Management of conditions other than multiple sclerosis in ofatumumab-treated patients

Abstract

To provide a therapy for treating or preventing relapsing multiple sclerosis (RMS) in a patient having a history of previous or ongoing conditions such as infections.SOLUTION: The present invention provides ofatumumab for use in treating or preventing relapsing multiple sclerosis (RMS), where the ofatumumab is used in a patient having a history of previous or ongoing conditions other than multiple sclerosis.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to ocrelizumab for treating or preventing (or for use in treatment or prevention of) relapsing-remitting multiple sclerosis (RMS), which is used in patients having a history of past or ongoing conditions other than multiple sclerosis.

Background Art

[0002] Invasive viruses, bacteria or fungi have various mechanisms to resist inactivation or destruction by the host. These sometimes produce toxins that interfere with the body's defense system, or can disguise themselves by changing their shape or outer structural proteins so that they are not recognized by the immune system (antigenic variation). Some bacteria produce adhesive elements that can adhere to mucous membranes and prevent the destruction of bacteria. Due to these mechanisms, patients with a history of conditions such as past or ongoing infections may not be able to tolerate immunosuppressive therapy or may be particularly sensitive. However, some diseases, such as multiple sclerosis (MS), may require immunosuppressive therapy. Therefore, it is necessary to provide MS therapy to patients

[0003] having a history of conditions such as past or ongoing infections. These mechanisms that resist inactivation or destruction by the host are more likely to succeed in immunocompromised or immunosuppressed patients (e.g., patients receiving MS therapy). Nevertheless, since this is part of the therapy (e.g., MS therapy), in many For example, to treat MS, it is necessary to prevent, reduce or alleviate viral, bacterial or fungal infections. It is necessary to prevent, reduce or alleviate viral, bacterial or fungal infections.

[0004] Importantly, immunosuppression is generally incompatible with some prophylactic or therapeutic measures, such as vaccination. In some cases, this poses a dilemma for patients who are immunocompromised or immunosuppressed (e.g., patients receiving MS therapy). For example, lower urinary tract infections are a common adverse event in immunocompromised or immunosuppressed patients (e.g., patients receiving MS therapy). Viruses are increasingly recognized as the cause of lower urinary tract infections, particularly hemorrhagic cystitis, among immunocompromised or immunosuppressed patients. BK virus, adenovirus and cytomegalovirus are the major pathogens involved in hemorrhagic cystitis. Cidofovir has become a generally preferred drug in viral urinary tract infections because it is active against the most common viral pathogens. However, it may not be desirable to expose these patients, who are already receiving treatment and / or are immunocompromised / immunosuppressed, e.g., MS patients receiving MS therapy, to a high drug load (including cidofovir). For example, it is known that cidofovir causes adverse events such as nephrotoxicity and neutropenia. Neutropenia can be dangerous for MS patients treated with fingolimod, for example. This is because fingolimod-induced leukopenia (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f Importantly, immunosuppression is generally incompatible with some prophylactic or therapeutic measures, such as vaccination. In some cases, this poses a dilemma for patients who are immunocompromised or immunosuppressed (e.g., patients receiving MS therapy). For example, lower urinary tract infections are a common adverse event in immunocompromised or immunosuppressed patients (e.g., patients receiving MS therapy). Viruses are increasingly recognized as the cause of lower urinary tract infections, particularly hemorrhagic cystitis, among immunocompromised or immunosuppressed patients. BK virus, adenovirus and cytomegalovirus are the major pathogens involved in hemorrhagic cystitis. Cidofovir has become a generally preferred drug in viral urinary tract infections because it is active against the most common viral pathogens. However, it may not be desirable to expose these patients, who are already receiving treatment and / or are immunocompromised / immunosuppressed, e.g., MS patients receiving MS therapy, to a high drug load (including cidofovir). For example, it is known that cidofovir causes adverse events such as nephrotoxicity and neutropenia. Neutropenia can be dangerous for MS patients treated with fingolimod, for example. This is because fingolimod-induced leukopenia (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f For example, it is known that cidofovir causes adverse events such as nephrotoxicity and neutropenia. Neutropenia can be dangerous for MS patients treated with fingolimod, for example. This is because fingolimod-induced leukopenia (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f For example, it is known that cidofovir causes adverse events such as nephrotoxicity and neutropenia. Neutropenia can be dangerous for MS patients treated with fingolimod, for example. This is because fingolimod-induced leukopenia (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f For example, it is known that cidofovir causes adverse events such as nephrotoxicity and neutropenia. Neutropenia can be dangerous for MS patients treated with fingolimod, for example. This is because fingolimod-induced leukopenia (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f (lymphopenia) is exacerbated, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity is caused by f ingolimod and can further damage the kidneys. because it can interfere with the body's ability to excrete fingolimod and its metabolites, leading to fluid imbalances and associated diseases. Therefore, different ways of dealing with adverse events are necessary. In particular, an MS therapy that enables vaccination during treatment is needed.

[0005] Epstein-Barr virus (EBV) is one of the most successful pathogens in humans, and more than 90% of the adult population is persistently infected (Cesarman 2014, Cohen 2015). EBV infections in immunocompromised individuals can be associated with all types of diseases, including malignancies such as cancer (gastric or nasopharyngeal) or lymphoma (e.g., Hodgkin lymphoma). In individuals with intact immune capabilities, the antiviral T cell response controls the infection, but EBV remains latent within memory B cells and some other cell types. However, the success of MS therapy depends on immunosuppressive drugs to prevent inflammatory events in the central nervous system (CNS). Therefore, in MS patients, current immunosuppressive therapies weaken the strength of the anti-EBV T cell response and leave EBV-induced B cell proliferation uncontrolled. Similarly, most individuals are infected as children with varicella-zoster virus (VZV), which causes episodes of chickenpox. The immune system eventually eliminates the virus from most sites, but the virus remains dormant (or latent) in ganglia adjacent to the spinal cord (called dorsal root ganglia) or the trigeminal ganglia at the base of the skull. The disease (shingles) occurs when virus particles within a single sensory ganglion switch from these latent lysogenic cycles to an active lytic cycle. VZV infections are adverse events in MS patients treated with fingolimod. ​​​​​​​​​​​​​​Reported as such (Cohen et al., New England Journal of Medicine 2010; 362: 402-15). Another virus, JC virus, is the cause of a feared complication of progressive multifocal leukoencephalopathy (PML). As in the case of EBV and VZV, JC virus-infected cells are under the control of antiviral T cells. Current immunosuppressive agents that affect T cell function increase the risk of activation of latent viruses such as EBV and JC. Therefore, there is an urgent need for new therapies to modulate, prevent or inhibit viral infections and related diseases such as EBV or JCV infections in MS patients who are particularly vulnerable. SUMMARY OF THE INVENTION

[0006] A method of treating multiple sclerosis (MS) in patients with a history of past or ongoing conditions other than MS is provided. Surprisingly, patients with a history of past or ongoing conditions other than multiple sclerosis, and patients in need of treatment or prevention of relapsing multiple sclerosis, can be successfully treated with ocrelizumab without substantially compromising the management of conditions other than MS. Furthermore, patients can receive vaccinations during ocrelizumab therapy. Ocrelizumab is an anti-CD20 antibody that depletes lymphocytes, which was completely unexpected. Thus, ocrelizumab was expected to have a negative impact on the immune system, so past or ongoing conditions, such as past or ongoing infections, could not be successfully treated in patients receiving ocrelizumab therapy. Consistent with this expectation, Pescovitz et al. reported that rituximab, another anti-CD20 antibody, ​ B demonstrated a reduction in IgM levels. "B-lymphocyte depletion with rituximab and β-cell function: two-year results", Diabetes Care, 2014 Feb; 37( 2); 453-9. See also

Brief Description of the Drawings

[0007]

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DETAILED DESCRIPTION OF THE INVENTION

[0008] General definitions The terms "treatment" or "treating" can be defined, for example, as the application or administration of ofatumumab to a patient, the purpose of which is to eliminate, reduce or alleviate the symptoms of a disease such as multiple sclerosis (MS). In particular, the term "treatment" includes the achievement of a clinically significant effect on the patient, for example, the achievement of a clinically significant reduction in the annual relapse rate during the treatment of RMS. For the purposes of this specification, a patient can be "in need of" treatment if such a patient would benefit medically or in terms of quality of life from such treatment. The term "patient" as used herein can be a mammal, for example, a primate, preferably a higher primate, and particularly preferably a human (e.g., a patient at risk of or having a disorder described herein). Preferably, the patient is an adult. As used herein, the term "administering" ofatumumab or "administration" of ofatumumab can mean providing ofatumumab to a patient in need of treatment. Administration "in combination" with one or more additional therapeutic agents can include simultaneous (concurrent) as well as sequential administration in any order and by any route of administration. As used herein, a "therapeutically effective amount" can refer to an amount of ofatumumab that is effective, i.e., achieves a clinically significant effect.

[0009] As used herein, the term "adverse event" (AE) refers to an event that the subject does not necessarily have a causal relationship with this treatment.

[0010]

[0011]

[0012] ​​​​​​​​​​​​It may be related to the occurrence of any adverse medical events in patients or clinical trials, such as when a pharmaceutical is administered. Therefore, an adverse event (AE) can be any undesirable and unintended sign (including abnormal findings by examination), symptom, or disease that is temporarily related to the use of a pharmaceutical (investigational), regardless of whether it is related to the pharmaceutical (investigational). The term "treatment regimen" can mean a regimen used to treat a disease or prevent the onset of a condition or disease, for example, the dosing used. The treatment regimen can include an induction regimen, a loading regimen, and a maintenance regimen.

[0013] The term "loading regimen" or "loading dose" can refer to the treatment regimen (or a portion of the treatment regimen) used in the initial treatment of a disease. In some embodiments, the disclosed methods, uses, kits, processes, and regimens use a loading regimen. In some cases, the loading period is the period until maximum effectiveness is reached. A general rule for a loading regimen can be to provide a high level of drug to the patient during an initial period of the treatment regimen. The induction regimen can use a "loading regimen" or "loading dosing" (partially or

[0014] entirely), administer a higher dose of drug than the dose the physician uses during the maintenance regimen, administer the drug at a higher frequency than the frequency at which the physician administers the drug during the maintenance regimen, or include both. An increase in dose can occur during or after the induction regimen. The term "maintenance regimen" or "maintenance dose" refers to the maintenance of a patient during the treatment of a disease. The disclosed methods, uses, kits, processes, and regimens can use a loading regimen. In some cases, the loading period is the period until maximum effectiveness is reached. A general rule for a loading regimen can be to provide a high level of drug to the patient during an initial period of the treatment regimen. The induction regimen can use a "loading regimen" or "loading dosing" (partially or entirely), administer a higher dose of drug than the dose the physician uses during the maintenance regimen, administer the drug at a higher frequency than the frequency at which the physician administers the drug during the maintenance regimen, or include both. An increase in dose can occur during or after the induction regimen. The induction regimen can use a "loading regimen" or "loading dosing" (partially or entirely), administer a higher dose of drug than the dose the physician uses during the maintenance regimen, administer the drug at a higher frequency than the frequency at which the physician administers the drug during the maintenance regimen, or include both. An increase in dose can occur during or after the induction regimen. The induction regimen can use a "loading regimen" or "loading dosing" (partially or entirely), administer a higher dose of drug than the dose the physician uses during the maintenance regimen, administer the drug at a higher frequency than the frequency at which the physician administers the drug during the maintenance regimen, or include both. An increase in dose can occur during or after the induction regimen.

