patient's perspective. Ofatumumab treatment reduced the impact of MS on patients' daily lives compared with teriflunomide. The mean change from baseline in MSIS-29 physical impact scores was significantly greater in the ofatumumab group than in the teriflunomide-treated group at all time points: 6 months (-2.75 vs. -0.44, mean difference -2.30, p=0.017), 12 months (-2.43 vs. 0.17, mean difference -2.59, p=0.009), 18 months (-2.37 vs. 0.67, mean difference -3.05, p=0.005), 24 months (-2.6 vs. 0.59, mean difference -3.19, p=0.008), and 30 months (-3.21 vs. 0.55, mean difference -3.76, p=0.026) (Tables 14.2–14.1).

[0199] Ofatumumab treatment was associated with a greater reduction in the impact of MS on patients' daily lives compared with the teriflunomide treatment group, as measured by the MSIS-29 psychological impact score, although the difference between the treatment groups reached statistical significance only at 12 months.

[0200] conclusion (i) Thalamic volume is an MRI-based marker associated with neurodegeneration that could accelerate the development of neuroprotective treatments. Using conventional techniques, thalamic volume is predicted to decline at a rate of -0.71% per year in MS subjects and -0.28% per year in healthy controls (see Azevedo 2018). Treatment with teriflunomide (-1.4% at 2 years) does not appear to have a beneficial effect on thalamic volume loss when compared with available conventional data. Conversely, switching to ofatumumab as a disease-modifying treatment shows promising results.

[0201] (ii) Analysis of the proportion of patients without clinical and MRI disease activity (i.e., patients with NEDA-4) and health-related MSIS-29 quality of life measures showed beneficial effects, supporting the demonstration of the robustness of the treatment effect of ofatumumab.

[0202] [Example 5] Sustained ofatumumab efficacy in relapsing MS patients transitioning from intravenous anti-CD20 therapy background: B-cell depletion in patients with relapsing multiple sclerosis (RMS) using anti-CD20 monoclonal antibodies (mAbs) reduces annualized relapse rates and inflammatory lesion activity on magnetic resonance imaging, and delays the time to documented worsening of disability. The anti-CD20 mAbs ocrelizumab and rituximab are administered intravenously in clinical settings. Ofatumumab is administered subcutaneously using a prefilled syringe or autoinjector (AI) pen to facilitate self-administration.

[0203] the purpose: A 12-month, prospective, single-arm, multicenter trial to confirm the sustained efficacy of ofatumumab in patients with RMS who had transitioned from intravenous anti-CD20 mAb therapy.

[0204] method:Approximately 100 adults with RMS were enrolled at 10-20 centers across the USA. Eligible patients had previously been treated with two to five consecutive courses of intravenous ocrelizumab or rituximab (other anti-CD20 mAbs were excluded), with the last dose administered 4-9 months prior to baseline. Other inclusion criteria were a Composite Disability 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 in the past 6 months (relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, clinical deterioration), or who discontinued anti-CD20 therapy due to severe infusion-related reactions or recurrent infections, or who had progressive disease, were excluded. All participants received ofatumumab 20 mg subcutaneously via an AI pen on days 1, 7, and 14, then monthly from months 1 through 12. The primary endpoint is stability or reduction in Gd+ lesion counts at month 12. Secondary endpoints include retention and change in participants' immune biomarkers, treatment satisfaction, safety, and tolerance at months 6 and 12. There is no 6-month interim analysis.

[0205] result: The trial complements the ofatumumab Phase 3 program in RMS by generating sustained efficacy, retention and satisfaction data based on monthly subcutaneous drug delivery with an AI pen in patients previously treated with ocrelizumab or rituximab.

