Treatment of rms by switching therapy

Abstract

To provide a means for responding to relapse and rebound after stopping DMT (e.g., natalizumab or fingolimod) in the treatment of relapsing multiple sclerosis.SOLUTION: Provided is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein the ofatumumab is used in patients treated with a disease-modifying therapy other than ofatumumab.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an anti-CD20 monoclonal antibody for use in the treatment or prevention of relapsing multiple sclerosis. Clonal antibody ofatumumab, and treated with disease-modifying therapy other than ofatumumab Regarding ofatumumab used in patients. [Background technology]

[0002] Multiple sclerosis (MS) is characterized by inflammation, demyelination, and axonal / neuronal destruction, ultimately leading to It is a chronic immune-mediated disease of the central nervous system that causes severe damage to the nervous system. There is no cure for the disease. However, 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 acetic acid and acetic acid. Glatiramer acetate, ocrelizumab, cladribine, fingolimod, natalizumab, teri Flunomide, mitoxantrone, or dimethyl fumarate (DMF).

[0004] These DMTs usually significantly reduce relapse rates and MRI disease activity, thus reducing disability. While delaying the onset of steroid use, (severe) adverse events are common with each of these DMTs. For example, natalizumab may reduce the risk of fatal opportunistic infections (i.e., progressive multifocal white matter infections). Fingolimod may increase the risk of S1P-related encephalopathy or PML. Potential safety risks, such as bradyarrhythmia, macular edema, hypertension, and liver toxicity at the time of treatment initiation This may be accompanied by increased transaminase.

[0005] Given that existing drugs for the treatment of MS carry risks, there are many potential solutions to reduce these risks. There remains a need to identify ways to prevent, minimize, or overcome these problems. discontinues a previous therapy, for example, if a patient discontinues a previous disease-modifying therapy (DMT), e.g. These and other risks that may arise when transitioning from fingolimod or DMF to another DMT There remains a need to address this risk.

[0006] This is because treatment for multiple sclerosis (MS) can take decades. This often requires changes to the treatment plan to adapt to changing circumstances. By switching drugs or discontinuing immunomodulators all together, patients In some cases, the patient may be left vulnerable to relapse or progression of the disease. After withdrawal, severe MS disease activity is noted clinically and on MRI. If the pattern is disproportionate to the pattern observed before treatment began, the patient is said to have experienced a rebound. I can say it.

[0007] Pregnancy planning is a common reason for discontinuing DMT. DMT has been shown to cause birth defects in animal studies. There is a consistent association and it is recommended that fingolimod be stopped before conception.

[0008] Some approved MS medications may cause rebound, i.e., a patient's pre-baseline DMT levels. Relapse is associated with severe disease reactivation after withdrawal from DMT, exceeding the normal range. This issue has been discussed for natalizumab and fingolimod (Barry B. et al.: Fingolimod Rebound: A Review of the Clinical Experience and Management Consideration Neurol Ther (2019) 8:241-250). Therefore, DMTs, such as natalizumab or reduces, minimizes, or overcomes the risk of rebound after discontinuation of fingolimod. It is necessary to

[0009] Additionally, patients who showed breakthrough disease during treatment with DMTs such as fingolimod Rebound has been reported in patients with breakthrough disease, making treatment of these patients difficult. Treatment strategies need to be improved.

[0010] Therefore, the problem underlying the present invention is to provide improved treatment for MS patients in need of treatment optimization. For example, MS is relapsing-remitting MS (RRMS), The treatment to be optimized is DMT. The reasons for treatment optimization are adverse effects, treatment failure, , breakthrough disease, disease progression, comorbidities, life cycle events, e.g., pregnancy and This may include lactation, and / or evolving patient preferences.

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

[0012] Reasons for treatment discontinuation or change included adverse effects, treatment failure, disease progression, comorbidities, Life cycle events, e.g., pregnancy and lactation, and evolving patient preferences are included. Fulminant MS rebound events, similar to immune reconstitution inflammatory syndrome (IRIS), are considered to be a major cause of MS treatment. have been reported with withdrawal from treatment, putting patients at risk for reactivation of serious disease. It is important for clinicians to recognize this situation.

[0013] Therefore, if treatment is interrupted or changed, the likelihood of this happening is reduced or eliminated. needs to be minimized.

[0014] Confidence in successful transitions between DMTs, despite the existing needs exemplified above There are no evidence-based recommendations that can be made. When switching from a drug with a specific immune system effect, consider the risk of additional immune system effects and consider the risk of rebound or must be balanced against the risk of recurrent disease activity.

[0015] In the art, B cell depletion using rituximab or ocrelizumab is considered to be a promising treatment for DMT arrest. It has been suggested as a treatment strategy to address relapse and rebound after rituximab. Mab has been suggested as a treatment strategy to address rebound after discontinuation of fingolimod. However, in a series published by Hatcher et al., rituximab infusion One case was characterized by clinical deterioration 1 day after the initial administration (Hatcher et al., Rebound syndrome). ndrome in patients with multiple sclerosis after cessation of fingolimod treatme nt, JAMA Neurol. 2016;73(7):790-4.) The other two cases were treated with steroids and rituximab. Despite treatment with mab, the lesions were characterized by persistent Gd-enhancing activity.

[0016] In separate reports, two patients with rebound disease after stopping fingolimod were Clinical deterioration and new Gd-enhancing MRI lesions 1 week after starting ocrelizumab It was pointed out that (Schmidt S, Schulten T., Severe rebound after cessation of fingol imod treated with ocrelizumab with coincidental transient aggravation: report of Two cases. Ther Adv Neurol Disord. 2019;12:1-6.) The two patients were treated with fingolimod. Despite immune reconstitution more than 3 months after withdrawal from ocrelizumab One of these patients subsequently showed significant progression in the Expanded Disability Status Scale (EDSS). This is shown in Figure 1.

[0017] Both patients with highly active RRMS experienced breakthroughs during fingolimod treatment disease, requiring treatment optimization, followed by severe rebound after fingolimod cessation In both patients, rebound symptoms were observed with fingolimod. Rebound occurred as early as 4-6 weeks after discontinuation of treatment. This could be explained by the release of T17 T cells trapped in lymphoid organs. , Schmidt and Schulten suggested. Pharmacodynamic data suggest that After a few days, lymphocyte counts began to recover rapidly. It depletes B cells and mature and memory B cells, thus inhibiting the regulatory pathways mediated by B cells. For example, B cells inhibit the differentiation of pathogenic Th1 and Th17 cells. A recently discovered compound that produces regulatory IL-10, which has important implications during autoimmune attacks. Regulatory B cells secrete the cytokine IL-35, 14, 15. Regulatory B cells also secrete TGF-β. Considering the regulatory function of certain B cell subsets, Removal of these B cells from the peripheral immune system, even weeks after cessation, was associated with a significant reduction in both patients. It seems reasonable to consider that this could be a cause of secondary deterioration.

[0018] Thus, considering the prior art, B cell depletion is associated with DMTs (e.g., natalizumab or fulvoxamine). has emerged as a promising means of managing relapse and rebound after discontinuation of cefotaxime (cefotaxime). There was nothing to do. Summary of the Invention

[0019] Despite this teaching in the prior art, the present invention surprisingly provides another B cell depletion agent. administration effectively reduces the risk of disease reactivation, recurrence and rebound and provide treatment strategies.

[0020] In particular, B cell depletion with ofatumumab is associated with a decline in the number of DMTs (e.g., natalizumab or finasteride). Potent and effective for addressing severe relapse and rebound after cessation of steroids (Golimod) It has been found quite surprisingly that this treatment strategy provides a therapeutic strategy for the treatment of rheumatoid arthritis. The method is most effective if initiated within 0-6 months.

[0021] As mentioned above, the risk of relapse after discontinuation of DMTs such as natalizumab or fingolimod is low. The risk of bounce needs to be reduced, minimized or overcome. This need is particularly met by the present invention.