[0015] The term "maintenance regimen" or "maintenance dose" refers to the maintenance of a patient during the treatment of a disease. For example, after the induction period, it can refer to a treatment regimen (or a portion of a treatment regimen) used to keep a patient in remission for a long period (several months or years). In some embodiments, the disclosed methods, uses, and regimens employ a maintenance regimen. The maintenance regimen can be continuous therapy (e.g., administering a drug at regular intervals, such as weekly, monthly [every 4 weeks], annually, etc.) or intermittent therapy (e.g., split therapy, intermittent therapy, therapy at recurrence, or therapy at the attainment of certain predefined criteria [e.g., pain, disease findings, etc.]). An increase in dosage can occur during the maintenance regimen.

[0016] The term "Multiple Sclerosis Impact Scale (MSIS-29)" is defined as follows : MSIS-29 version 2 is a self-administered questionnaire covering 29 items across two domains: physical and psychological. Responses are recorded on a 4-point ordinal scale ranging from 1 (not at all true) to 4 (highly true), and higher scores reflect a greater impact on daily life. MSIS-29 takes about 5 minutes to complete and is designed to determine the patient's view on the impact of MS on their daily life over the past 2 weeks. Hobart J and Cano S (2009), “Improving the evaluation of therapeutic interv entions in multiple sclerosis: the role of new psychometric methods”, Health Te chnol 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 is referred to.

[0017] The expression “patients with a history of past conditions other than multiple sclerosis” can mean that the patient has or has had a pre-existing condition. A pre-existing condition is defined as a “medical condition that occurred before the health benefit program took effect” (“Billing terminology”. Pittsburgh: University of Pittsburgh Medical Center (UPMC).2010. Archived from the original on October 3, 2010. Retrieved January 16, 2010). In the context of the present invention, a “health benefit program” can be related to a therapy that includes the administration of ofatumumab. Thus, a pre-existing condition occurred or was initiated before the start of ofatumumab therapy. In a preferred embodiment, the ofatumumab therapy is for treating (R)MS.

[0018] Vaccination can be the administration of a vaccine to help the immune system create a defense against a disease. The vaccine preferably contains an attenuated, live or killed microorganism or virus, or a protein or toxin derived from an organism. By stimulating the body's adaptive immunity, these help prevent getting sick from infectious diseases. When a sufficiently high percentage of the population is vaccinated, herd immunity results. Vaccination can be the most effective method to prevent infectious diseases. and a person is using a treatment to cure or modify the symptoms of a primary disease (e.g., MS) or to treat a primary disease. If you are already receiving treatment to alleviate the symptoms of your disease (e.g., MS), Research in the field has shown that it is difficult to vaccinate a person against a second disease. Or it is not possible.

[0019] In a preferred embodiment, the vaccine comprises tetanus toxoid, 13-valent pneumococcal conjugate 13-PCV, 23-valent pneumococcal polysaccharide vaccine (23-PPV), seasonal 4 not the 2-valent influenza vaccine, the HPV vaccine and / or the Hepatitis B vaccine.

[0020] RRMS Relapsing-remitting multiple sclerosis (MS) is characterized by relapses, e.g., when there is a fever or infection. A new episode of neurological deficit or deterioration lasting more than 24 hours in the absence of It is justified.

[0021] During remission there is no obvious progression of the disease. RRMS may be active at different times. active (with evidence of recurrence and / or new MRI activity) or inactive; and whether the condition worsens (increased disability observed over a specified period following relapse) The condition can be further characterized as either worsening or not worsening. 2014, Neurology. 2014 Jul 15; 83(3): 278-286.

[0022] RMS The term RMS (relapsing multiple sclerosis) includes RRMS, SPMS and clinically isolated includes clinically isolated syndrome (CIS).

[0023] Primary progressive MS (PPMS) PPMS is characterized by a progressive worsening of neurological function (accumulation of disability) from symptom onset without early relapses or remissions. PPMS can be further characterized at different time points as either active (with evidence of sporadic relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014. and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014. and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014. and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014. and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014. and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses or new MRI activity) or non - progressive. Referring to Lublin 2014.

[0024] Each person's experience of PPMS is unique. PPMS can have short periods of disease stability regardless of the presence or absence of MRI relapses or new activity, and similarly, can have periods of increasing disability regardless of the presence or absence of new relapses or lesions on MRI. Each person's experience of PPMS is unique. PPMS can have short periods of disease stability regardless of the presence or absence of MRI relapses or new activity, and similarly, can have periods of increasing disability regardless of the presence or absence of new relapses or lesions on MRI. Each person's experience of PPMS is unique. PPMS can have short periods of disease stability regardless of the presence or absence of MRI relapses or new activity, and similarly, can have periods of increasing disability regardless of the presence or absence of new relapses or lesions on MRI. Each person's experience of PPMS is unique. PPMS can have short periods of disease stability regardless of the presence or absence of MRI relapses or new activity, and similarly, can have periods of increasing disability regardless of the presence or absence of new relapses or lesions on MRI.

[0025] Secondary progressive MS (SPMS) SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. SPMS occurs following an initial relapsing - remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course, in which there is a progressive worsening of neurological function (accumulation of disability) over time. SPMS can be further characterized at different time points as either active (with evidence of relapses and / or new MRI activity) or inactive, and similarly, as either progressive (with evidence that the disease is worsening in terms of an objective measure of change over time regardless of the presence or absence of relapses) or non - progressive. It can be levied. Referring to Lublin 2014.

[0026] The experience of each person with SPMS is unique. SPMS occurs following the relapsing-remitting form of MS. Disability increases gradually over time regardless of the presence or absence of evidence of disease activity (relapses or changes on MRI). In SPMS, sporadic relapses can occur even during stable periods.

[0027] Clinically isolated syndrome (CIS): Clinically isolated syndrome (CIS) can refer to a single clinical episode of inflammatory demyelinating symptoms of the central nervous system (CNS) that suggests multiple sclerosis (MS). CIS symptoms can be single or multiple and typically can involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral hemispheres of the brain. Referring to Miller et al, Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169. 11:157-169.

[0028] T1 and T2 lesions T1 and T2 relate to different MRI methods used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time 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 refer 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 the burden or lesion load (total amount of old and new lesion areas) of the disease.

[0029] Relapse Relapse can be defined as a new episode of nerve loss or nerve deterioration that preferably lasts longer than 24 hours. In other words, relapse can be regarded as separate episodes of neurological dysfunction (also referred to in the art as "attacks", "episodes" or "deteriorations") that preferably last at least 24 hours. Usually, after a relapse, there follows a period of remission during which there is no complete or partial recovery and no progression of symptoms or accumulation of disabilities.

[0030] Ocrelizumab: Ofatumumab is a human monoclonal antibody against the CD20 protein. Ofatumumab can bind specifically 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 functions to bring about 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 the mouse NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains, with a molecular weight of approximately 146 kDa.

[0031] Ofatumumab is described in European Patent No. 1558648 and European Patent No. 328475 3. Further reference is made to the descriptions in drugbank.ca, accession number DB06650 and WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the protein chemical formula is C 6480 H 10022N 1742 O 2020 S 44 and, The average protein weight is approximately 146,100 Da.

[0032] The metabolic pathway of ofatumumab can be degradation into small peptides and amino acids by proteolytic enzymes present everywhere. Ofatumumab can be removed by two pathways: a target-independent pathway as in the case of other IgG molecules, and a target-mediated pathway related to binding to B cells.

[0033] Particularly after repeated subcutaneous administration of a 20 mg dose, the half-life of ofatumumab at steady state can be approximately 16 days.

[0034] Ofatumumab preferably does not share a common clearance pathway with chemical drugs that are metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. Preferably, ofatumumab

[0035] Detailed description of the invention Low levels of immunoglobulin G (IgG) and / or IgM over a long period are associated with a higher risk of infection. Some MS therapies have been found to reduce immunoglobulin levels, which raises concerns. In particular, treatment with B cell depletion therapy has been reported to also result in a decrease in serum levels of immunoglobulin (Ig) G, IgM and / or IgA. Furthermore, since MS therapies are usually lifelong therapies, the risk of

[0036] infection increases in MS patients. can result in a higher infection rate. Ocrelizumab is approved for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS) in the United States. Another antibody similar to rituximab and o crelizumab has been reported to be associated with a higher risk of infectious diseases, especially in patients with low levels of IgM or IgG .

[0037] In June 2019, the European Commission updated the prescribing information for ocrelizumab and described the association between the reduction of immunoglobulins and severe infectious diseases as follows: "Treatment with Ocrevus induced mainly a reduction of IgM over the controlled experimental period, leading to a reduction of total immunoglobulins . The trial data show an association between the reduction of IgG (and to a lesser extent IgM or IgA) and severe infectious diseases."

[0038] K. Smoot et al. ("The Impact of Ocrelizumab on Immunoglobulin Levels and t he Risk of Infection", 09 / 12 / 19; 278212; P1010) studied MS patients treated with ocrelizumab and reported that there was no evidence of a significant difference in IgM levels between patients who developed infectious diseases and those who did not. However, they emphasized that infectious diseases were more commonly seen in patients with low IgG levels .

[0039] T.Derfuss et al. ("Serum immunoglobulin levels and risk of serious infect ions in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and th ​​​​"eir open-label extensions", ECTRIMS Online Library. Derfuss T. 09 / 11 / 19; 279399 ; 65) evaluated serum Ig levels over 5.5 years. They observed a decrease in serum Ig levels, along with an apparent association with an increase in the rate of severe infections. This association was strongest for IgG, but less so for IgM or IgA. The decrease in serum Ig levels progressed at an average rate of approximately 3-4% per year (see Figure 1). There was an apparent association between the decrease in IgG levels and severe infections.

[0040] Overall, in clinical trials, one of the most common adverse events associated with B-cell depletion therapies, such as ocrelizumab therapy, is a reduction in immunoglobulin (e.g., IgM) in the blood and has been reported.

[0041] Therefore, it is completely surprising that ofatumumab therapy is advantageous compared to other B-cell depletion therapies in causing a lower degree of reduction in immunoglobulin (e.g., IgM) in the blood. Consequently, the risk of severe infections is unexpectedly reduced in patients treated with ofatumumab. Furthermore, the fact that there is no adverse effect on the immune system or that it is improved has opened up new avenues for patients treated with ofatumumab. For example, these patients can receive vaccinations while undergoing ofatumumab therapy. Furthermore, they can be treated with ofatumumab despite having past or ongoing conditions other than multiple sclerosis. This is an important clinical advantage and will be described in detail below in this specification.