[0206] Conclusion: The trial provides important data on the sustained efficacy of ofatumumab in patients with RMS who have transitioned from intravenous anti-CD20 therapy. The present invention includes the following aspects. <1> Ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis in patients who have been treated with a disease-modifying therapy other than ofatumumab. <2> the disease-modifying therapy lacks efficacy; <1> 2. Ofatumumab for the use described in <3> the patient develops breakthrough disease upon treatment with the disease-modifying therapy; <1> or <2> 2. Ofatumumab for the use described in <4> the breakthrough disease is evidenced by one or more clinically reported recurrences or one or more signs of activity on MRI; <3> 2. Ofatumumab for the use described in <5> the activity on MRI includes Gd+ enhancement and / or new or enlarging T2 lesions, <4> 2. Ofatumumab for the use described in <6> the patient lacks tolerance to the disease-modifying therapy; <1> from <5> ofatumumab for the use according to any of the preceding claims. <7> the patient has had at most one or two or three disease-modifying therapies; <1> from <6> ofatumumab for the use according to any of the preceding claims. <8> The disease-modifying therapy was administered for a period of at least 6 months prior to the first dose of ofatumumab. <1> from <7> ofatumumab for the use according to any of the preceding claims. <9> the patient is neurologically stable within one month prior to the first dose of ofatumumab; <1> from <8> ofatumumab for the use according to any of the preceding claims. <10> The patient has an EDSS score of 1 to 4 before the first administration of ofatumumab. <1> from <9> ofatumumab for the use according to any of the preceding claims. <11> the previous disease-modifying therapy was administered orally; <1> from <10> ofatumumab for the use according to any of the preceding claims. <12> the prior disease-modifying therapy drug is selected from teriflunomide, dimethyl fumarate, and fingolimod; <1> from <11> ofatumumab for the use according to any of the preceding claims. <13> the previous disease-modifying therapy is fingolimod; <11> or <12> 2. Ofatumumab for the use described in <14> Fingolimod was administered at a daily dose of 0.5 mg. <13> 2. Ofatumumab for the use described in <15> the prior disease-modifying therapy drug is selected from natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab, and glatiramer acetate; <1> from <10> ofatumumab for the use according to any of the preceding claims. <16> the previous disease-modifying therapy is selected from intravenous anti-CD20 therapy; <1> from <10> and <15> ofatumumab for the use according to any of the preceding claims. <17> administered to patients who have a suboptimal response to anti-CD20 therapy, preferably to patients who have had a suboptimal response in the past 6 months; <16> 2. Ofatumumab for the use described in <18> Administered to patients with adverse events to anti-CD20 therapy, particularly infusion-related reactions or recurrent infections, <16> or <17> 2. Ofatumumab for the use described in <19> Patients had been previously treated with at least two consecutive courses of intravenous ocrelizumab or rituximab, <16> from <18> ofatumumab for the use according to any of the preceding claims. <20> The last dose was administered 4 to 9 months before ofatumumab administration. <16> from <19> ofatumumab for the use according to any of the preceding claims. <21> Administered after relapse, <1> from <20> ofatumumab for the use according to any of the preceding claims. <22> administered after detection of at least one Gd+ lesion, <1> from <21> ofatumumab for the use according to any of the preceding claims. <23> Administered after detection of new or enlarging T2 lesions, <1> from <22> ofatumumab for the use according to any of the preceding claims. <24> the prior disease-modifying therapy is discontinued prior to initiation of administration of ofatumumab; <1> from <23> ofatumumab for the use according to any of the preceding claims. <25> discontinuation of said previous disease-modifying therapy results in rebound; <24> 2. Ofatumumab for the use described in <26> ofatumumab administration is initiated in said patient before the half-life of the drug used in said previous disease-modifying therapy. <1> from <25> ofatumumab for the use according to any of the preceding claims. <27> ofatumumab administration will begin after a washout period of 1 day to 3 weeks. <1> from <26> ofatumumab for the use according to any of the preceding claims. <28> ofatumumab administration will be initiated without a washout period, <1> from <26> ofatumumab for the use according to any of the preceding claims. <29> If the previous disease-modifying treatment did not sufficiently reduce thalamic volume loss, then ofatumumab is administered. <1> from <28> ofatumumab for the use according to any of the preceding claims. <30> 1. Ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab reduces thalamic volume loss, preferably by less than 0.65% per year. <31> If a sufficient reduction in MSIS-29 score has not been achieved with the previous disease-modifying therapy, then ofatumumab is administered. <1> from <30> ofatumumab for the use according to any of the preceding claims. <32> the MSIS-29 score decreased by less than 2.5 with the previous disease-modifying treatment; <31> 2. Ofatumumab for the use described in <33> It is administered at a dose of 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks. <1> from <32> ofatumumab for the use according to any of the preceding claims. <34> Administered subcutaneously, <1> from <33> ofatumumab for the use according to any of the preceding claims. <35> Administered in a loading dose, <1> from <34> ofatumumab for the use according to any of the preceding claims. <36> 20 mg ofatumumab will be administered as a loading dose at weeks 0, 1, and 2. <35> 2. Ofatumumab for the use described in <37> Administered without a loading dose, <1> from <34> ofatumumab for the use according to any of the preceding claims. <38> The relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome. <1> from <37> ofatumumab for the use according to any of the preceding claims. <39> a pre-medication is administered to the patient before the first dose of ofatumumab is administered; <1> from <38> ofatumumab for the use according to any of the preceding claims. <40> the pre-administration comprises acetaminophen, an antihistamine, and / or a steroid; <39> 2. Ofatumumab for the use described in <41> The premedication is administered 30 to 60 minutes before the ofatumumab injection. <39> or <40> 2. Ofatumumab for the use described in <42> No prior medication is administered before the first dose of ofatumumab, <1> from <38> ofatumumab for the use according to any of the preceding claims. <43> Avoidance of rebound or recurrent disease activity, <1> from <42> ofatumumab for the use according to any of the preceding claims. <44> Lack of efficacy is defined as failure to halt or adequately slow disease progression. <2> 2. Ofatumumab for the use described in <45> 1. A method for treating or preventing relapsing multiple sclerosis, comprising administering ofatumumab to a patient suffering from relapsing multiple sclerosis, wherein the patient has received a disease-modifying therapy other than ofatumumab. <46> 1. Ofatumumab for the production of a medicament for use in the treatment or prevention of relapsing multiple sclerosis, wherein said medicament has been used in a patient who has been treated with a disease-modifying therapy other than ofatumumab.