[0022] Although natalizumab and fingolimod have distinct modes of action, The "anti-trafficking" strategy shared by both Fingolimod and IL-16 is to block lymphocyte Reduce CNS entry and why discontinuing these drugs can result in a rebound phenomenon Although further research is needed, fingolimod is a simple It has a more complex mechanism of action than simple anti-trafficking function, possibly involving adverse interactions within the immune system. It prevents harmful processes while increasing beneficial processes. For example, peripheral blood CD4+ cells In small-scale analyses of intracellular messenger RNA expression, e.g., fingolimod treatment Treatment was associated with changes in the transcription levels of 890 different genes. secrete cytokines, Toll receptors, which may be involved in T cell function to suppress inflammation and autoimmunity. Remarkably, ofatumumab affects the expression of IL-1-like receptors and cell adhesion molecules. It has been found to reduce the rebound phenomenon, but it has been thought to cause rebound. It does not appear to directly affect the process.

[0023] Unexpectedly, ofatumumab was not associated with fingolimod or another D There is a risk of rebound in patients with breakthrough disease activity while treated with MT. It has the ability to reduce

[0024] Without being bound by theory, ofatumumab acts by upregulating signals (e.g., by B cells) Preserving the regulatory T cells or B cells themselves, possibly preserving the regulatory T cells or B cells (subsets) themselves It is believed that even the body is preserved. This is based on Theil et al., 2019, Imaging Mass Cytomegalovirus (IMC). etry and Single-Cell Genomics Reveal Differential Depletion and Repletion of BC ell Populations Following Ofatumumab Treatment in Cynomolgus Monkeys. Frontiers in Immunology (2019), Volume 10: 1-11. Therefore, DMT treatment Treatment, e.g., administration of ofatumumab after cessation of fingolimod treatment, may result in secondary deterioration (e.g., For example, it is thought that a significant reduction in the risk of rebound after breakthrough disease activity That's reasonable.

[0025] Taken together, rebound after DMT discontinuation (e.g., fingolimod discontinuation) is associated with another DMT. T, for example, may be exacerbated by initiation of treatment with ocrelizumab. and there are potential pitfalls and undesirable consequences of continuous application of immunosuppressive drugs. In particular, ocrelizumab may complicate rebound recovery after stopping fingolimod. Therefore, it is not possible to say that ofatumumab does not cause these complications or that It was quite surprising that the risk was at least significantly reduced.

[0026] Experimental withdrawal from fingolimod leads to lymphoid overexpression of S1P1 receptors, This resulted in increased lymphocyte exit from lymph nodes and increased severity of recurrent symptoms. Withdrawal from steroids also likely results in NF-κB activation and the production of inflammatory cytokines and monophosphates. Astrocyte overexpression of S1P1 and downstream nitric oxide release mediated Overexpression of S1P and / or its receptors can also lead to inflammatory responses. ofatumumab may play a role in the pathogenesis of cross-sectional disease, Suitable for the treatment of recurrent diseases and recurrent syndromes, e.g. those resulting from rebound phenomena It is reasonable to consider this to be the case.

[0027] Furthermore, B-cell depletion with ofatumumab has been shown to improve DM in pregnant or pre-pregnant women. It is quite surprising that we can provide an effective strategy to avoid the unwanted risks of T therapy. This is a very important thing.

[0028] The subject of the present invention is therefore a compound of formula (I) for use in the treatment or prevention of relapsing multiple sclerosis. ofatumumab for rheumatoid arthritis and previously treated with a disease-modifying therapy (DMT) other than ofatumumab The DMT is defined as follows: All preferred embodiments shown 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. the administration of ofatumumab to a patient suffering from relapsing multiple sclerosis, The patient has received disease-modifying therapy other than ofatumumab. All preferred embodiments mentioned also apply to the method of the present invention.

[0030] A further subject of the present invention is a compound for use in the treatment or prevention of relapsing multiple sclerosis. ofatumumab for producing a medicament, wherein the medicament comprises a disease-modifying agent other than ofatumumab. The following are examples of the use of rituximab in patients treated with chemotherapy: All preferred embodiments mentioned above also apply to this subject matter of the invention.

[0031] In a preferred embodiment, the disease-modifying therapy other than ofatumumab is a previous DMT. In a preferred embodiment, patients are switched from a previous DMT to ofatumumab. In other words, the present invention provides a method for treating or preventing relapsing multiple sclerosis. ofatumumab for use in patients transitioning from disease-modifying therapy Regarding atumumab.

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

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

[0034] In a preferred embodiment of the invention, ofatumumab administration is Therapeutic half-lives of drugs used in non-disease-modifying therapies are initiated before the half-life of the drug is reached.

[0035] In a preferred embodiment of the invention, ofatumumab therapy is administered after a prior DMT (e.g., acetate Glatiramer, ocrelizumab, cladribine, fingolimod, natalizumab, terif This should be started immediately after discontinuation of the other medications (e.g., lunomide, mitoxantrone, or dimethyl fumarate). In this context, immediately means within a week, preferably within 3 days, more preferably within 2 days, more preferably within 3 days. For the first time in about 1 day, most preferably the previous DMT (e.g., glatiramer acetate, ocrelizumab) b, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone or dimethyl fumarate) within 12 hours after discontinuation.

[0036] In another embodiment of the invention, ofatumumab therapy may be administered after a prior DMT (e.g., guanidinium acetate). Tiramar, ocrelizumab, cladribine, fingolimod, natalizumab, terifluno It is started before discontinuation of the previous The DMT may be continued until the ofatumumab loading dose regimen is administered. The dosing regimen consisted of 20 mg off-day on days 1, 7, and 14 of the dosing regimen. Alternatively, the loading dose regimen may include subcutaneous (sc) injection of atumumab. 20 mg ofatumumab sc on days 0, 7, and 14 of the treatment regimen It may involve injection.

[0037] ofatumumab therapy and previous DMTs (e.g., glatiramer acetate, ocrelizumab) , cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or or dimethyl fumarate) may proceed in parallel. That is, ofatumumab administration may be For example, the therapy may be administered for 1 day, 3 days, or both in parallel. It may proceed for 1, 1, 2 weeks or 1 month.

[0038] In one embodiment of the present invention, ofatumumab therapy is administered in combination with a disease-modifying therapy other than ofatumumab. It is initiated when the previous DMT (e.g., the previous DMT) is no longer effective. The drug used in the treatment can be washed out. Preferably, the drug is DMD. Therefore, ofatumumab therapy is a promising treatment option for patients with previous DMTs (e.g., DMD) who have not yet received the treatment. 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 administered for 25% of its half-life, preferably 25% of its half-life, until the final dose is administered. At most 50%, more preferably 75%, even more preferably 85%, and most preferably 95% If % has elapsed, the first DMT drug is considered to have washed out.

[0039] In an alternative embodiment, 30% of the amount administered as the final dose of the first DMT drug, preferably Preferably 20%, more preferably 10%, even more preferably 5%, most preferably 2% If only 0.5% or less was detectable in a sample (e.g., blood or serum) from a patient, the first The DMT drug is considered to have been washed out. The amount is C max , i.e., the final dose of the first DMT drug before discontinuation of the first DMT The maximum (or peak) serum concentration that the first DMT drug achieves in serum after administration can be replaced with

[0040] In one embodiment of the present invention, ofatumumab therapy is administered after a prior disease-modifying therapy (e.g., finasteride). Within 0 to 6 months, more preferably within 1 to 5 months, and even more preferably within 1 to 6 months after discontinuing It is usually started within 2 to 4 months, and even more preferably within the 3rd month. More specifically, Ofatumumab therapy should be initiated 4 to 16 weeks after discontinuing a previous DMT, e.g., fingolimod. more preferably between 5 and 15 weeks, more preferably between 6 and 14 weeks, Between 7 and 13 weeks, more preferably between 8 and 12 weeks, more preferably between 9 and 11 weeks, Preferably, ofatumumab therapy can be initiated between about 10 weeks. More than 10 weeks, preferably more than 9 weeks, after stopping the previous DMT, e.g., fingolimod , more preferably before 8 weeks, more preferably before 7 weeks, more preferably before 6 weeks, More preferably, it can be started before 5 weeks, more preferably before 4 weeks.