[0042] In contrast, other immunomodulatory or immunosuppressive treatments (e.g., ocrelizumab) expose the patient to a higher risk of a stronger immune response (e.g., activation of the complement system and / or reduction of the interaction between B cells and T cells and / or changes in cytokine production and / or bystander activation). Furthermore, these other treatments require more caution regarding the timing of vaccination, even if vaccination is possible or recommended (see Tobias Zrzavy et al.: Vaccination in Multiple Sclerosi s: Friend or Foe?, FRONTIERS IN IMMUNOLOGY, vol. 10, 1 January 2019, page 1883). See also).

[0043] One aspect of the invention relates to ofatumumab for use in the treatment or prevention of relapsing-remitting multiple sclerosis (RMS) in patients having a history of past or ongoing conditions other than multiple sclerosis. The expression "patients having a history of past conditions other than multiple sclerosis" means that the patient has, or has had, a pre-existing condition. A pre-existing condition is defined as "a medical condition that occurred before the health benefit program became operative" ("Billing terminology". Pittsburgh: University of Pittsburgh Medical Center (UPMC). 2010. Archived from the original on October 3, 2010. Ret rieved January 16, 2010). In the context of the present invention, a "health benefit program" is ofatumumab ​​​​​​It relates to a therapy including the administration of mab. Therefore, the pre-existing condition occurred or started before the initiation of ocrelizumab therapy. It occurred or started before the initiation of

[0044] Conditions other than multiple sclerosis may be nasopharyngitis headache injection site reaction upper respiratory tract infection urinary tract infection back pain fatigue influenza nausea decrease in blood immunoglobulin M or G alopecia arthralgia diarrhea pain in the extremities depression macular edema varicella common cold increase in gamma-glutamyl transferase abdominal pain skin cancer bradycardia hemorrhagic localized encephalitis herpes infection progressive multifocal leukoencephalopathy (PML) hypertension paresthesia It may be one or more of these.

[0045] These conditions other than multiple sclerosis can result from viral, bacterial or other infectious diseases as described below.

[0046] Alternatively, these conditions other than multiple sclerosis can also result from drugs, such as immunosuppressive drugs. Immunosuppressive drugs include corticosteroids, such as prednisone (Deltasone, Orasone), budesonide (Entocort EC), prednisolone (M illipred); Janus kinase inhibitors, such as tofacitinib (Xeljanz ); Calcineurin inhibitors, such as cyclosporine (Neoral, Sandimmune, SangCya) and tacrolimus (Astagraf XL, Envarsus XR, Prograf); mTOR inhibitors, such as sirolimus (Rapamune) and everolimus (Afinitor, Zortress); IMDH inhibitors, such as azathioprine (Azasan, Imuran), leflunomide (Arava) and mycophenolate (CellCept, Myfortic); lymphocyte sequestrants, such as fingolimod (Gilenya); biological agents, such as abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio); monoclonal antibodies, such as basiliximab (Simulect), daclizumab (Zinbryta), ocrelizumab (Ocrevus) are exemplified. In a preferred embodiment, the immunosuppressive drug is fingolimod (Gilenya), ocrelizumab (Ocrevus), natalizumab (Tysabri) or rituximab (Rituxan). Fingolimod (Gilenya) is particularly preferred. une, SangCya) and tacrolimus (Astagraf XL, Envars us XR, Prograf); mTOR inhibitors, such as sirolimus (Rapamun e) and everolimus (Afinitor, Zortress); IMDH inhibitors, such as azathioprine (Azasan, Imuran), leflunomide (Arava) and mycophenolate (CellCept, Myfortic); lymphocyte sequestrants, such as fingolimod (Gilenya); biological agents, such as abatacept (Orenc ia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi) , infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosent yx), tocilizumab (Actemra), ustekinumab (Stelara), vedoli zumab (Entyvio); monoclonal antibodies, such as basiliximab (Simul ect), daclizumab (Zinbryta), ocrelizumab (Ocrevus) are exem plified. In a preferred embodiment, the immunosuppressive drug is fingolimod (Gilenya), ocrelizumab (Ocrevus), natalizumab (Tysabri) or rituxim ab (Rituxan). Fingolimod (Gilenya) is particularly preferred.

[0047] As a further alternative, the said condition other than multiple sclerosis can result from diseases such as autoimmune diseases other than multiple sclerosis. patients.

[0048] In a preferred embodiment of this aspect of the invention, a past or ongoing medical history of conditions other than multiple sclerosis is a past or ongoing history of infectious diseases. The expression "past or ongoing history of infectious diseases" means that the patient has or had a pre-existing infectious disease. A pre-existing infectious disease is defined in the same way as a pre-existing condition as shown above. In the context of the present invention, a "health benefit program" relates to a therapy including the administration of ocrelizumab. Thus, a pre-existing infectious disease occurred or began prior to the start of ocrelizumab therapy.

[0049] Patients suffering from an infectious disease are more likely to exhibit more severe signs and symptoms when receiving immunosuppressive therapy. Since anti-CD20 antibodies suppress the immune system, it is not at all surprising that ocrelizumab, which is an anti-CD20 antibody, can cause or favorably act on more severe signs and symptoms.

[0050] Past or ongoing infectious diseases include the following Respiratory syncytial virus (RSV), Influenza or parainfluenza virus, Human polyomavirus (BK virus), Adenovirus, Rhinovirus, Coronavirus, especially SARS-CoV-2, Human herpesviruses such as herpes simplex virus (HSV), Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Beta polyomaviruses such as John Cunningham virus (JCV), Bordetella pertussis, Bordetella parapertussis, Corynebacterium diphtheriae, E. coli, Staphylococcus spec. (e.g., Staphylococcus saprophyticus or Staphylococcus aureus), , Chlamydia trachomatis, Haemophilus influenzae, Meningococcus spec., Klebsiella spec., Pseudomonas spec., Enterococcus spec., Streptococcus spec., yeast (e.g., Candida albicans), Pneumocystis spec. (e.g., Pneumocystis murina), Cryptococcus spec (e.g., Cryptococcus neoformans), Aspergillus spec., Mycoplasma genitalium and may be caused by a virus or microorganism selected from the group consisting of.

[0051] Thus, a history of past conditions other than multiple sclerosis may have been triggered by a viral infection and the virus causing the infection may be, for example, respiratory syncytial virus (RSV ), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, rhinovirus, coronavirus, human herpesvirus such as herpes simplex virus (HSV), varicella-zoster virus (VZV), EBV or also cytomegalovirus (CMV) or betapolyomavirus such as John Cunningham virus (JCV). Three of the four types of influenza virus affect humans: type A, type B and

[0052] type C. Type D is not known to infect humans but is thought to have the potential to infect. Usually, the virus spreads through the air via coughing or sneezing. The virus can also spread by touching a surface contaminated with the virus and then touching the eyes, nose or mouth . People can infect others before and during the period when they show symptoms. Annual vaccination against influenza is recommended by the World Health Organization (WHO) for high-risk people and by the Centers for Disease Control and Prevention (CDC) in the United States for people 6 months of age and older. However, patients who are likely to receive or initiate immunosuppressive therapy usually are not eligible for vaccination and do not respond because their immune system is suppressed. Since anti-CD2 0 antibodies suppress the immune system, it was completely surprising that ofatumumab, an anti-CD20 antibody, did not interfere with vaccination against influenza virus .

[0053] ​​​​​​ Antiviral drugs, among others, for example, neuraminidase inhibitors, oseltamivir, are used to treat influenza. It has surprisingly been found that said drugs can be used in patients who have been treated with or are starting treatment with ofatumumab. Accordingly, aspects of the present invention are based on the surprising finding that ofatumumab, in contrast to other anti-CD20 therapies, does not interfere with the control of influenza.

[0054] Coronaviruses are a group of viruses that cause diseases in mammals and birds. In humans, coronaviruses usually cause mild respiratory infections, for example, in some cases of the common cold (among other prominent causes, mainly rhinoviruses), although rarer forms, such as SARS, MERS, and COVID-19, can be lethal. Vaccines or antiviral drugs to prevent or treat human coronavirus infections do not yet exist. Patients infected with coronaviruses, such as SARS-CoV-2, are assumed to be treatable with or able to start treatment with ofatumumab.

[0055] There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). HSV-1 more commonly causes infections around the mouth, while HSV-2 more commonly causes genital infections. These are transmitted by direct contact with the body fluids or lesions of an infected individual. After infection, the virus is transported along sensory nerves to the nerve cell bodies and lodges there for life. Recurrences can be caused by a decrease in immune function, stress, and exposure to sunlight. Thus, patients who are undergoing immunosuppressive therapy ​​​​​​​It is prone to recurrence. Since anti-CD20 antibodies suppress the immune system, it is completely surprising that ofatumumab, an anti-CD20 antibody, neither causes recurrence nor acts favorably on them. It was quite astonishing.

[0056] By taking antiviral drugs daily, the spread can be reduced in people infected with this infectious disease. There is no available vaccine, and once infected, it cannot be cured. Paracetamol (acetaminophen) and topical lidocaine can be used to relieve symptoms. Treatment with antiviral drugs, such as acyclovir or valacyclovir, can reduce the severity of symptomatic episodes. It has been surprisingly found that the drug can be used in patients treated with or starting treatment with ofatumumab. Therefore, an aspect of the present invention is based on the surprising discovery that ofatumumab does not interfere with HSV control, in contrast to other anti-CD20 therapies.

[0057] Human alphaherpesvirus 3 (HHV-3), also known as varicella-zoster virus (VZV), is one of nine known herpesviruses that infect humans. It is the most common cause of chickenpox, a disease that generally affects children, adolescents, and young adults, and shingles (zoster herpes), a disease that affects adults and is rare in children. VZV replicates in the lungs and causes a wide variety of symptoms. After the primary infection (chickenpox), the virus becomes latent within nerves, including the cranial, dorsal root, and autonomic ganglia. After many years have passed since this person has recovered from chickenpox, VZV can reactivate and cause a neurological condition. In the human body, this ​ The condition is acyclovir for chickenpox, famciclovir for shingles, and bacillovir for varicella. Several, including lacyclovir, varicella zoster immune globulin (ZIG), and vidarabine It can be treated with a variety of drugs and therapeutic agents. VZV immune globulin is also a treatment. Acyclovir is frequently used as the drug of choice in primary VZV infection. By initiating its administration early, the duration of any symptoms can be significantly shortened. The drugs and therapeutic agents are Surprisingly, it was found that this could be used as a VZV therapy. During vaccination, patients can be further vaccinated against VZV. An aspect of the invention is that ofatumumab, in contrast to other anti-CD20 therapies, prevents VZV control. Thus, the present disclosure is based on the surprising discovery that VZV-associated disease in patients is not A method for preventing a patient suffering from a rheumatoid arthritis comprising administering to said patient a therapeutically effective dose of ofatumumab. It relates to the method of including

[0058] In one embodiment of the present invention, ofatumumab is administered to patients with active HBV infection. Not administered.