Claims

1. A pharmaceutical composition comprising ofatumumab for the treatment of relapsing multiple sclerosis, wherein the ofatumumab is used in patients who have been treated with a disease-modifying therapy other than ofatumumab, the disease-modifying therapy being discontinued prior to initiation of administration of ofatumumab, and the disease-modifying therapy being selected from dimethyl fumarate, fingolimod, natalizumab, and glatiramer acetate.

2. 10. The pharmaceutical composition of claim 1, wherein the disease-modifying therapy lacks efficacy.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient develops breakthrough disease upon treatment with the disease-modifying therapy.

4. 4. The pharmaceutical composition of claim 3, wherein the breakthrough disease is evidenced by one or more clinically reported recurrences or one or more signs of activity on MRI.

5. 5. The pharmaceutical composition of claim 4, wherein the activity on MRI comprises Gd+ enhancement and / or new or enlarging T2 lesions.

6. 6. The pharmaceutical composition of claim 1, wherein the patient lacks resistance to the disease-modifying therapy.

7. 7. The pharmaceutical composition of claim 1, wherein the patient has a history of at most one or two or three disease-modifying therapies.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the disease-modifying therapy was administered for a period of at least 6 months prior to the first administration of ofatumumab.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is neurologically stable within one month prior to the first dose of ofatumumab.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the patient has an EDSS score of 1 to 4 before the first administration of ofatumumab.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the previous disease-modifying therapy is administered orally.

12. (a) the previous disease-modifying therapy was fingolimod; 12. The pharmaceutical composition of claim 1, wherein (b) the previous disease-modifying therapy drug is dimethyl fumarate.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the previous disease-modifying therapy drug was fingolimod, and the fingolimod was administered at a daily dose of 0.5 mg.

14. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the prior disease-modifying therapy drug is selected from natalizumab and glatiramer acetate.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein ofatumumab is administered after relapse.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein ofatumumab is administered after detection of at least one Gd+ lesion.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein ofatumumab is administered after detection of new or enlarging T2 lesions.

18. 18. The pharmaceutical composition of claim 17, wherein discontinuation of a previous disease-modifying therapy results in rebound.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein ofatumumab administration is initiated in the patient before the half-life of the drug used in the previous disease-modifying therapy.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein ofatumumab administration is initiated after a washout period of 1 day to 3 weeks.

21. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein ofatumumab administration is initiated without a washout period.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein ofatumumab is administered when previous disease-modifying treatment has not sufficiently reduced thalamic volume loss.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, wherein ofatumumab is administered when a reduction in MSIS-29 score has not been sufficiently achieved by a previous disease-modifying treatment.

24. 24. The pharmaceutical composition of claim 23, wherein the MSIS-29 score has been reduced by less than 2.5 with a previous disease-modifying treatment.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein ofatumumab is administered subcutaneously.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein ofatumumab is administered as a loading dose.

28. 28. The pharmaceutical composition of claim 27, wherein 20 mg ofatumumab is administered as a loading dose at weeks 0, 1 and 2.

29. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein ofatumumab is administered without a loading dose.

30. 30. The pharmaceutical composition of any one of claims 1 to 29, wherein the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome.

31. 31. The pharmaceutical composition of any one of claims 1 to 30, wherein a pre-medication is administered to the patient before the first dose of ofatumumab is administered.

32. 32. The pharmaceutical composition of claim 31, wherein the pre-administration comprises acetaminophen, an antihistamine, and / or a steroid.

33. 33. The pharmaceutical composition of claim 31 or 32, wherein the pre-administration is administered 30 to 60 minutes before injection ofatumumab.

34. 31. The pharmaceutical composition of any one of claims 1 to 30, wherein no prior administration is administered prior to the first dose of ofatumumab.

35. 35. The pharmaceutical composition of any one of claims 1 to 34, wherein rebound or recurrent disease activity is avoided.

36. 3. The pharmaceutical composition of claim 2, wherein the lack of efficacy is defined as failure to stop or adequately slow disease progression.

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