[0041] Instead, ofatumumab therapy is preferred for 3 to 18 weeks after stopping the previous DMT. or 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 Between 12 weeks, more preferably between 10 and 11 weeks, and more preferably at about 10.5 weeks. do.

[0042] In a preferred embodiment of the invention, ofatumumab administration begins without a washout period. It will begin.

[0043] In a preferred embodiment of the invention, the patient is at least 18 years of age and has not received any disease-modifying therapy other than ofatumumab. More preferably, 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 or had been on treatment for at least 11 months, more preferably at least 12 months. is a DMT other than ofatumumab, for example, for up to 10 years, for up to 8 years, or for up to 6 years. They had been treated for up to 4 years or up to 2 years.

[0044] In a particularly preferred embodiment, the use of ofatumumab according to the present invention prevents rebound Rebound is defined as follows: Rebound is a condition that is caused by other disease modifiers. 0-6 months, or 1-5 months, or 2 months after stopping oral therapy (e.g., fingolimod) It may appear within 1-4 months, and even more preferably within the 3rd month. The drug should be administered for 4 to 16 weeks after stopping other disease-modifying therapies (e.g., fingolimod) and between 5 and 15 weeks, or between 6 and 14 weeks, or between 7 and 13 weeks, or between 8 and 12 weeks The rebound effect may occur between 1 week and 9 weeks, or between 9 and 11 weeks, or around 10 weeks. Between 3 and 18 weeks after stopping other or previous disease-modifying therapies (e.g., fingolimod) , or between 4 and 17 weeks, or between 5 and 16 weeks, or between 6 and 15 weeks, or between 7 and 1 Between 4 weeks, between 8 and 13 weeks, between 9 and 12 weeks, or between 10 and 11 weeks. More preferably, it may appear between about 10.5 weeks.

[0045] In a preferred embodiment of the invention, disease-modifying therapies other than ofatumumab lack efficacy. The lack of efficacy may be due, for example, to the fact that patients who have received disease-modifying therapies (DMTs) Signs of disease activity, such as recurrence or lesions, are present. This can be defined as progression not stopping or not slowing down appropriately. The disclosure covers the use of ofatumumab to treat non-responders to prior DMTs. do.

[0046] In a preferred embodiment, ofatumumab is used in combination with DMT therapy, e.g., anti-CD20 therapy. In a preferred embodiment, the compound is administered to a patient with a suboptimal response to the compound. occurred within the past 6 months. In a preferred embodiment, a suboptimal response is defined as a relapse, ≥2 activity Dynamic gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions and / or clinical It can be characterized by subclinical deterioration.

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

[0048] In a preferred embodiment of the invention, ofatumumab is used in the detection of new or enlarging T2 lesions. The term T2 lesion is described below.

[0049] In one embodiment of the present invention, the patient may be treated with other disease-modifying therapies, e.g., Breakthrough disease has developed from prior treatment with a DMT. In this case, rebound or recurrent disease activity is avoided.

[0050] Generally, breakthrough disease is defined as one or more clinically reported recurrences or Evidenced by one or more signs of activity on MRI, where the activity on MRI is Gd+-enhancing and / or new or enlarging T2 lesions. The definition of Lew's disease is used as a reference.

[0051] Breakthrough disease is defined as 0% or more of the disease-modifying therapy before stopping other disease-modifying therapies (e.g., fingolimod). Within 6 months, or within 1 to 5 months, or within 2 to 4 months, and even more preferably Breakthrough disease may occur within three months. More specifically, breakthrough disease may occur after treatment with other disease-modifying therapies ( Between 4 and 16 weeks, or between 5 and 15 weeks, before stopping a drug (e.g., fingolimod), or Between 6 and 14 weeks, or between 7 and 13 weeks, or between 8 and 12 weeks, or between 9 and 11 weeks Alternatively, breakthrough disease may occur within 10 weeks of treatment with other disease-modifying therapies. Between 3 and 18 weeks or between 4 and 17 weeks before stopping steroids (e.g., fingolimod), and between 5 and 16 weeks, or between 6 and 15 weeks, or between 7 and 14 weeks, or between 8 and 13 weeks Between 9 and 12 weeks, or between 10 and 11 weeks, and more preferably at about 10.5 weeks. It is possible.

[0052] In an alternative preferred embodiment of the present invention, the patient is evaluated for resistance to other or previous disease-modifying therapies. Therefore, in a preferred embodiment, ofatumumab is It is administered to patients who have discontinued a previous DMT.

[0053] Preferably, the lack of tolerance is due to adverse events, such as headache, dizziness, nausea, infections (e.g., zostaphylococcus aureus ... - herpes, etc.), macular edema, infusion-related reactions, or the presence of recurrent infections.

[0054] In one embodiment of the present invention, the patient is receiving one, two, or three other diseases other than ofatumumab. Has a history of modifying therapy.

[0055] The term "two or three disease-modifying therapies" refers to two or three different drugs, preferably More specifically,

[0056] In a preferred embodiment of the invention, the patient has received at least one dose of ofatumumab for at least one month prior to the first administration of ofatumumab. The term "neurologically stable" is defined below. are.

[0057] In a preferred embodiment of the invention, ofatumumab is administered after relapse, which relapse is It may also be called an "acute relapse." The term relapse is defined below.

[0058] Furthermore, thalamic volume can serve as a marker associated with neurodegeneration. reported that thalamic atrophy is present early in the disease and may be involved in several aspects of MS pathology, including gray matter damage. It was reported that the condition reflects the state of mind and correlates well with physical and cognitive impairment. , thalamic volume has been proposed as a potentially interesting MRI metric related to neurodegenerative features of MS. Azevedo et al. reported that thalamic volume was significantly higher in MS subjects compared to healthy controls (HC). found significantly faster decline in MS patients, with predicted decline at 1 year The mean age was -0.71% (95% confidence interval [CI] = -0.77% to -0.64%) per 1000 people. In HC, the rate was −0.28% (95% CI = −0.58% to 0.02%) per year ( p=0.007 for the difference). The rate of decline was significant across MS disease duration and for MS clinical subtypes. The results were consistent across the types. “Resonance Imaging Marker of Neurodegeneration throughout Disease”, Ann Neurol. 2018 February; 83(2): 223-234. See doi:10.1002 / ana.25150.

[0059] The present invention predicts that administration of ofatumumab will result in a beneficial reduction in thalamic volume loss. This turned out to be unexpected, as seen in the Experimental section below.

[0060] Thus, in a preferred embodiment of the present invention, the loss of thalamic volume is associated with a prior disease-modifying treatment. If the reduction in serotonin levels is not sufficient, ofatumumab will be administered. In comparison, a loss of thalamic volume of less than 30%, less than 25%, or less than 20% In this regard, the untreated baseline loss was 1 This can be thought of as 0.71% per year.

[0061] For example, if the administration of previous disease-modifying treatments reduced thalamic volume loss by less than 0.70% or If the tax rate is not reduced by less than 0.65% per year or 0.60% per year, Alternatively, if the administration of a previous disease-modifying therapy has reduced thalamic volume, then fatumumab may be administered. Reduce losses by less than 1.40%, 1.3%, or 1.2% within 24 months. If not, ofatumumab can be administered.

[0062] In this regard, a further subject of the present invention is a compound useful in the treatment or prevention of relapsing multiple sclerosis. ofatumumab for use in treating thalamic volume loss, preferably Less than 0.70% per annum, or less than 0.65% per annum, or less than 0.6% per annum For example, the loss is reduced by 0.30% to 0.70% per year or or 0.45% to 0.60% per annum. Alternatively, the present invention provides a compound for use in the treatment or prevention of relapsing multiple sclerosis. ofatumumab for thalamic resection reduced thalamic volume loss by 1.4% within 24 months For example, the loss is reduced by less than 0%, 1.3%, or 1.2% over a 24-month period. Within 0.6% to 1.40%, 0.8% to 1.3%, or 0.9% to 1.2% It can be done.