[0059] Epstein-Barr virus (EBV) is a human herpesvirus 4 (HHV4). It belongs to the genus Lymphocryptovirus within the subfamily of Gammaherpesviruses. These viruses establish a latent infection of their host cells. and induces proliferation of latently infected cells (Roizman B. Herpesviridae: general description n, taxonomy and classification. In: Roizman B, editor. The herpesviruses. London : Plenum Press, 1996:1_ / 23. (summarized in). EBV is associated with an ever-increasing range of clinical disorders, from acute and chronic inflammatory diseases to lymphoid and epithelial malignancies . Epstein-Barr virus is associated with different types of lymphoid cells, such as lymphoproliferative diseases, T cells, B cells, or natural killer (NK) cells in diseases where Epstein-Barr virus infects. Infected cells divide excessively and develop various lymphoproliferative disorders (LPD, non-cancerous, pre-cancerous, and cancerous). These LPDs include infectious mononucleosis and subsequent disorders that may occur . Although not LPD, diseases associated with EBV include malignancies, sarcomas, multiple sclerosis, systemic lupus erythematosus, Hodgkin and non-Hodgkin lymphomas, nasopharyngeal carcinoma, gastric cancer, leiomyosarcoma, and "Alice in Wonderland syndrome" (Middeldorp et al., Critical Reviews in Oncology / Hematology 45 (2003) 1- / 36 2003). One aspect of the present invention is based on the surprising discovery that ofatumumab, in contrast to other anti-CD20 therapies, does not interfere with EBV control in vitro . Thus, the surprising discovery that immunosuppressive anti-CD20 therapies do not interfere with EBV control is an essential requirement and foundation for the development of treatment methods in patients at risk of developing diseases associated with EBV (Middeldorp et al., Critical Reviews in Oncology / Hematology 45 (2003) 1- / 36 2003).

[0060]

[0061] ​​​​​​​​​​​Cytomegalovirus (CMV) is a member of the order Herpesvirales. Family Herpesviridae, subfamily Betaherpesvirinae y Betaherpesvirinae) is a genus of viruses. Humans and monkeys serve as natural hosts. Human beta-herpesvirus 5 (HCMV, human cytomegalovirus, HHV- HHV-5 is a species that infects humans. Diseases associated with HHV-5 include mononucleosis and pneumonia. Most people who are otherwise healthy but who become infected with CMV will develop any signs and symptoms. However, some people experience little, if any, congenital A small percentage of infants with CMV develop symptoms over time (sometimes months or even years after birth). The most common of these delayed symptoms is hearing loss. A small number of infants and young children may also develop vision problems. In addition, Somatized people may experience more severe signs and symptoms affecting: eye, lung, liver, esophagus, stomach, Intestines, brain.

[0062] In a preferred embodiment, control of viral infection (viral control) is possible, i.e. and that despite ofatumumab therapy, there was no substantial or at least tolerable The disease will progress without delay or restriction. The term also refers to the treatment described above and includes the viral load in the whole blood of the treated patient. , less than 5,000 copies of viral genome / μg DNA, 4,500 copies / μg DNA less than, less than 4000 copies / μg DNA, less than 3500 copies / μg DNA, 300 less than 0 copies / μg DNA, less than 2500 copies / μg DNA, 2000 copies / μ g DNA, less than 1500 copies / μg DNA or less than 1000 copies / μg DN A. In a preferred embodiment, the viral load in whole blood described above is maintained for at least 6 months, at least 9 months, at least 12 months , at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years or longer after transplantation.

[0063] The term controlling the virus or controlling a viral infection also refers to the treatment described above, and the viral load in plasma is less than 3000 copies / 100 μl, 2500 copies / 1 00 μl, less than 2000 copies / 100 μl, less than 1500 copies / 100 μl or less than 1000 copies / 100 μl. In a preferred embodiment, the viral load in plasma described above is maintained for at least 6 months, at least 9 months after transplantation, at least 12 months, at least 15 months, at least 18 months period, at least 21 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years period, at least 8 years or longer.

[0064] Furthermore, the term "controlling the virus" or "controlling a viral infection" also refers to the treatment of a patient as used herein, wherein the patient is a patient with MS, and more specifically, the patient requires immunosuppression, and a therapeutically effective dose of ocrelizumab results in a reduction in viral titer or viral load or viral infection status, and the viral load (e.g., viral DNA load) is reduced by at least 20%, at least 30%, at least 40%, at least 50% , at least 60%, at least 70%, at least 80%, at least 90% or 9 0% reduction. In a preferred embodiment, the reduced viral load is maintained for at least 6 months, at least 9 months, at least 12 months after the start of ocrelizumab therapy, for at least 15 months, at least 18 months, at least 21 months , at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years or longer than this.

[0065] In a preferred embodiment, the treatment according to the invention provides for the prevention of virus-associated diseases by providing suitable means (e.g., dosing or vaccination) that are not normally used during immunosuppressive treatment. Since anti-CD20 antibodies suppress the immune system, it is completely surprising that ocrelizumab, an anti-CD20 antibody, does not prevent the prevention of virus-associated diseases. The terms "prevent" or "preventing" generally refer to prophylactic treatment or treatment to prevent. These terms relate to delaying or preventing the onset of a disease, disorder and / or symptoms associated therewith. " Prevent" or "preventing" generally refers to prophylactic treatment or treatment to prevent. These terms relate to delaying or preventing the onset of a disease, disorder and / or symptoms associated therewith. The term "preventing a virus-associated disease" as used herein refers to the outcome of treatment of a patient with a therapeutically effective dose of ocrelizumab, particularly when the patient is an MS patient, more specifically a patient in need of immunosuppression, and the patient does not develop a virus-associated disease, particularly the patient does not develop lymphoproliferative disorders (LPD, non-cancerous, pre-cancerous and cancerous) including infectious mononucleosis, and subsequent disorders that may occur thereafter, or malignancies, sarcomas, multiple sclerosis, systemic lupus erythematosus and "Alice in Wonderland syndrome", which are not LPD but do not develop a virus-associated disease. The term "preventing a virus-associated disease" also refers to the treatment outcome of a patient as described above, and the patient does not develop a virus-associated disease as described herein for at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years or longer after the start of ocrelizumab therapy. As previously described, a history of past conditions other than multiple sclerosis may be a gold mine for bacterial infections, and bacteria that cause infections include, for example, Bordetella pertussis, Bordetella parapertussis, Corynebacterium diphtheriae, Escherichia coli, Staphylococcus species (e.g., Staphylococcus saprophyticus)

[0066] or Staphylococcus aureus), Chlamydia trachomatis a trachomatis), Haemophilus influenzae, meninges inflammatory species (Meningococcus spec.), Klebsiella spec., Pseudomonas species (Pseudomonas spec.), Enterococcus spec., Streptococcus ccus spec.).

[0067] Bordetella pertussis is a Gram-negative coccobacillus and is the causative agent of pertussis or whooping cough. Its virulence factors include pertussis toxin, adenylate cyclase toxin, filamentous hemagglutinin, pertactin, fimbriae, and tracheal cytotoxin.

[0068] Diphtheria is an infectious disease caused by Corynebacterium diphtheriae. Complications can include myocarditis, neuritis, kidney damage, and bleeding disorders due to low levels of platelets. Myocarditis can lead to abnormal heart rates, and neuritis can lead to motor paralysis.

[0069] Escherichia coli, also known as E. coli, is a Gram-negative bacterium commonly found in the lower intestine. Most E. coli strains are harmless, but some serotypes can cause severe food poisoning in these hosts and sometimes ​​​​​Causes food contamination incidents, etc. Toxic Escherichia coli (E. coli) strains can cause gastroenteritis, urinary tract infections, meningitis in newborns, hemorrhagic colitis, and Crohn's disease. Common signs and symptoms include severe abdominal cramps, diarrhea, hemorrhagic colitis, vomiting, and sometimes fever. In rare cases, the toxic strain is also involved in hemolytic uremic syndrome, peritonitis, mastitis, sepsis, and gram-negative pneumonia that do not progress to intestinal necrosis (tissue death) and perforation. Some strains of Escherichia coli (E. coli), such as O157:H7, can produce Shiga toxin (classified as a bioterror pathogen). Shiga toxin causes an inflammatory response within the target cells of the intestine, leaving lesions that result in the hemorrhagic diarrhea that is a symptom of Shiga toxin-producing Escherichia coli (STEC) infection. This toxin further causes premature destruction of red blood cells, then clogs the kidneys, which are the body's filtration system, and in some rare cases (usually in children and the elderly) causes hemolytic uremic syndrome (HUS), which can lead to kidney failure and even death. Uropathogenic Escherichia coli (E. coli) (UPEC) is one of the main causes of urinary tract infections. It is part of the normal gut microbiota and can be introduced in many ways. Enterotoxigenic Escherichia coli (E. coli) (ETEC) is the most common cause of traveler's diarrhea, with 840 million cases annually in developing countries around the world. The bacteria are usually transmitted via contaminated food or drinking water, adhere to the intestinal wall, and secrete one of two types of enterotoxins there, resulting in watery diarrhea.

[0070]

[0071]

[0072]

[0073] ​​​​​​​​​​​​​​ A specific strain of Escherichia coli (E. coli) is a major cause of food poisoning. Enterohemorrhagic E. coli (EHEC) bacteria cause hemolytic uremic syndrome (HUS), which is a medical emergency requiring urgent treatment.

[0074] Staphylococcus is a genus of Gram-positive bacteria in the family Staphylococcaceae of the order Bacillales. Staphylococcus can cause a wide variety of diseases in humans and animals, either through toxin production or invasion. These diseases can be caused by bacteria that grow in improperly stored food products, so staphylococcal toxins are a common cause of food poisoning. The most common form of cellulitis is caused by Staphylococci as a bacterial infection.

[0075] Chlamydia infections are sexually transmitted infections caused by the bacterium Chlamydia trachomatis. Most people who are infected are asymptomatic. If symptoms do actually develop, it takes several weeks after the infection occurs. The infection can spread to a woman's upper genital organs, causing pelvic peritonitis, which can lead to future infertility or ectopic pregnancy. Repeated infections of the eye can lead to trachoma if left untreated, which is a common cause of blindness in the developing world. Chlamydia can spread during vaginal, anal or oral sex and can be transmitted from an infected mother to her newborn during childbirth.

[0076] In a preferred embodiment, it is possible to control a bacterial infection (control of bacteria), i.e., to proceed substantially or at least without an unacceptable delay or limitation, despite the initiation of ofatumumab therapy. The term control of bacteria or control of a bacterial infection also refers to the treatment described above, and bacteremia is prevented or reduced. Bacteremia is most commonly diagnosed by blood culture, and a blood sample obtained by venipuncture by needle is incubated using a medium that promotes bacterial growth. If bacteria are present in the bloodstream at the time the sample is obtained, the bacteria will increase and can thereby be detected.

[0077] In another embodiment, a history of past conditions other than multiple sclerosis may have triggered a fungal infection, and the fungi that cause the infection are yeast (e.g., Candida albicans), Pneumocystis species (e.g., Pneumocystis murina), Cryptococcus species (e.g., Cryptococcus neoformans), and Aspergillus species.

[0078] Candida albicans is an opportunistic pathogenic yeast and a common member of the human gut flora. It is a normally commensal organism but can become a pathogen in immunocompromised individuals under various conditions. Candida albicans is one of several species of the genus Candida that cause the human infection candidiasis. ​​​​​​​​​​​​​ is one of them, and this human infectious disease candidiasis results from abnormal growth of fungi. Candida sis is, for example, often observed in patients infected with HIV. C. albicans (C. alb icans) is the most common fungal species isolated from biofilms formed on (permanently) implanted medical devices or human tissues. C. albicans (C. albicans) , C. tropicalis, C. parapsilosis and C . glabrata together are involved in 50 - 90% of all cases of candidiasis in humans. A mortality rate of 40% has been reported for patients with systemic candidiasis caused by C. albicans (C. alb icans). Recent experiments suggest that C . albicans can cross the blood - brain barrier . . .

[0079] The genus Pneumocystis represents related fungal species that are members of the phylum / division Ascomycota, subphylum Taphrinomycotina, class Pneumo - cystidomycetes, order Pneumocystidales and family Pneumocystidaceae, all of which fall within the field of fungi. A population of cases of Pneumocystis pneumonia (PCP) reported in immunocompromised patients. Pneumocystis infections have a worldwide distribution among humans, and most individuals show serological evidence of infection by the age of 2 years. Affected by AIDS . . . . . As demonstrated by the frequent onset of PCP in the following patients, the incidence of PCP is related to the degree of immunosuppression , particularly in relation to dysfunction in cellular immunity.

[0080] In a preferred embodiment, controlling fungal infections (controlling fungi) is possible, i.e., even in the face of (the initiation of) ofatumumab therapy, this proceeds without substantial or at least acceptable delay or limitation.

[0081] In another embodiment, a history of past conditions other than multiple sclerosis may be caused by Mycoplasma infections where the Mycoplasma that causes this infection is Mycoplasma genitalium .

[0082] Mycoplasma is a genus of bacteria without a cell wall around their cell membranes. This characteristic makes Mycoplasma naturally resistant to antibiotics that target cell wall synthesis (such as beta-lactam antibiotics ). Mycoplasma genitalium is a small and pathogenic bacterium that is sexually transmitted and lives on the skin cells of the human urinary and reproductive organs. Mycoplasma genitalium can have a negative impact on the health of both men and women. Furthermore, different organisms require different start times (incubation times) from when they enter the body until symptoms occur. Some of the common pathogens of upper respiratory infections and

[0083] their respective incubation times are as follows: - Rhinovirus, 1 - 5 days; ​​​- Group A streptococci, 1 - 5 days; - Influenza and parainfluenza viruses, 1 - 4 days; - Respiratory syncytial virus (RSV), 7 days; - Whooping cough (pertussis), 7 - 21 days; - Diphtheria, 1 - 10 days; and - Epstein - Barr virus (EBV), 4 - 6 weeks.

[0084] Therefore, some of these pathogens allow for therapeutic intervention for up to several weeks after entering the body but before they cause disease. Thus, treatment strategies can be changed during the incubation period.

[0085] Therefore, according to another aspect of the present disclosure, a method of preventing, reducing or alleviating such adverse events in a patient (e.g., an MS patient) at risk of developing such adverse events is provided, the method comprising administering ocrelizumab to the patient, wherein the patient is a patient with multiple sclerosis (MS) treated with a disease - modifying therapy other than ocrelizumab. In one embodiment ocrelizumab treatment is initiated when the patient is exposed to the risk of viral, bacterial or fungal infections. Alternatively, ocrelizumab treatment is initiated when signs (e.g., DNA) of viral, bacterial or fungal infections are detected but the patient still shows no symptoms. Adverse events include injection - related reactions, nasopharyngitis, headache, injection - site reactions, upper respiratory tract infections, urinary tract infections, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, arthralgia, diarrhea, limb pain, depression, macular edema, varicella (chickenpox) ​​​​​​​ One or more of herpes infection, progressive multifocal leukoencephalopathy (PML), hypertension, and paresthesia may be present.

[0086] In another embodiment, the method according to the disclosure is a method in which a patient at risk of developing a disease associated with an infectious disease is immunosuppressed or receiving administration of an immunomodulatory drug. In one embodiment the method according to the disclosure is a method in which the adverse event is cancer or a lymphoproliferative disorder.

[0087] In a preferred embodiment of this aspect of the invention, a patient being treated with ofatumumab receives vaccination during ofatumumab therapy. In another embodiment of the invention, a patient being treated with ofatumumab receives vaccination during ofatumumab therapy, and the patient has no history of past or ongoing conditions other than multiple sclerosis.

[0088] The vaccination is any one of the following rhinovirus, respiratory syncytial virus (RSV), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, human herpesvirus such as herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), beta polyomavirus such as John Cunningham virus (JCV), Bordetella pertussis, Bordetella parapertussis, Corynebacterium diphtheriae, E. coli, Staphylococcus saprophyticus, Staphylococcus aureus, Chlamydia trachomatis, Klebsiella spec., Pseudomonas spec., Enterococcus spec., Streptococcus spec., yeast (e.g., Candida albicans), Pneumocystis spec. (e.g., Pneumocystis murina), Cryptococcus spec (e.g., Cryptococcus neoformans), Aspergillus spec., Mycoplasma genitalium, coronavirus, particularly SARS-CoV-2 can be obtained against.

[0089] Ofatumumab is an anti-CD20 antibody and depletes lymphocytes, so it is completely unexpected that vaccination can be successful in patients treated with ofatumumab. Thus, ofatumumab affects the immune system, this aspect necessary for immune acquisition after vaccination. was expected to have a negative impact on immunoglobulins. Consistent with this expectation, Pes covitz et al. demonstrated that rituximab, another anti-CD20 antibody, results in a decrease in IgM levels Pescovitz et al., “B-lymphocyte depletion with rituximab and β-cell function: two-year results”, Diabetes Care, 2014 Feb; 37(2); 453-9 should be referred to.

[0090] Surprisingly, therefore, vaccination can be carried out during ofatumumab therapy. Vaccination can be carried out in patients regardless of a history of past or ongoing conditions other than multiple sclerosis Accordingly, a further subject of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein vaccination is carried out during ofatumumab therapy. Generally, the embodiments described (e.g., the amount and dosage regimen of ofatumumab administration) for vaccinated patients with a medical history can also be applied to patients without a medical history.

[0091] In another embodiment of this aspect of the invention, patients with a history of past or ongoing conditions other than multiple sclerosis have a history of transient ischemic attack (TIA); a history of cerebral infarction without residual defects; a history of thrombotic stroke without persistent effects; a history of thrombotic stroke without residual defects; a history of transient ischemic attack; a history of ischemic stroke without residual defects; a history of non-atherosclerotic stroke without residual defects; a history of parietal cerebrovascular attack; ​​​​​​History of cerebrovascular attack without residual defect; History of embolic stroke without defect; History of embolic stroke without persistent effect; History of embolic transient ischemic attack; History of hemorrhagic cerebrovascular attack without residual defect; History of atherosclerotic cerebrovascular attack without residual defect; History of cardiogenic cerebral embolism may be present.

[0092] Here, the expression "patient with a history of ~" means that the patient has or had a pre-existing condition (e.g., TI A). The pre-existing condition is defined as "a medical condition that occurred before the health benefit program takes effect" ("Billing terminology". Pittsbur gh: University of Pittsburgh Medical Center (UPMC). 2010. Archived from the orig inal on October 3, 2010. Retrieved January 16, 2010). In the context of the present invention, "health benefit program" relates to therapies including the administration of ofatumumab. Thus, a pre-existing condition (e.g., TIA) occurred or began before the start of ofatumumab therapy.

[0093] Patients with a history of past or ongoing conditions other than multiple sclerosis are expected to follow a treatment to cure, relieve or eliminate said condition before starting ofatumumab therapy. This treatment is glucocorticoids, e.g., cortisol, and / or or non-steroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen (Motrin , Advil) and naproxen (Naprosyn) or COX-2 inhibitors, e.g ​​​may include administration of celecoxib and / or immunosuppressive drugs.

[0094] In a preferred embodiment of this aspect of the invention, the past or ongoing condition is an autoimmune disease other than multiple sclerosis. Autoimmune diseases other than multiple sclerosis are as follows type 1 diabetes, rheumatoid arthritis (RA), psoriasis / psoriatic arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Addison's disease, Graves' disease, Sjögren's syndrome, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, celiac disease and can be selected from.

[0095] Thus, the autoimmune disease may be rheumatoid arthritis (RA). In this case, rheumatoid arthritis (RA) can be treated with disease-modifying antirheumatic drugs (DMARDs) selected from the group of methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-alpha inhibitors (certolizumab, infliximab, and etanercept), abatacept, anakinra, rituximab, and tocilizumab. Alternatively, the autoimmune disease may be psoriasis. Psoriasis can be treated with methotrexate, cyclosporine, hydroxycarbamide, fumarates, such as dimethyl fumarate, retinoids, anti-TNF therapy, such as infliximab, adalimumab, golimumab, and certolizumab pegol, etanercept, ixekizumab, ustekinumab, guselkumab, efz and can be treated with.

[0096] Instead, the autoimmune disease may be psoriasis. Psoriasis can be treated with methotrexate, cyclosporine, hydroxycarbamide, fumarates, such as dimethyl fumarate, retinoids, anti-TNF therapy, such as infliximab, adalimumab, golimumab, and certolizumab pegol, etanercept, ixekizumab, ustekinumab, guselkumab, efz It can be treated with ocrelizumab and alefacept.

[0097] In a preferred embodiment of this aspect of the invention, a history of past or ongoing conditions other than multiple sclerosis The history of the condition is a hospital admission history. The expression "hospital admission history" means that the patient was admitted to or was in the hospital before the start of ocrelizumab therapy. In particular, the hospital admission history is assumed to include a history of inpatient treatment and / or surgery. Preferably, the term "hospital admission history" does not include childbirth. Patients with a history of surgery can be treated with immunosuppressive agents other than ocrelizumab. The immunosuppressive agent is a glucocorticoid (e.g., cortisone, prednisone, dexamethasone, and hydrocortisone), a cytostatic agent (e.g., methotrexate, anthracycline, mitomycin C, bleomycin, mitramycin), an antibody (e.g., basiliximab (Simulect) and daclizumab (Zenapax)) or a drug acting on immunophilin (e.g., tacrolimus and cyclosporine) and can be selected from the group consisting of. For example, methotrexate, anthracycline, mitomycin C, bleomycin, mitramycin), an antibody (e.g., basiliximab (Simulect) and daclizumab (Zenapax)) or a drug acting on immunophilin (e.g., tacrolimus and (Zenapax)) or a drug acting on immunophilin (e.g., tacrolimus and cyclosporine) and can be selected from the group consisting of.

[0098] Alternatively, the history of past conditions other than multiple sclerosis may be a surgical history. The expression "surgical history" means that the patient has received or has received surgical treatment intervention before the start of ocrelizumab therapy. Patients with a surgical history can be treated with immunosuppressive agents other than ocrelizumab. The immunosuppressive agent is a glucocorticoid (e.g., cortisone, prednisone, dexamethasone, and hydrocortisone), a cytostatic agent (e.g., methotrexate, anthracycline, mitomycin C, bleomycin, mitramycin), an antibody (e.g., basiliximab (Simulect) and daclizumab cyclosporine) and can be selected from the group consisting of. For example, cortisone, prednisone, dexamethasone, and hydrocortisone), a cytostatic agent (e.g., methotrexate, anthracycline, mitomycin C, bleomycin, mitramycin), an antibody (e.g., basiliximab (Simulect) and daclizumab Mitomycin), an antibody (e.g., basiliximab (Simulect) and daclizu mab (Zenapax)) or a drug acting on immunophilins (e.g., tacrolimus and cyclosporine) can be selected from the group consisting of.