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

[0064] In the present invention, the administration of ofatumumab is performed in accordance with the MS impact schedule as defined below. It was unexpectedly found that this resulted in a beneficial reduction of the steroid hormone MSIS-29. This is based on the previous article.

[0065] Therefore, in a preferred embodiment of the present invention, MSIS-2 under previous disease-modifying therapy If a sufficient reduction in the 9-point score is not achieved, ofatumumab will be administered. A decrease in the -29 score of less than 2.5, less than 2.0, or less than 1.5 is not considered a sufficient decrease. It is impossible to think that this has happened.

[0066] For example, administration of a previous disease-modifying treatment may result in an MSIS-29 score of 1.5 or higher within 24 months. or administer ofatumumab if a 2.0 or 2.5 reduction is not achieved can be done.

[0067] In this regard, a further subject of the present invention is a compound useful in the treatment or prevention of relapsing multiple sclerosis. ofatumumab for use, and ofatumumab reduced MSIS-29 scores Preferably, ofatumumab will improve MSIS-29 score by at least 1 within 24 months. 0.5, more preferably at least 2.0, and even more preferably at least 2.5 The reduction may be up to 3.0 or 3.5 or 4.0.

[0068] In a preferred embodiment of the invention, the patient has EDSS symptoms prior to the first administration of ofatumumab. It has cores 1 to 4. EDSS stands for Expanded Disability Status Scale and is defined as follows:

[0069] In a preferred embodiment, ofatumumab is administered without regard to weight, sex, age, race, or baseline It can be administered regardless of the patient's B cell count. For example, Preferably, women receive the same dose as a 50 year old man weighing 90 kg. Weight, sex, age, race, or baseline B-cell count were not associated with ofatumumab drug It has no clinically significant effect on pharmacokinetics.

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

[0071] Generally, the term DMT is known in the art and is defined below. Regarding clarity, examples of suitable DMTs are treatment with the following drugs: teriflunomide, leflunomide, Nomid, dimethyl fumarate, fingolimod, natalizumab, rituximab, ocreliz mab, alemtuzumab, daclizumab, glatiramer acetate and la Kinimodo.

[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, and dimethicone fumarate. These are fluoxetine and fingolimod.

[0073] In certain preferred embodiments of the invention, the disease modifying therapy other than ofatumumab is fingolimod. Preferably, fingolimod is administered at a dose of 0.5 mg once daily. In an alternative embodiment, fingolimod is administered in a daily dose of 0.1 mg to 2.5 mg, e.g., 0.25 mg. It is administered in doses.

[0074] In certain preferred embodiments of the invention, the disease modifying therapy other than ofatumumab is fumaric acid Dimethyl methacrylate (DMF) is preferably used in an amount of 120 mg to 480 mg, particularly 480 mg. It is administered at a daily dose of mg.

[0075] In certain preferred embodiments of the invention, the disease modifying therapy other than ofatumumab is laquinimo. Preferably, laquinimod is administered at a daily dose of 0.2 to 1.0 mg, preferably 0.6 mg. It is administered in doses.

[0076] In certain preferred embodiments of the invention, the disease modifying therapy other than ofatumumab is Teriful. Preferably, teriflunomide is administered at a dose of 6 to 18 mg, preferably 14 mg, per day. It is administered in doses.

[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, and 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 at a dose of 100 to 500 mg, preferably 300 mg, every 4 weeks. It is administered intravenously in a dose of 100 mg.

[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 to 250 mg, preferably 150 mg, once a month. It is administered at a dose of .c.

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

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

[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, especially intravenously. It is administered.

[0083] Preferably, the patient receives at least two of intravenous ocrelizumab or rituximab, e.g. For example, patients have been previously treated with 2 to 5 consecutive courses of ofatumumab. It may be administered, for example, 4 to 9 months before the patient is given the drug.

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

[0085] In a preferred embodiment, ofatumumab is administered to patients with ≥ 18 years of age who have not previously received anti-CD20 therapy in the past 6 months. Patients with a suboptimal response (e.g., relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, clinical deterioration) and / or intense i.v. Patients who discontinued anti-CD20 therapy due to adverse events such as related reactions or recurrent infections is administered.

[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. will be done.

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

[0088] In a preferred embodiment of the 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: It is administered at weeks 0, 1, and 2 after initiating ofatumumab therapy. This means that the first loading dose at week 0 constitutes the start of therapy. In embodiments, the three loading doses are administered on days 1, 5, and 6 after initiating ofatumumab therapy. Administered on days 1-9, preferably day 7, and days 12-16, preferably day 14 This means that the first loading dose on day 1 constitutes the start of therapy.

[0089] In a preferred embodiment of the present invention, the loading dose is 10 to 30 mg, preferably 20 mg. It is fatumumab.

[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, wait until the next scheduled dose. Subsequent doses should be administered as soon as possible, preferably without delay. should be administered at intervals.

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

[0093] In a preferred embodiment of the invention, the pre-administration is performed after the first dose of ofatumumab is administered. Preferably, the pre-administration includes acetaminophen, an antihistamine, and and / or steroids. Methylprednisolone may be the preferred steroid. 100 mg iv may be a preferred dose. Preferably, premedication is with ofatumumab injection. It is administered 30 to 60 minutes before the shot.

[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 to Multiple sclerosis, including isolated syndromes, relapsing-remitting disease, and active secondary progressive disease It is administered for the treatment of relapsing forms of multiple sclerosis (MS).

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

[0097] In an alternative embodiment of the invention, the patient to be treated meets one or more of the following criteria: Does not satisfy: - No active disease and diagnosed with primary progressive multiple sclerosis or secondary progressive multiple sclerosis It has been Meets criteria for neuromyelitis optica Breastfeeding - have an active, chronic immune system disease other than multiple sclerosis, or have an immunodeficiency syndrome R - Neurological findings consistent with or confirmed progressive multifocal leukoencephalopathy (PML) do Have an active systemic infection or AIDS, or have a non-human immunization status on screening Tests positive for antibodies to the epidemic virus - at risk of developing or reactivating hepatitis, syphilis, or tuberculosis - Have received any live or live attenuated vaccines in the 2 months prior to the start of therapy be.

[0098] Preferably, ofatumumab is administered parenterally, e.g., epidermally, intravenously, intramuscularly, or intraarterially. , intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, interstitial Intranodal, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injections and infusions The preferred route of administration is subcutaneous injection.

[0099] In one embodiment of the present invention, the ofatumumab composition is administered intravenously to humans. The pharmaceutical composition is formulated according to a predetermined procedure. Typically, the composition for intravenous administration is , a solution in sterile isotonic aqueous buffer. If appropriate, the composition may also contain a solubilizing agent and the injection It may also include a local anesthetic such as lignocaine to relieve pain at the site. The formulation may be prepared, for example, as a lyophilized powder or a water-free concentrate, with a concentration of active agent. In unit dose form in a hermetically sealed container such as an ampoule or sachet, labeled are supplied mixed together.

[0100] If the composition is to be administered by injection, it is preferably administered in sterile, pharmaceutical grade The medication can be administered with an infusion bottle containing water or saline.

[0101] When the composition is to be administered by injection, the formulation components may be mixed prior to administration. Ampoules of sterile water for injection or saline can be provided.

[0102] In one embodiment, the formulation of ofatumumab is as described in WO 2009 / 009407. The formulation can be made according to the formulation disclosed in Fret.

[0103] In one embodiment, ofatumumab is an antibody formulation in which ofatumumab Approximately 20~300mg / mL, 50~300mg / mL, 100~300mg / mL, 15 0-300mg / mL, 200-300mg / mL, or 250-300mg / mL The antibody formulation is present in an amount of 50 mg / ml, preferably 50 mg / ml.