[0099] Ofatumumab can be used for the treatment or prevention of relapsing-remitting multiple sclerosis (RMS) in elderly patients. Elderly patients may suffer from age-related macular degeneration (AMD) or Alzheimer's disease or atherosclerosis or benign prostatic hyperplasia (BPH).

[0100] Ofatumumab can be used for the treatment or prevention of relapsing-remitting multiple sclerosis (RMS) in pediatric patients. to be used.

[0101] In a preferred embodiment of this aspect of the invention, conditions other than multiple sclerosis are cancer or lymph proliferative diseases.

[0102] In all embodiments described so far, ofatumumab can be administered when the serum neurofil lament light chain (NfL) concentration is 4 - 13 pg / mL. Neurofilament light chain is a human neurofil lament protein encoded by the NEFL gene. Neurofilament light chain can be measured in cerebrospinal fluid and plasma using immunoassays, and is a biomarker that reflects axonal damage in a variety of neurological disorders. Surprisingly, this has become a useful marker for the disease monitoring ring in multiple sclerosis. This has been demonstrated by the ASCLEPIOS I and II trials. The Expanded Disability Status Scale (Expanded Disabi between 0 and 5.5 ring in multiple sclerosis. This has been demonstrated by the ASCLEPIOS I and II trials. The Expanded Disability Status Scale (Expanded Disabi between 0 and 5.5 Patients aged 18 to 55 years with multiple sclerosis (MS) having an Expanded Disability Status Scale (EDSS) score were enrolled. The experiment was conducted at 350 sites in 37 countries. Additional secondary endpoints included disability improvement confirmed at 6 months, serum levels of neurofilament light chain (NfL), and brain volume loss rate.

[0103] Generally, the dosing regimen of ofatumumab is described in WO2018 / 033841 and can be applied to the present invention.

[0104] MSIS-29 (see above definition) is a clinically useful and scientifically sound assessment criterion for the impact of MS suitable for clinical research and epidemiological studies from the patient's perspective. MSIS-29 is a reliable, valid, and responsive patient-reported outcome (PRO) assessment criterion that complements other indicators of disease severity used to improve understanding of the impact of MS.

[0105] In the present invention, it was unexpectedly found that the administration of ofatumumab results in a favorable reduction in the MS impact scale MSIS-29 as defined below.

[0106] In this context, a further object of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein ofatumumab reduces the MSIS-29 score. Preferably, ofatumumab reduces the MSIS-29 score by at least 1.5, more preferably by at least 2.0, even more preferably by at least 2.5 within 24 months. The reduction may be up to 3.0 or 3.5 or 4.0.

[0107] In all embodiments described so far, ofatumumab can be administered at a dose of 10 to 3 0 mg, preferably 20 mg every 4 weeks. Such a dose can be referred to as a maintenance dose.

[0108] In a preferred embodiment, ofatumumab can be administered regardless of body weight, gender, age, race or baseline B cell count. For example, a 35-year-old female weighing 60 kg is preferably administered the same dose as a 50-year-old male weighing 90 kg. In particular, body weight, gender, age, race or baseline B cell count do not have a clinically significant effect on the pharmacokinetics of ofatumumab.

[0109] In a preferred embodiment, ofatumumab is administered to patients who have prematurely discontinued DMT, such as anti-CD20 therapy, due to side effects such as severe infusion-related reactions or recurrent infections.

[0110] Ofatumumab can be administered by injection. In a preferred embodiment, it is administered subcutaneously. Surprisingly, subcutaneous injection has been found to be advantageous compared to other parenteral administration forms, such as intravenous injection.

[0111] In a preferred embodiment, ofatumumab can be administered as a loading dose. A loading dose can be considered an initial higher dose of drug that can be administered at the start of the treatment course before tapering down to a lower maintenance dose. In a preferred embodiment, 20 mg of ofatumumab can be administered as a loading dose on days 1, 7 and 14. In a particularly preferred embodiment, 20 mg of ofatumumab is administered as a loading dose at week 0, week 1 and 2 weeks. It can be administered in the second week.

[0112] In a preferred embodiment of the present invention, the loading dose is 10 - 30 mg, preferably 20 mg of ofatumumab. ofatumumab.

[0113] The preferred dose of ofatumumab is - Initial dosing by subcutaneous injection of 20 mg at week 0, week 1, and week 2, followed by - Subsequent dosing by subcutaneous injection of 20 mg once a month starting from week 4 is.

[0114] If the injection of ofatumumab is not performed, it should be administered without waiting until the next scheduled dosing, preferably as soon as possible. Subsequent doses should be administered at the recommended intervals. Instead, ofatumumab is administered without a loading dose. Intervals.

[0115] Instead, ofatumumab is administered without a loading dose.

[0116] In a preferred embodiment of the present invention, ofatumumab is administered to patients treated with disease - modifying therapies other than ofatumumab. Patients treated with disease - modifying therapies other than ofatumumab.

[0117] In a particularly preferred embodiment, the disease - modifying therapy other than ofatumumab is dimethyl fumarate ( DMF). Preferably, DMF is administered at a daily dose of 120 mg - 480 mg, particularly 480 mg. Dose.

[0118] In a particularly preferred embodiment of the present invention, the disease - modifying therapy other than ofatumumab is laquinimod. Preferably, laquinimod is administered at a daily dose of 0.2 - 1.0 mg, preferably 0.6 mg. Dose.

[0119] In a particularly preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is teriflunomide. Preferably, teriflunomide is administered at a daily dose of 6 to 18 mg, preferably 14 mg.

[0120] In a preferred embodiment of the present 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.

[0121] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is natalizumab. Preferably, natalizumab is administered by intravenous injection at a dose of 100 to 500 mg every 4 weeks, preferably 300 mg.

[0122] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is daclizumab. Preferably, daclizumab is administered at a dose of 50 to 250 mg once a month, preferably 150 mg s.c.

[0123] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is glatiramer acetate. Preferably, glatiramer acetate is administered at a dose of s.c. injection of 20 mg / mL in a once-daily regimen, or at a dose of s.c. injection of 40 mg / mL three times a week.

[0124] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is rituximab. Preferably, rituximab is administered at a dose of 500 or 1,000 mg every 6 to 12 months, especially intravenously.

[0125] ​​​​In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is ocrelizumab Preferably, ocrelizumab is administered at a dose of 600 mg every 6 months, particularly intravenously .

[0126] Preferably, the patient has been previously treated with at least two courses of intravenous ocrelizumab or rituximab , for example, 2 to 5 consecutive courses. The last dose may be administered, for example , 4 to 9 months before ofatumumab is administered.

[0127] According to the present invention, in patients with RMS who are transitioning from intravenous anti-CD20 therapy , the efficacy of ofatumumab is maintained.

[0128] 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., recurrence, ≥2 active gadolinium-enhanced [Gd+ lesions, any new / enlarging T2 lesions, clinical worsening) and / or who have discontinued anti-CD20 therapy due to adverse events such as severe infusion-related reactions or recurrent infections. .

[0129] In a preferred embodiment of the present invention, the disease-modifying therapy other than ofatumumab is alemtuzumab . Preferably, alemtuzumab is administered at a dose of 12 mg / day and administered as an intravenous infusion .

[0130] In a preferred embodiment of the present invention, ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks , preferably at a dose of 20 mg every 4 weeks. Preferably, ofatumumab is administered by subcutaneous injection (s.c.) .

[0131] ​Ofatumumab can be administered in the form of a pharmaceutical preparation, for example, as described in WO2009 / 009407. It can be administered in the preparations described therein.

[0132] In a preferred embodiment, the ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each pre-filled pen or pre-filled syringe of 20 mg / 0.4 mL delivers a 0.4 mL solution. Preferably, each 0.4 mL contains 20 mg of ofatumumab and arginine (4 mg), disodium edetate (0.007 mg), poly sorbate 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 also be added to adjust the pH. It can also be added to adjust the pH. pH. Hydrochloric acid can also be added to adjust the pH.

[0133] In a preferred embodiment, the ofatumumab preparation is intended for self-administration by the patient, preferably by subcutaneous injection. It is intended for self-administration by the patient, preferably by subcutaneous injection.

[0134] In a preferred embodiment, the preparation is administered subcutaneously in the abdomen, thigh or outer upper arm. In a preferred embodiment, the preparation is not administered in areas with warts, scars or soft, bruised, red, hard or non-intact skin.

[0135] In one embodiment, the first injection of the ofatumumab preparation can be performed under the guidance of a healthcare professional. Symptomatic treatment is recommended if injection-related reactions occur. Before administration, the pen or pre-filled syringe is preferably removed from the refrigerator and returned to room temperature, for example, over about 15 to 3 0 minutes. In a preferred embodiment, the ofatumumab preparation of the present invention is transparent. 0 minutes. In a preferred embodiment, the ofatumumab preparation of the present invention is transparent. 0 minutes. In a preferred embodiment, the ofatumumab preparation of the present invention is transparent. A slightly milky white and faintly yellow solution with a slight brownish tint from colorless, as follows Available: - Injection: 20 mg / 0.4 mL, single-dose pre-filled pen, for example, Sensoread y (registered trademark) pen - Injection: 20 mg / 0.4 mL, single-dose pre-filled syringe.

[0136] In a preferred embodiment, the subcutaneous ofatumumab dose of 20 mg every 4 weeks results in an average AUC ta u of about 400 - 550, more preferably 450 - 500, for example 483 mcg h / mL, and / or an average C max of 1.0 - 2.5, more preferably 1.2 - 1.7, for example 1 .43 mcg / mL at steady state. In a preferred embodiment, after subcutaneous administration of repeated ofatumumab doses of 20 mg, the steady-state volume of distribution can be 4.5 - 6.5, more preferably 5.0 - 6.0, for example 5.42 L.

[0137] After subcutaneous administration, ofatumumab can be absorbed via the lymphatic system.

[0138] In all embodiments described so far, relapsing multiple sclerosis can be selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Currently, the United States National Multiple Sclerosis Society and the Multiple Sclerosis International Federation describe four types of MS (revised in 2013): Clinically Isolated Syndrome (CIS) Federation describe four types of MS (revised in 2013): Clinically Isolated Syndrome (CIS) Relapsing remitting multiple sclerosis (RRMS) Primary progressive multiple sclerosis (PPMS) Secondary progressive multiple sclerosis (SPMS)

[0139] In a preferred embodiment of the present invention, ocrelizumab is administered for the treatment of relapsing forms of multiple sclerosis (MS) which preferably includes clinically isolated syndromes, relapsing remitting diseases and active secondary progressive diseases in adults.

[0140] Relapsing remitting MS is characterized by unpredictable relapses followed by a relatively quiet (remission) period of several months to several years without new signs of disease activity. During an attack the deficits that occur may resolve or persist, with the latter occurring in about 40% of attacks and being more common in those with longer disease duration. This describes the initial course in 80% of individuals with MS. If deficits always resolve during an attack, this is sometimes called benign MS . However, people will still accumulate some degree of disability over the long term . On the other hand, the term malignant multiple sclerosis is used to describe people with MS who reach significant levels of disability in a short period of time. The relapsing remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack that suggests demyelination but does not meet the criteria for multiple sclerosis. 30 - 70% of people experiencing CIS will later develop MS. Thus, CIS patients can become patients as described herein , i.e., patients in need of treatment or prevention of relapsing multiple sclerosis .

[0141] .

[0141] Primary progressive MS occurs in approximately 10 - 20% of individuals who, after initial symptoms, have no remission.​ Is there no remission or improvement, or only occasional and minor remission and improvement, and characterized by the progression of the resulting disability? The usual onset age of the primary progressive subtype is later than that of the relapsing-remitting subtype. The secondary progressive type is usually around 40 years of age, similar to the onset age in relapsing-remitting MS. The secondary progressive type of MS occurs in approximately 65% of people with an initial relapsing-remitting MS and ultimately has progressive neurological decline between each acute attack without any definite remission period. Occasional relapses and minor remissions can occur. The most common length of time between disease onset and the conversion from relapsing-remitting to secondary progressive MS is 19 years. Unusual variants of MS have been described; these include tumefactive multiple sclerosis, Baló concentric sclerosis, Schilder diffuse sclerosis, and Marburg multiple sclerosis. There is debate as to whether these are variants of MS or different diseases. Some diseases previously thought to be variants of MS, such as Devic's disease, are now considered outside the MS spectrum.

[0142] All embodiments described so far can administer a premedication to the patient before the first dose of ocrelizumab is administered. The premedication can include acetaminophen, an antihistamine agent, and / or a steroid. It can be administered 30 to 60 minutes before the ocrelizumab injection. Alternatively, it is also possible not to administer a premedication before the first dose of ocrelizumab.

[0143]

[0144]

[0145]

[0146] ​​​​​​​​​​​​ The prophylactic effects of past or ongoing conditions, such as diseases associated with infectious diseases, can be evaluated by standard prescribed health checks performed by physicians and other persons skilled in the art using state-of-the-art assays and techniques for diagnosing and monitoring diseases. Persons skilled in the art are aware of the respective state-of-the-art diagnostic techniques that can be applied to the purposes described above. For example, the amount of virus or the state of infection can be analyzed, for example, by measuring the viral DNA load, and the quantification of viral DNA can be analyzed in whole blood, plasma, and / or B cells. Persons skilled in the art are aware of the techniques for analyzing the amount of virus and the state of infection in patients. The viral DNA load can be evaluated by analyzing the expression of viral genes. The present disclosure further relates to a method for reducing the likelihood of a patient developing an adverse event, the method comprising administering to the patient a therapeutically effective dose of ofatumumab. The term "reducing the likelihood" as used herein in the context of the development of an adverse event refers to the outcome of the patient's treatment, and more specifically, when the patient is a patient with MS, and more specifically still, when the patient requires immunosuppression with a therapeutically effective dose of ofatumumab, the risk of the patient developing an adverse event is reduced. Adverse events include injection-related reactions, nasopharyngitis, headache, injection site reactions, upper respiratory tract infections, urinary tract infections, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, joint pain, diarrhea, limb pain, depression, macular edema, varicella (chickenpox), common cold, increased gamma-glutamyl transfer, abdominal pain, skin cancer, bradycardia, hemorrhagic necrotizing encephalitis,

[0147] G, alopecia, joint pain, diarrhea, limb pain, depression, macular edema, varicella (chickenpox), common cold, increased gamma-glutamyl transfer, abdominal pain, skin cancer, bradycardia, hemorrhagic necrotizing encephalitis, The present disclosure further relates to a method for reducing the likelihood of a patient developing an adverse event, the method comprising administering to the patient a therapeutically effective dose of ofatumumab. The term "reducing the likelihood" as used herein in the context of the development of an adverse event refers to the outcome of the patient's treatment, and more specifically, when the patient is a patient with MS, and more specifically still, when the patient requires immunosuppression with a therapeutically effective dose of ofatumumab, the risk of the patient developing an adverse event is reduced. Adverse events include injection-related reactions, nasopharyngitis, headache, injection site reactions, upper respiratory tract infections, urinary tract infections, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, joint pain, diarrhea, limb pain, depression, macular edema, varicella (chickenpox), common cold, increased gamma-glutamyl transfer, abdominal pain, skin cancer, bradycardia, hemorrhagic necrotizing encephalitis, ​​​​​​One or more of herpes infection, progressive multifocal leukoencephalopathy (PML), hypertension, and paresthesia may be present.

Example

[0148] [Example 1] Design / Method APLIOS was a 12-week, open-label, phase 2 bioequivalence study. Patients received an offatumumab 20 mg (0.4 mL) s.c. loading dose on days 1, 7, and 14, and maintenance doses from week 4 every 4 weeks via prefilled syringes or an autoinjector pen (SensoReady). Fluorescence-activated cell sorting (FACS) was used to longitudinally analyze changes in B and T cell subsets in blood samples from the patient population. The offatumumab treatment showed rapid and sustained depletion in total B cells (CD19+CD45+), measured on days 4 and 7. The mean level of total B cells decreased to ≤5 cells / μL from day 7 to day 14 of the loading regimen and was maintained for the remainder of the study period. More efficient depletion of memory B cells (CD19+CD45+CD27+) was observed compared to naive B cells (CD19+CD45+IgD+CD27-CD38-). A specific subset of CD20+CD3+ T cells also rapidly and potently depleted, which was consistent with findings previously reported in primate studies.

[0149] Results dim

[0150] Conclusion Offatumumab 20 mg s.c. in patients with RMS showed CD20+B and C ​​​​​​​​​​​resulted in both rapid and sustained depletion of both D20+ T cells and specific subsets, namely depletion of memory B cells while sparing naive B cells, which is likely relevant to both the efficacy and long-term safety of ocrelizumab in the pathophysiology of MS. The differential effects on specific subsets, namely depletion of memory B cells while sparing naive B cells, are likely relevant to both the efficacy and long-term safety of ocrelizumab in the pathophysiology of MS.

[0151] [Example 2] Background Ocrelizumab, the first fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy to teriflunomide in the ASCLEPIOS I / II Phase 3 trial. See EC TRIMS Online Library, Hauser S.et.al. 09 / 13 / 19;279581;336. MS patients treated with ocrelizumab had an annualized relapse rate (ARR) that was reduced by 50.5% (0.11 vs 0.22) and 58.5% (0.10 vs 0.25), respectively, compared to Aubagio® (teriflunomide) in the ASCLEPIOS I and II trials (both p<0.0 01). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. MS patients treated with ocrelizumab had an annualized relapse rate (ARR) that was reduced by 50.5% (0.11 vs 0.22) and 58.5% (0.10 vs 0.25), respectively, compared to Aubagio® (teriflunomide) in the ASCLEPIOS I and II trials (both p<0.0 * (teriflunomide) in the ASCLEPIOS I and II trials (both p<0.0 01). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. .22) and 58.5% (0.10 vs 0.25) in the ASCLEPIOS I and II trials (both p<0.0 01). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. (teriflunomide). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. (teriflunomide). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. (teriflunomide). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®. (teriflunomide). Ocrelizumab demonstrated a highly significant suppression of gadolinium (Gd) T1 lesions and potent suppression of new inflammatory activity compared to Aubagio®. Ocrelizumab showed a 34.4% relative risk reduction (p=0.002) in confirmed disability progression (CDP) at 3 months and a 32.5% relative risk reduction (p=0.012) in 6-month CDP in a pre-specified pooled analysis compared to Aubagio®.

[0152] Objective Serum immunoglobulin (Ig) levels were determined and the IgG or IgM levels were correlated with new treatment To investigate the relationship with the position, patients with multiple sclerosis were treated with ocrelizumab.

[0153] Method ASCLEPIOS I and II were double-blind, double-dummy, placebo-controlled parallel-group, innovative, adaptive-design, multi-center clinical trials. Patients were randomized (1:1) and received either ocrelizumab 20 mg sc injections every 4 weeks (after an initial loading regimen of 20 mg sc doses on days 1, 7, and 14) or teriflunomide 14 mg, once daily orally for up to 30 months. The trial had a flexible period during which it could be stopped according to pre-specified criteria during a pre-defined core treatment period. Patients aged 18 - 55 years, with an Expanded Disability Status Scale (EDSS) score of 0 - 5.5 (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444 - 52) at screening and who 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 were included.

[0154]

[0155] Serum IgG / IgM levels were monitored at baseline, week 4 (W), week 12, and every 12 weeks. See Figure 1. The lower limit of normal (LLN) was defined as 7 g / L for IgG and 0.4 g / L for IgM. The results included, among other things, the proportion of patients with particularly low IgG / IgM levels and the relationship between particularly low IgG / IgM levels and the incidence of infections. See Figure 1. Results regarding IgG and IgM levels

[0156] ​​​​​​​​​​

Table 1

[0157] The change from the baseline of serum IgG level is shown in Figure 2. Serum IgM level The change from the baseline is shown in Figure 3.

[0158] In patients treated with ofatumumab, there is no decrease in IgG level at week 72 and thereafter. Furthermore, there is a bifurcation point at week 36, at which the decreasing trend of IgG level is reversed, and finally, starting from about week 72, IgG results in a net increase. The decrease in IgG is less prominent and shorter in patients treated with ofatumumab compared to those treated with teriflunomide. The decrease in IgG is less prominent and shorter in patients treated with ofatumumab compared to those treated with teriflunomide.

[0159] The decrease in IgG is less prominent and shorter in patients treated with ofatumumab compared to those treated with teriflunomide. The decrease in IgG is less prominent and shorter in patients treated with ofatumumab compared to those treated with teriflunomide.

[0160] Results in infectious diseases: Favorable, a low incidence of infectious diseases was found.

[0161] Conclusion Ig levels, especially IgG levels, were unexpectedly high, and the incidence of infectious diseases was advantageously low. .

[0162] [Example 3] Method In the differential analysis, the results of Example 3 were compared with the results obtained by Derfuss et al. See Figure 5.

[0163] Results After 2 years (96 weeks), ocrevus treatment (pooled OPERA trial, see Figure 4 ) resulted in an approximately 5% reduction in IgG level, while ofatumumab resulted in an approximately 3 % increase. See Figure 2.

[0164] Conclusion Ofatumumab results in long-term persistence and even an increase in IgG levels, while o crelizumab may rather result in a continuous reduction in IgG levels.

[0165] [Example 4] Ofatumumab is administered s.c. to RRMS patients. If injection-related reactions occur, symptomatic treatment is provided. For patients who experience pain, redness or itching, hydrocortisone cream is applied after injection to help with itching, redness and swelling. Analgesics are also used.

[0166] Findings The levels of (total) IgG in patients treated with ofatumumab with injection-related reactions are expected to be equivalent to those in patients treated with ofatumumab without injection-related reactions and not receiving hydrocortisone treatment. Overall, no signs of immunosuppression or toxicity are expected from the combination of ofatumumab and hydrocortisone.