[0104] In one embodiment, ofatumumab is an antibody formulation containing 10-100 mM sodium acetate. 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02- Contains 0.2 mM EDTA, 0.01-0.2% polysorbate 80, pH 5.0-7 Preferably, the ofatumumab formulation is formulated in a 50 mM acetic acid solution. Sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA TA, containing 0.02% polysorbate 80 and adjusted to pH 5.5.

[0105] In one embodiment, the ofatumumab formulation is administered in a prefilled syringe or autoinjector. Preferably, a pre-filled autoinjector intended for sc administration is provided. Used.

[0106] In a preferred embodiment, ofatumumab injection is provided in a sterile, preservative-free formulation for subcutaneous use. It is a drug-free solution. Preferably, each 20 mg / 0.4 mL pre-filled pen or pre-filled The pre-filled syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg of Ofatumumab and arginine (4 mg), edetate disodium (0.007 mg) , Polysorbate 80 (0.08 mg), Sodium acetate trihydrate (2.722 mg), Contains sodium chloride (1.192 mg) and water for injection, USP at pH 5.5. Hydrochloric acid can be added to adjust the H.

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

[0108] In a preferred embodiment, the formulation is administered subcutaneously in the abdomen, thigh, or outer upper arm. In a preferred embodiment, the formulation is used to soothe bruises, scars or tender, bruised, red skin. It should not be administered to areas that are small, hard, or not intact.

[0109] In one embodiment, the first injection of the ofatumumab formulation is administered under the guidance of a healthcare professional. If an injection-related reaction occurs, symptomatic treatment is recommended. The pen or pre-filled syringe is preferably removed from the refrigerator and left for, e.g., about 15-3 In a preferred embodiment, the ofatumumab formulation of the present invention is a transparent It is a colorless to slightly brownish yellow solution with a white to slightly milky white color, and is Available at: Injection: 20 mg / 0.4 mL, single-dose prefilled pen, e.g., Sensoready (registered trademark) 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 ta u Approximately 400 to 550, more preferably 450 to 500, for example, 483 mcg h / mL , and / or average C max 1.0 to 2.5, more preferably 1.2 to 1.7, for example In a preferred embodiment, repeated doses provide 1.43 mcg / mL at steady state. After subcutaneous administration of a 20 mg dose of tumab, the steady-state volume of distribution is 4.5 to 6.5, more preferably can be 5.0 to 6.0, for example 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, immunoglobulin An antibody is a molecule that binds specifically to an antigen, or a fragment of a molecule, or any derivative thereof. The binding preferably occurs under typical physiological conditions for a substantial period of time. The term "antigen-binding portion" of an antibody, as used herein, refers to a portion of an antibody that binds to an antigen (e.g., CD4 20) refers to a fragment of an antibody that retains the ability to specifically bind to the antibody. Please refer to the International Publication No. 2018 / 033841 pamphlet, especially pages 9-13. do.

[0114] Breakthrough Diseases For purposes of this invention, breakthrough diseases are defined as follows: At least one recurrence documented in the past year or two recurrences documented in the past two years Recorded, 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 the human B lymphocyte-restricted differentiation antigen or Bp35) is a pre-B and a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on mature B lymphocytes. CD20 is expressed on the surface of more than 90% of B cells derived from peripheral blood or lymphoid organs. CD20 is found to be expressed during early pre-B cell development and remains until plasma cell differentiation. It is present on both normal and malignant B cells. The carboxyl-terminal region is located in the cytoplasm. GenBank, accession number NP_6906 This is based on the description in 05.

[0116] Disease Modifying Therapy (DMT) The term "disease-modifying therapy" refers to the treatment that remains a curative treatment for multiple sclerosis (MS). Although there are no approved disease-modifying drugs (DMDs), several are approved for MS. In general, DMTs for RMS reduce the frequency and / or severity of relapses. So, while DMT is not a cure for RMS patients, patients can reduce their relapses. The frequency and severity of urinary tract infections can be reduced.

[0117] EEDS The Expanded Disability Status Scale (EDSS) quantifies disability in multiple sclerosis and measures its progression over time. This is a method of monitoring changes in the level of damage caused by an accident.

[0118] The EDSS scale ranges from 0 to 10 in increments of 0.5, with higher values ​​indicating more disability. The scoring system is based on examination by a neurologist.

[0119] EDSS steps 1.0 to 4.5 are for patients with MS who are able to walk without any assistance. This refers to people with disabilities based on eight functional disability measures: 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) are neuronal networks in the brain that are responsible for specific tasks. Each FS represents a scale ranging from 0 (no impairment) to 5 or 6 (more severe impairment). Kurtzke JF. Rating Neurologic Impairment in Multiple Sci. erosis: An Expanded Disability Status Sclale (EDSS). Neurology. 1983, Nov;33(11) :1444-52 is used as a reference.

[0121] Gd+ lesions Gadolinium ("contrast") is a chemical that is injected into a person's veins during an MRI scan. Gadolinium is a compound that is normally unable to pass from the bloodstream to 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. This allows the gadolinium to pass through. The gadolinium then enters the brain or spinal cord. It can leak into MS lesions, emitting light and creating highlighted spots on MRI. Such MS lesions are called gadolinium-enhancing or Gd+ lesions.

[0122] 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 released into the body through biological processes. This concept is based on the assumption that the rate of removal is approximately exponential. In the medical context, half-life is the time it takes for a substance to reach its plasma concentration while circulating in the whole blood of an organism. The time it takes for the concentration to decrease to half of its steady state (plasma half-life) is explicitly stated.

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

[0124] Neurologically stable A clinical condition characterized by no change in mental status or level of consciousness. seizure control; new neurological deficits, e.g., aphasia, ataxia, dysarthria, paresis, motor Neurological stability, which can include the absence of paralysis, visual field loss, or blindness is defined.

[0125] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 Version 2 contains 29 items across two domains: physics and psychology. The questionnaire is self-administered and ranges from 1 (not at all applicable) to 4 (extremely applicable). The scores were recorded on a 4-point ordinal scale ranging from 0 to 10, with higher scores indicating greater impact on daily life. The MSIS-29 takes approximately five minutes to complete and questions are asked about the patient's experience during the past two weeks. designed to determine patients' views of the impact of MS on their daily lives . Hobart J and Cano S (2009), “Improving the evaluation of therapeutic intervention tions in multiple sclerosis: the role of new psychometric methods”, Health Tech nol 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-b Based on "Assessed outcome measure", Brain; 124(Pt 5):962-73.

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

[0127] Ofatumumab is disclosed in European Patent Application Publication No. 1558648 and European Patent Application Publication No. Drugbank.ca, access ion number DB06650 and WHO Drug Information, Vol. 20, No. 1, 20 Further reference is made to the description of .06. In one embodiment, the protein formula is C 6480 H 10 022 N 1742 O 2020 S 44 The average protein weight is approximately 146,100 Da. be.

[0128] The metabolic pathway of ofatumumab involves the degradation of small peptides by ubiquitous proteolytic enzymes. Ofatumumab can be eliminated in two ways: by degradation into thiols and amino acids. target-independent pathways, such as those for IgG molecules, and those involving binding to B cells. Target-mediated pathways.

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

[0130] Ofatumumab is preferably metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. It does not share common clearance pathways with metabolized chemical drugs. Mabs are 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 Following withdrawal from DMT, reactivation of severe disease above a patient's pre-DMT baseline This is considered a rebound event. Barry et al., Fingolimod Rebound: A Review of the Cl inical Experience and Management Considerations. Neurol Ther (2019) 8:241-250 I use it as a reference.

[0133] recurrence A relapse is a new neurological deficit or deterioration, preferably lasting longer than 24 hours. In other words, a recurrence can be defined as a recurrence of a disease that has occurred for at least 24 hours. Discrete episodes of neurological dysfunction (known in the art as "attacks," "outbursts," etc.) lasting for a period of time Relapse can be considered a complete or partial exacerbation of the condition. A period of partial recovery and no progression of symptoms or accumulation of disability follows (remission).