[0167] A significant decrease in follicular B cell subtypes is expected to be observed with ofatumumab treatment, while marginal zone and germinal center B cell subtypes are expected to be less affected.

[0168] [Example 5] a) Animal tests A single dose of anti-CD20 antibody (mIgG1) was administered to mice (C57BL / 6 female mice, 6 weeks old) via two different routes of administration (i.v. or s.c.) and the effect of B cell depletion on antibody-mediated immunity against Streptococcus pneumoniae was investigated.​ 50 μg / mouse of anti-CD20 (mIgG1, n = 8 per group) via either the i.v. or s.c. route of administration depleted B cells. Mice without B cell depletion received administration of an isotype control antibody (s.c.) at the same concentration. Mice were vaccinated with the pneumococcal 13-valent conjugate vaccine Prevnar13® (20 μL / mouse i.p.). - One-dose vaccination study: a single dose of Prevnar13® - Two-dose vaccination study: two doses of Prevnar13® - Control animals (neither depleted nor vaccinated) received administration of PBS (phosphate-buffered saline) (i.p.) (see Figure 6). Serum pneumococcal-specific IgG levels were measured on day 16 (after the first vaccine dose) and day 29 (endpoint) by whole cell ELISA on plates coated with pneumococci (TIGR4 strain) (see Figure 7). Pneumococci were incubated with mouse sera (on day 29), and antibody binding to the pneumococcal surface was measured by flow cytometry (FACS); pneumococcal-specific IgG and IgM levels were measured by serum accumulation assay (see Figure 7). On day 14, spleens and lymph nodes were analyzed to observe the effect on blood and B cell repertoire levels. Fourteen days after anti-CD20 antibody treatment, the number of B cells was approximately 20% of the B cell count of the untreated group (see Figures 8 and 9).

[0169] Evaluation

[0170]

[0171]

[0172] ​​​​​​​​​​​ Single vaccination test: B cell subtypes on day 14 A marked decrease in follicular B cell subtypes was observed in both the i.v. and s.c. anti-CD20 treatment groups (see Figures 10 and 11).

[0173] Double vaccination test: Depletion of B cells on day 29 - Only 60% of the B cell population was reconstituted 4 weeks after anti-CD20 treatment (see Figure 12). (see Figure 12). - No significant differences in B cell subtypes were observed between the s.c. and i.v. anti-CD20 treatment groups (see Figure 13). (see Figure 13). - Pneumococcal-specific immunoglobulin levels (IgG / IgM) · IgG levels against pneumococcus in mice treated with anti-CD20 (i.v. and s.c.) were equivalent to those in the vaccinated group after the first vaccine dose (day 16 (see Figure 14). (see Figure 14). · No significant differences in IgG levels were observed between the s.c. and i.v. anti-CD20 treatment groups (see Figure 14). · Accumulation of antibodies on the bacterial surface suggested lower levels of IgG binding to pneumococcus in the anti-CD20 treatment groups (depleted samples) compared to vaccinated samples; however IgM levels were equivalent (see Figure 15).

[0174] Conclusion - The route of administration did not affect the non-depleted B cell population. - A marked decrease in follicular B cell subtypes was observed with anti-CD20 treatment, while the marginal zone and germinal center B cell subtypes appeared to be less affected. - The B cell population was not completely reconstituted 4 weeks after anti-CD20 treatment. - B cell depletion reduced pneumococcal-specific IgG levels, while the reduction in IgM levels was much less. The reduction was much less.

[0175] b) Clinical trials 100 patients with relapsing-remitting MS received subcutaneous ocrelizumab.

[0176] - During the loading dose regimen, it included administering 20 mg of ocrelizumab on days 0, 7, and 14 of the dosing regimen; and - During the maintenance dose regimen, starting from the 4th week of the dosing regimen, it included initiating the administration of 20 mg of ocrelizumab and then continuing every 4 weeks throughout the treatment protocol period. The general clinical status of the patients was investigated weekly by physical examination and clinical tests. Changes in the disease state and disease progression were evaluated every 2 months by radioactive substance examination (MRI) and health diagnosis. In patients who suffered from infections as adverse events, blood samples were collected for laboratory analysis. If an infection caused by Staphylococcus aureus was confirmed by analysis, each patient was treated with oral trimethoprim-sulfamethoxazole. Ocrelizumab treatment continued.

[0177] During treatment with trimethoprim-sulfamethoxazole, blood samples were collected every other day. From the analysis of these samples, the levels of IgG against Staphylococcus aureus in patients treated with ocrelizumab, as proven by meta-analysis, were not present in those without MS and were reported in the literature for infected subjects not treated with ocrelizumab. The changes in the disease state and disease progression were evaluated every 2 months by radioactive substance examination (MRI) and health diagnosis.

[0178] In patients who suffered from infections as adverse events, blood samples were collected for laboratory analysis. If an infection caused by Staphylococcus aureus was confirmed by analysis, each patient was treated with oral trimethoprim-sulfamethoxazole. Ocrelizumab treatment continued. During treatment with trimethoprim-sulfamethoxazole, blood samples were collected every other day.

[0179] From the analysis of these samples, the levels of IgG against Staphylococcus aureus in patients treated with ocrelizumab, as proven by meta-analysis, were not present in those without MS and were reported in the literature for infected subjects not treated with ocrelizumab. From the analysis of these samples, the levels of IgG against Staphylococcus aureus in patients treated with ocrelizumab, as proven by meta-analysis, were not present in those without MS and were reported in the literature for infected subjects not treated with ocrelizumab. hylococcus aureus) in patients treated with ocrelizumab, as proven by meta-analysis, were not present in those without MS and were reported in the literature for infected subjects not treated with ocrelizumab. were not present in those without MS and were reported in the literature for infected subjects not treated with ocrelizumab. It is expected to be clearly shown to be equivalent to the level of IgG. Furthermore, ofatumumab Patients treated with the mab are expected to recover more rapidly from infections when compared to past clinical trials.

[0180] [Example 6] a) Animal tests In mice (C57BL / 6 female mice, 6 weeks old), an endovascular filament model was used to occlude the middle cerebral artery (MCA) (as described in Hata R, Mies G, Wiessner C, Fritze K, Hesselbarth D, Brinker G, et al. A reproducible model of middle cerebral artery occlusion in mice: hemodynamic, biochemical, and magnetic resonance imaging. J Cereb Blood Flow Metab. 1998;18:367-375. doi: 10.1097 / 00004647-199804000-00004). The occlusion is known to cause infarction in the MCA region. After reperfusion by removal of the occlusion filament, blood flow quickly recovered. The control group was subjected to sham occlusion of the MCA.

[0181] One week later, a single dose of anti-CD20 antibody (mIgG1) was administered s.c. to subsets of mice in both groups (MCA occlusion group and sham group). B cells were depleted by administering 50 μg / mouse of anti-CD20 mIgG1 at n = 8 per group. Mice without B cell depletion received administration of the same concentration of isotype control antibody (s.c.).

[0182] ​​A significant decrease in follicular B cell subtypes was observed with anti-CD20 therapy (in both groups ), while marginal zone and germinal center B cell subtypes appeared to be less affected .

[0183] Recovery after MCA occlusion (including tissue repair) did not appear to be affected by anti-CD20 therapy .

[0184] b) Clinical trials The first group of patients was monitored after ischemic stroke. Subgroup patients are expected to have problems with urinary leakage or be unable to completely empty their bladders due to muscle weakness. For these reasons, a catheter is inserted into the bladder. However, the risk of urinary tract infections associated with catheter use increases . These infections are treated with one of the following - Trimethoprim / sulfamethoxazole (Bactrim, Septra, and others ), - Fosfomycin (Monurol), - Nitrofurantoin (Macrodantin, Macrobid), - Cephalexin (Keflex) or - Cefotaxime . The second group of patients consisted of MS patients treated with ocrelizumab. Subgroup patients

[0185] developed adverse events including urinary tract infections. These infections are treated with one of the following - Trimethoprim / sulfamethoxazole (Bactrim, Septra, and others ), - Fosfomycin (Monurol), - Nitrofurantoin (Macrodantin, Macrobid), - Cephalexin (Keflex) or - Cefotaxime - Treat with one of ceftriaxone.

[0186] Conclusion - A significant decrease in follicular B cell subtypes is expected to be observed with ofatumumab treatment, while the marginal zone and germinal center B cell subtypes are expected to be less affected. - No significant differences are expected regarding the management of urinary tract infections. - The correlation of the data suggests that ofatumumab can be safely administered even after the occurrence of adverse events such as urinary tract infections after stroke.

[0187] [Example 7] Treat MS patients with either ofatumumab or ocrevus (ocrelizumab). Select patients with psoriatic arthritis are monitored under a special test program. Subgroups of patients have more severe disease activity and / or do not respond adequately to NSAIDs. Some patients are unable to take disease-modifying antirheumatic drugs (DMARDs), such as - leflunomide (Arava), - methotrexate (Otrexup, Rasuvo, Rheumatrex, Trexall) or - sulfasalazine (Azulfidine). Therefore, patients are treated with an immunosuppressant, namely

[0188] - azathioprine (Imuran, Azasan) or - cyclosporine (Gengraf, Neoral, Sandimmune).

[0189] Findings: The IgG levels in patients treated with ofatumumab are expected to be significantly higher than those in patients treated with ocrevus. A significant decrease in follicular B cell subtypes is expected with ofatumumab treatment,

[0190] while the marginal zone and germinal center B cell subtypes appear to be less affected. Following treatment with immunosuppressive agents, significantly more adverse events (e.g., infections) are expected in the ocrevus group.

[0191] Equivalent responses in psoriatic arthritis are expected in both groups.

[0192]

[0193] References

[0194]

Table 2

Claims

1. A pharmaceutical composition comprising ofatumumab, said pharmaceutical composition being for use in a method for treating multiple sclerosis, said method comprising administering a therapeutically effective amount of ofatumumab to a patient in need thereof, wherein said patient is vaccinated during ofatumumab therapy.

2. The pharmaceutical composition of claim 1, wherein ofatumumab is administered by a pre-filled pen or a pre-filled syringe.

3. The pharmaceutical composition described in claim 1 or 2, wherein the patient has an EDSS score of 1 to 4 before the first administration of ofatumumab.

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the method sustains IgG levels.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the method includes monitoring serum IgG levels.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).

7. The pharmaceutical composition described in claim 6, wherein the RMS is relapsing-remitting multiple sclerosis (RRMS), active secondary progressive multiple sclerosis (SPMS) or clinically isolated syndrome (CIS).

8. A pharmaceutical composition described in any one of claims 1 to 7, wherein the patient is an adult.

9. The pharmaceutical composition of claim 1, wherein the patient is vaccinated against Bordetella pertussis.

10. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against Corynebacterium diphtheriae.

11. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against Haemophilus influenzae.

12. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against respiratory syncytial virus (RSV).

13. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against the SARS-CoV-2 virus.

14. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against influenza virus.

15. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient is vaccinated against varicella zoster virus (VZV).

16. The pharmaceutical composition of claim 1, wherein ofatumumab is administered subcutaneously.

17. The invention described in the present specification.

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