[0134] Relapses are characterized by new or expanding demyelination at the site of the inflammatory event within the central nervous system (CNS). It is thought to be caused by vasculitis.

[0135] Revised McDonald's Criteria (Thompson et al 2018) Under the revised McDonald criteria, myelin is present as seen on MRI: Distinct spatial lesions (DIS) may lead to a diagnosis of MS: At least one T2 bright disease in at least two or four CNS locations Affected: paracortical, periventricular, and subtentorial regions of the brain, as well as the spinal cord. (T2 is used to diagnose MS and detect areas of old and new myelin damage in the brain and spinal cord. (This is the most common MRI scan used for this purpose.) -These lesions do not necessarily have to be gadolinium-enhancing (contrast material) .

[0136] Regarding temporal myelin damage (DIT), MRI evidence is as follows: R: - Follow-up scan compared to baseline scan (regardless of time since baseline) New T2 and / or gadolinium-enhancing lesions on MRI scan. At least 30 days were required to have elapsed between the initial and first seizure. - The simultaneous presence of asymptomatic gadolinium enhancement and non-enhancing lesions at any time .

[0137] Primary progressive MS (PPMS) has special diagnostic requirements. Specifically, The McDonald's criteria require at least one year of demonstrated progress (either prospective or retrospective). (conducted retroactively), plus two of the following three findings: -Demonstration of DIS in the brain, in three major brain regions (periventricular, paracortical or subtentorial) Observed in at least one T2 lesion - Proof of intraspinal DIS, based on at least two T2 lesions DIS (≥2 T2 lesions) Ku; - Positive CSF involvement, again with oligoclonal bands and / or high Ig Observed in the presence of G index.

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

[0139] There is no obvious progression of the disease during remission. RRMS is characterized by active and inactive symptoms at different time points. (with evidence of recurrence and / or new MRI activity) or inactive and whether the condition worsens (increased disability over a specified period after relapse) Lu Reference is made to blin 2014, Neurology. 2014 Jul 15; 83(3): 278-286.

[0140] RMS The term RMS (relapsing multiple sclerosis) is used to refer to RRMS, SPMS and clinically isolated multiple sclerosis. This includes the classified infectious diseases syndrome (CIS).

[0141] Primary progressive MS (PPMS) PPMS is characterized by a progressive deterioration of neurological function (disability) from symptom onset without early relapse or remission. PPMS are characterized by the accumulation of PPMS (accidental recurrence) at different time points. Evidence of new and / or new MRI activity) or inactivity; and Is there progression (change over time with or without recurrence or new MRI activity)? Evidence of disease worsening or no progression on objective measures of progression It can be further characterized by either:

[0142] Each person's experience with PPMS is unique. PPMS can be characterized by relapses or new activity on MRI. There may be short periods of stable disease, with or without new May have periods of increased disability, with or without recurrence or MRI lesions There is also gender.

[0143] Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people diagnosed with RRMS eventually transitions to a secondary progressive process in which neurological function deteriorates over time. There is a progressive worsening of the condition (accumulation of disability). SPMS is characterized by active active (with evidence of recurrence and / or new MRI activity) or inactive and whether there is progression (with or without recurrence) as an objective measure of change over time. further by either (evidence of disease worsening) or no progression This can be characterized as follows. Reference is made to Lublin 2014.

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

[0145] Clinically isolated syndrome (CIS): Clinically isolated syndrome (CIS) is a central nervous system disorder suggestive of multiple sclerosis (MS). CIS can refer to a single clinical episode of an inflammatory demyelinating condition of the central nervous system (CNS). They can be single or multiple and usually involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral cortex. May involve the hemisphere. Miller et al, Clinically isolated syndromes, Lancet Neurol. 2012 ;11:157-169 is referenced.

[0146] T1 and T2 lesions T1 and T2 refer to different MRI techniques used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time taken 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 lesions are lesions that are detected using either T1 or T2 methods. T1 MRI images highlight areas of active inflammation, Provides information about current disease activity. T2 MRI images provide information about disease burden or lesions. Provides information about the burden (total area of ​​old and new lesions).

[0147] Washout The term washout refers to the time from the first treatment (e.g., first DMT) to the first Any drug(s) being administered must be partially or completely removed from the patient before a second treatment (e.g., a second DMT) is initiated. A period between clinical treatments (preferred) allowing for the drug to be gradually or completely washed out During the washout period, patients are preferably and not receiving any other medications (e.g., DMTs for the treatment of MS). In this case, the drug is a disease-modifying drug (DMD).

[0148] In a preferred embodiment, the final dose of the first DMT drug is administered prior to discontinuation of the first DMT. 25%, preferably 50%, more preferably 75% of the drug's half-life until administration. Preferably 85%, most preferably 95%, of the first DMT The drug is considered to have washed out.

[0149] In an alternative embodiment, only 30% of the amount administered as the final dose of the first DMT drug. , preferably 20%, more preferably 10%, even more preferably 5%, most preferably If 2.5% or less of the antibody was detectable in a patient sample (e.g., blood or serum), the first In a particularly preferred embodiment, the DMT drug is washed out. The weight is C maxi.e., the final dose of the first DMT drug was administered before discontinuation of the first DMT. The maximum (or peak) serum concentration that the first DMT drug achieves in serum after administration can be replaced with

[0150] First, DMT detection was performed using PAGE, Western blotting, ELISA, HPLC, and and mass spectrometry, capillary electrophoresis, Fourier transform infrared spectroscopy, circular dichroism, DL S, thermal shift assay, NMR, X-ray, chromatography and fluorescence spectroscopy One or more of these may be implemented. [Example]

[0151] [Example 1] In vitro data suggest that anti-CD20 antibodies may be involved in the induction of complement-dependent cytotoxicity (CDC). Showing differences between bodies In vivo, anti-CD20 antibodies bind to B cells by cell- and / or complement-dependent mechanisms. CDC is an important mechanism of ofatumumab-induced B cell lysis. be.

[0152] PBMCs (peripheral blood mononuclear cells) were prepared, and human primary B cells were collected by centrifugation and then incubated. Sei medium (RPMI 1640 + G supplemented with 0.1% BSA and 20 mM HEPES) Lutamax) 2 x 10 5 The B cells were then resuspended in 3x increments of 1000 cells / mL. with human serum (30%) as a source of diluted antibodies and complement at 37°C, 5% CO The cells were incubated simultaneously in a V-bottom 96-well plate at RT for 1 h at RT. The cells were stained with SYTOX Blue (0.25 μM) and then analyzed by FACS Fortescue. B cell lysis was analyzed by flow cytometry at 5°C. Cell death was assessed by SYTOX. Blue + The results are shown in Figure 2. Compared with CDC, ofatumumab showed a strong concentration-dependent induction of CDC in primary human B cells. This demonstrates guidance.

[0153] In a second experiment, B cells were incubated with the previously described antibodies, but The procedure was performed in the absence of a source of complement. Cells were washed as previously described. After 6 hours Then, a source of complement was added. Only antibodies with low off rates remained bound to the cells and bound complement. However, after this delayed addition of complement, ofatumumab potently induced CDC. 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 has the ability to activate complement components and induce CDC. In terms of potency and efficacy, ofatumumab outperforms ocrelizumab in this respect. are clearly distinguished from each other.

[0155] [Example 2] Patient data showing reduction in recurrence and Gd+ lesions after switching The effects of ofatumumab administered to patients treated with DMTs other than ofatumumab are as follows: was investigated as described in.

[0156] 1. Ofatumumab Ofatumumab contains 20 mg ofatumumab (50 mg / ml, 0.4 ml content) It is supplied in a prefilled syringe for subcutaneous administration containing: The matching placebo had the same appearance as the study drug.

[0157] Control treatment was teriflunomide (Aubagio®) 14 mg. do.

[0158] Ofatumumab treatment group: Days 1, 7, 14, Week 4 (Month 1 of the study) and thereafter followed by ofatumumab 20mg s.c. injection every 4 weeks plus teriflunomide - matching placebo Administer orally in capsule form once daily.

[0159] Eligible patients were randomized 1:1 to receive either active ofatumumab 20 mg or Patients can be randomized to either the active or teriflunomide 14mg group. Stratification was 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 with disease activity, as defined by Lublin et al., 2014 type process (RRMS), or secondary progressive type (SPMS) process.

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

[0163] The patient had previously received glatiramer acetate, dimethyl fumarate (DMF), daclizumab, and finasteride. Patients were treated with DMTs selected from ngolimod, natalizumab, and laquinimod.

[0164] Documented evidence of at least: 1 relapse in the past year or 2 relapses in the past year prior to screening Two recurrences within a year or a positive Gd-enhanced MRI scan within the year prior to randomization. Note: Positive If no Gd-enhanced scan has been performed since the previous year, a screening MRI scan should be used. It is possible.

[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 participating in the study. (Results of studies 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 the results for 27 patients randomized to ofatumumab (Study 1). was assessed at each visit, i.e., baseline, 12 months, and 24 months. In the 12 months prior to screening, the number of recurrences per patient was approximately This ratio was approximately 0.23 12 months after switching treatment, and 1.26 12 months after switching treatment. and unexpectedly dropped to about 0.30 over the 24-month period.

[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, surprisingly, the number of Gd+ lesions increased among patients randomized to ofatumumab. This shows a remarkable decrease.

[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 a clinical trial as described below. Confirmed.

[0184] 1. Group The study population consisted of adult subjects with RMS. The study was conducted in approximately 120-170 It is carried out at the center.

[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, including RMS and secondary progressive MS (SPMS) RMS). 3. Disability at screening with an EDSS score of 0-4 (inclusive) situation. 4. MS treatment history with up to three DMTs 5. Have been on these last DMTs for a period of at least 6 months prior to the first study drug administration Subjects who transition from administered fingolimod or dimethyl fumarate 6. One or more clinically reported recurrences or one or more MRI activity as evidenced by signs of movement (e.g., Gd+ enhancement, new or enlarging T2 lesions). Before the transition, participants were taking fingolimod or dimethyl fumarate appropriately. Walkthrough disease activity occurred 7. Neurologically stable within 1 month prior to administration of the first study drug.

[0186] 2.Treatment drug, treatment group, and treatment period Ofatumumab contains 20 mg ofatumumab (50 mg / ml, 0.4 ml content) It is delivered in an autoinjector (AI) containing acetaminophen for subcutaneous administration. It is a light 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 considered the transition period to be the same as the current treatment (fingolimod or D The exact timing of the transition is defined as the time between the cessation of MF and the initiation of ofatumumab treatment. The timing is based on the investigator's clinical judgment.

[0190] During the washout period, subjects were not permitted to receive any other DMTs for the treatment of MS. I can't.

[0191] 4. Instructions for prescribing and taking the study treatment Study drug (ofatumumab injection) will be administered beginning at Visit 1. Drug will then be administered at the end of treatment. Medication will be administered at scheduled visits throughout the treatment period. The lower injections are given at 4-week intervals (+ / - 3 days).

[0192] To assess the tolerance of the initial dose of study drug, any Subjects were closely monitored for any reaction.

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

[0194] After Visit 1, subjects may self-inject the study drug at home or at the study site. The experiment was administered by a team of caregivers trained in proper technique and safety precautions. Before home administration is permitted, the ability to self-inject must be demonstrated and documented. The second injection (day 7) should be administered at home and supported by the appropriate Staff in designated positions will monitor from a distance to provide additional training as needed. Subjects will return to the site for dosing at weeks 2 and 4.

[0195] [Example 4] Clinical trial shows reduced thalamic volume loss and improvement in MSIS-29 background Ofatumumab was compared with teriflunomide in the ASCLEPIOS I / II and Phase 3 trials. ECTRIMS Online Library, Haus See er S. et al., 09 / 13 / 19;279581;336. MS patients treated with Aubag in the ASCLEPIOS I and II studies compared with io® (teriflunomide) (p<0.001 in both studies). The average recurrence rate (ARR) was 50.5% (0.11 vs. 0.22) and 58.5%, respectively. ofatumumab was compared with Aubagio® showed a highly significant suppression of gadolinium (Gd) T1 lesions compared with the control group, and demonstrated the potentiation of novel inflammatory activity. Ofatumumab demonstrated significant inhibition of Aβ in a prespecified pooled analysis. in confirmed disability progression (CDP) at 3 months compared with ubagio® There was a 34.4% relative reduction in 125% of patients at 6 months (p=0.002) and a 32.5% relative reduction in 125% of patients at 6 months (p=0.002). There was a relative risk reduction of 5% (p=0.012).

[0196] Objectives and Methods In ASCLEPIOS I, patients were randomized (1:1) to receive one of the four weekly offers Tumor 20 mg sc injection (loading regimen 20 mg on days 1, 7, and 14) g sc dose) or teriflunomide 14 mg orally once daily for 30 days The subjects were aged 18 to 55 years and had an Expanded Disability Status Scale (ED) score at screening. SS) score of 0 to 5.5 (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444-52) and have experienced ≥1 recurrence within the past year or ≥2 recurrences in the past 2 years, or Patients who had a positive gadolinium-enhanced (Gd+) MRI scan within the year prior to randomization Included.

[0197] result (i) Thalamic volume loss Ofatumumab significantly improved visual acuity between baseline and 24 months compared with teriflunomide significantly reduced bed volume loss (mean percentage change -1.00 vs. -1.40, mean 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 showed a greater effect on patients compared with teriflunomide. reduced the impact of MS on daily life in patients with MS. MSIS-29 physical scores from baseline The mean change in the impact score was significantly greater at all time points, i.e., 6 months (-2.75 vs. -0.4 4, mean difference -2.30, p=0.017), and 12 months (-2.43 vs. 0.17, mean difference difference -2.59, p=0.009), and 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=0.02 6) (Tables 14.2-7.1) showed that the ofatumumab group showed a higher incidence of urinary tract infections than the teriflunomide group. Significantly greater.

[0199] Ofatumumab treatment improved teri as measured by the MSIS-29 psychological impact score. A greater reduction in the impact of MS on patients' daily lives compared with flunomide treatment However, the difference between the treatment groups reached statistical significance only at 12 months.

[0200] conclusion (i) Thalamic volume is a promising MRI-based model associated with neurodegeneration that could accelerate the development of neuroprotective therapies. According to conventional techniques, thalamic volume decreases by -0.71 per year in MS subjects. % decline per year in healthy controls, and -0.28% decline per year in healthy controls. See Azevedo 2018. Treatment with teriflunomide (-1.4% at 2 years) , which has a beneficial effect on the loss of thalamic volume when compared with the data available in the prior art. On the contrary, switching to ofatumumab as a disease-modifying treatment does not appear to Showing more promising results.

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

[0202] [Example 5] Maintenance of ofatumumab efficacy in relapsing MS patients transitioning from intravenous anti-CD20 therapy efficacy background:Treatment of relapsing multiple sclerosis (RM) using anti-CD20 monoclonal antibody (mAb) B cell depletion in patients with S) correlates with annualized relapse rate and magnetic resonance imaging Reduces inflammatory lesion activity on the skin and delays the time to worsening of disability. 20 The mAbs ocrelizumab and rituximab are administered intravenously in clinical settings. Fatumumab is administered subcutaneously using a prefilled syringe or autoinjector (AI) pen. It is administered subcutaneously to facilitate self-administration.

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

[0204] method: Approximately 100 adults with RMS will be enrolled at 10-20 centers across the USA. Eligible patients had received 2 to 5 consecutive courses of intravenous ocrelizumab or rituximab. Previously treated with anti-CD20 mAbs (other anti-CD20 mAbs excluded), final dose was 4 times higher than baseline Other inclusion criteria were Expanded Disability Status Scale scores at screening. Core 5.5 or less and CD19 B cells depleted to <1% of baseline on anti-CD20 therapy Suboptimal response to anti-CD20 therapy in the past 6 months Patients with ≥2 active gadolinium-enhancing [Gd+] lesions (recurrence, ≥2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging lesions) T2 lesions, clinical deterioration), or severe infusion-related reactions or recurrent infections Patients who discontinued anti-CD20 therapy or who had progressive disease were excluded. Participants were asked to complete an AI questionnaire on days 1, 7, and 14, and then every month from month 1 to month 12. Patients will receive 20 mg ofatumumab subcutaneously via a steroid therapy. The primary endpoint is The secondary endpoints were no change or a decrease in Gd+ lesion counts. The study will assess participants' immune biomarkers, treatment satisfaction, and overall survival at 6 and 12 months. Maintenance and change in safety and tolerability. There is no 6-month interim analysis.

[0205] result: The trial is aimed at evaluating AI in patients previously treated with ocrelizumab or rituximab. Sustained efficacy, retention, and satisfaction data based on monthly subcutaneous drug delivery using a pen This will complement the ofatumumab Phase 3 program in RMS by generating

[0206] Conclusion: The trial is aimed at preventing the development of steroids in patients with RMS who have transitioned from intravenous anti-CD20 therapy. It provides important data on the sustained efficacy of atumumab.

Claims

1. 1. Ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, comprising Ofatumumab for patients who have been treated with disease-modifying therapies other than ofatumumab.

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

3. wherein the patient develops breakthrough disease upon treatment with the disease-modifying therapy. Ofatumumab for use according to claim 1 or 2.

4. The breakthrough disease is characterized by one or more clinically reported recurrences or MRI 5. The method for use according to claim 3, wherein the method is evidenced by one or more of the above symptoms of activity. Fatumumab.

5. The MRI activity includes Gd+ enhancement and / or new or enlarging T2 lesions 5. Ofatumumab for use according to claim 4.

6. 6. Any of claims 1 to 5, wherein the patient lacks tolerance to the disease-modifying therapy. Ofatumumab for use according to one aspect.

7. the patient has a history of at most one or two or three disease-modifying therapies. Ofatumumab for use according to any one of items 1 to 6.

8. The disease-modifying therapy is administered for a period of at least 6 months prior to the first administration of ofatumumab.

8. Ofatumumab for use according to any one of claims 1 to 7.

9. the patient is neurologically stable within one month prior to the first dose of ofatumumab; Ofatumumab for use according to any one of claims 1 to 8.

10. Claim 1 wherein the patient has an EDSS score of 1 to 4 before the first dose of ofatumumab.

10. Ofatumumab for use according to any one of claims 1 to 9.

11. 11. The method of claim 1, wherein the previous disease-modifying therapy is administered orally. Ofatumumab for use.

12. The previous disease-modifying therapy drugs were teriflunomide, dimethyl fumarate, and fingolimod.

12. The offer for use according to any one of claims 1 to 11, selected from the group consisting of rimod Mumab.

13. 13. The use according to claim 11 or 12, wherein the previous disease-modifying therapy is fingolimod. ofatumumab for.

14. 14. The use according to claim 13, wherein fingolimod is administered in a daily dose of 0.5 mg. ofatumumab.

15. The previous disease-modifying therapy drugs were natalizumab, rituximab, ocrelizumab, and azathioprine.

10. A compound according to claim 1, selected from the group consisting of lemtuzumab, daclizumab and glatiramer acetate. ofatumumab for the use according to any one of the preceding claims.

16. 10. The method of claim 1, wherein the previous disease-modifying therapy is selected from intravenous anti-CD20 therapy. and ofatumumab for use according to any one of claims 15.

17. Patients with a suboptimal response to anti-CD20 therapy, preferably those with a suboptimal response in the past 6 months 17. The method of claim 16, wherein the ofatumumab is administered to a patient with a lower response.

18. Patients with adverse events to anti-CD20 therapy, especially infusion-related reactions or recurrent infections 18. Ofatumumab for use according to claim 16 or 17, administered to a subject.

19. Patients must have received at least two consecutive courses of intravenous ocrelizumab or rituximab 19. An offer for use according to any one of claims 16 to 18, which has previously been treated with Tumors.

20. The final dose was administered 4 to 9 months before administration of ofatumumab.

20. Ofatumumab for use according to any one of 19.

21. 21. The use of any one of claims 1 to 20, administered after relapse. Mumab.

22. 22. Any one of claims 1 to 21, administered after detection of at least one Gd+ lesion.

2. Ofatumumab for the use described in

23. 23. Any one of claims 1 to 22, administered after detection of a new or enlarging T2 lesion.

2. Ofatumumab for the use described in

24. 3. The method of claim 1, wherein the previous disease-modifying therapy is discontinued prior to the initiation of ofatumumab administration.

3. Ofatumumab for use according to any one of claims 3.

25. 25. The method of claim 24, wherein discontinuation of the previous disease-modifying therapy results in rebound. ofatumumab.

26. ofatumumab administration is ineffective in the patient with a drug used in the previous disease-modifying therapy 26. The method of claim 1, wherein the method is initiated before the half-life of the ofatumumab.

27. Claim 1, wherein ofatumumab administration is initiated after a washout period of 1 day to 3 weeks.

27. Ofatumumab for use according to any one of claims 1 to 26.

28. 27. Any of claims 1 to 26, wherein ofatumumab administration is initiated without a washout period. Ofatumumab for the use according to any one of claims 1 to 4.

29. If the previous disease-modifying treatment did not sufficiently reduce thalamic volume loss, 29. The method of claim 1, wherein rituximab is administered. Mumab.

30. ofatumumab reduces thalamic volume loss, preferably by less than 0.65% per year ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis.

31. MSIS-29 score reduction was not adequately achieved with the previous disease-modifying treatment. ofatumumab is administered when ofatumumab for

32. the MSIS-29 score was reduced by less than 2.5 with the prior disease-modifying treatment. Ofatumumab for use according to item 31.

33. 1. The method of claim 1, wherein the dose is 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks.

33. Ofatumumab for use according to any one of claims 1 to 32.

34. Ofatumuma for use according to any one of claims 1 to 33, administered subcutaneously. Boo.

35. 35. An offer for use according to any one of claims 1 to 34, administered in a loading dose. Tumors.

36. 20 mg ofatumumab was administered as a loading dose at weeks 0, 1, and 2.

36. Ofatumumab for use according to claim 35.

37. 35. The method of claim 1, wherein the composition is administered without a loading dose. Fatumumab.

38. Relapsing multiple sclerosis is divided into relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (PSMS), and 38. The method of claim 1, wherein the schizophrenia syndrome is selected from the group consisting of schizophrenia, ...

10. Ofatumumab for the use according to any one of claims 1 to 9.

39. a pre-medication is administered to the patient before the first dose of ofatumumab is administered. Item 39. Ofatumumab for use according to any one of items 1 to 38.

40. the pre-administration comprises acetaminophen, an antihistamine, and / or a steroid; 40. Ofatumumab for use according to claim 39.

41. 39. The method of claim 39, wherein the pre-administration is administered 30 to 60 minutes before injection of ofatumumab.

40. Ofatumumab for use as described in 40.

42. 39. Any of claims 1 to 38, wherein no prior administration is administered before the first dose of ofatumumab. ofatumumab for use according to any one of claims 1 to 4.

43. 43. The method of claim 1, wherein rebound or recurrent disease activity is avoided. ofatumumab for the described uses.

44. Lack of efficacy is defined as failure to halt or adequately slow disease progression. Ofatumumab for use according to claim 2.

45. A method for treating or preventing relapsing multiple sclerosis, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, acetaminophen, benzodiazepine ... The method comprises administering ofatumumab to a patient suffering from a disease other than that described above, wherein the patient is receiving the Have received modifying therapy, method.

46. 2. A method for producing a medicament for use in the treatment or prevention of relapsing multiple sclerosis. ofatumumab, wherein the medicament is administered to patients who have been treated with a disease-modifying therapy other than ofatumumab. The drug being used is ofatumumab.

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