Management of Conditions Other than Multiple Sclerosis in Patients Treated with Ofatumumab

Abstract

The present disclosure relates to methods of providing treatment for multiple sclerosis (MS) that allow for control of conditions other than MS, such as infections.

Description

Technical Field

[0001] The present invention relates to ofatumumab for treating or preventing (or for use in the 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 can sometimes produce toxins to interfere with the body's defense system, or can disguise themselves by changing their shape or outer structural proteins so as not to be recognized by the immune system (antigenic variation). Some bacteria produce adhesive elements, by which they can adhere to mucous membranes and prevent the destruction of the bacteria. Due to these mechanisms, patients having 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 having a history of conditions such as past or ongoing infections.

[0003] These mechanisms that resist inactivation or destruction by the host are more likely to succeed in patients who are immunocompromised or immunosuppressed (for example, patients receiving MS therapy). Nevertheless, since this is part of the therapy (for example, MS therapy), there is often no option to stop immunosuppression. Therefore, it is necessary to prevent, reduce or alleviate viral, bacterial or fungal infections while proceeding with immunosuppression (for example, for treating MS).

[0004] Importantly, immunosuppression is generally incompatible with some prophylactic or therapeutic means, such as vaccination. In some cases, this poses a dilemma for immunocompromised or immunosuppressed patients (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 the drug of choice in viral urinary tract infections because it is active against the most common viral pathogens. However, it may not be desirable to expose patients (e.g., patients receiving MS therapy) to a high drug load (including cidofovir) if these patients are already being treated and / or are immunocompromised / immunosuppressed, e.g., MS patients receiving MS therapy. 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 exacerbates the leukopenia (lymphopenia) caused by fingolimod, thus impairing the immune system. Nephrotoxicity can be dangerous for MS patients treated with fingolimod, for example. This is because nephrotoxicity can prevent the body's ability to excrete fingolimod and its metabolites, leading to fluid imbalances and associated diseases. Therefore, adverse events need to be addressed in different ways. In particular, there is a need for MS therapies that allow vaccination during therapy.

[0005] Epstein-Barr virus (EBV) is one of the most successful pathogens in humans, with over 90% of the adult population being 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 immunocompetent individuals, antiviral T cell responses control the infection, but EBV remains latent within memory B cells and some other cell types. However, the success of MS therapies relies on immunosuppressive drugs to prevent inflammatory events in the central nervous system (CNS). Thus, in MS patients, current immunosuppressive therapies weaken the strength of anti-EBV T cell responses 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 ultimately 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 viral particles within a single sensory ganglion switch from these latent lysogenic cycles to an active lytic cycle. VZV infections have been reported as an adverse event in MS patients treated with fingolimod (Cohen et al., New England Journal of Medicine 2010; 362: 402-15). Another virus, JC virus, is the cause of the 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. Thus, there is an urgent need for new therapies to modulate, prevent, or inhibit viral infections and related diseases such as EBV or JCV infections, particularly in MS patients who are particularly vulnerable. SUMMARY OF THE INVENTION

[0006] A method of treating multiple sclerosis (MS) in patients having a history of past or ongoing conditions other than MS is provided. Surprisingly, patients having a history of past or ongoing conditions other than multiple sclerosis, and patients in need of treatment or prevention of relapsing multiple sclerosis, have been found to be successfully treated with ocrelizumab without substantially compromising the management of conditions other than MS. Further, patients can receive vaccinations during ocrelizumab therapy. Ocrelizumab is an anti-CD20 antibody and depletes lymphocytes, which was not at all expected. Thus, since ocrelizumab was expected to have a negative impact on the immune system, 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. demonstrated that rituximab, another anti-CD20 antibody, results in a decrease in IgM levels. See “B-lymphocyte depletion with rituximab and β-cell function: two-year results”, Diabetes Care, 2014 Feb; 37(2); 453-9. BRIEF DESCRIPTION OF THE DRAWINGS

[0007]

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DETAILED DESCRIPTION OF THE INVENTION

[0008] General definition The term "treatment" or "treating" can be defined, for example, as the application or administration of ocrelizumab 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.

[0009] As used herein, a patient can "require" 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, particularly preferably a human (e.g., a patient at risk of or having a disorder described herein). Preferably, the patient is an adult.

[0010] As used herein, the terms "administering" of 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 includes concurrent (simultaneous) as well as sequential administration in any order and by any route of administration.

[0011] As used herein, "therapeutically effective amount" can refer to an amount of ofatumumab that is effective, i.e., achieves a clinically significant effect.

[0012] The term "adverse event" (AE) can be related to the occurrence of any adverse medical event in a patient or clinical trial, such as when a subject is administered a pharmaceutical product to which the subject does not necessarily have a causal relationship with this treatment. Thus, 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 product (investigational), whether or not related to the pharmaceutical product (investigational).

[0013] The phrase "treatment regimen" can mean a regimen used to treat a disease or to prevent the onset of a condition or disease, e.g., the dosing used. A treatment regimen can include an induction regimen, a loading regimen and a maintenance regimen.

[0014] The term "loading regimen" or "loading dose" can refer to a treatment regimen (or a portion of a treatment regimen) that is used in the initial treatment of a disease. In some embodiments, the disclosed methods, uses, kits, processes, and regimens employ a loading regimen. In certain cases, the loading period is the period until maximum efficacy is reached. A general goal of a loading regimen may be to provide a patient with a high level of drug during an initial period of a treatment regimen. An induction regimen can use a "loading regimen" or "loading dosing" (in part or in whole), administer a higher dose of drug than the dose used by a physician during a maintenance regimen, administer the drug at a higher frequency than the frequency at which a physician administers the drug during a maintenance regimen, or can include both. An increase in dose can occur during or after an induction regimen.

[0015] The term "maintenance regimen" or "maintenance dose" can refer to a treatment regimen (or a portion of a treatment regimen) that is used to maintain a patient during the treatment of a disease, e.g., to keep a patient in remission for an extended period (months or years), e.g., after an induction period. In some embodiments, the disclosed methods, uses, and regimens employ a maintenance regimen. A maintenance regimen can use continuous therapy (e.g., administer the drug at regular intervals, e.g., weekly, monthly [every 4 weeks], annually, etc.) or intermittent therapy (e.g., fractionated treatment, intermittent treatment, treatment at recurrence, or treatment upon reaching certain predefined criteria [e.g., pain, disease findings, etc.]). An increase in dose can occur during a maintenance regimen.

[0016] The term "Multiple Sclerosis Impact Scale (MSIS-29)" is defined as follows: The MSIS-29 version 2 is a self-administered questionnaire over 29 items that includes two domains: physical and psychological. Responses are recorded on a 4-point ordinal scale ranging from 1 (not at all true) to 4 (very true), and higher scores reflect a greater impact on daily life. The MSIS-29 takes about 5 minutes to complete and the questions are designed to determine the patient's opinion about the impact of MS on the patient's daily life during the past two weeks. Refer to Hobart J and Cano S (2009), “Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods”, Health Technol Assess; 13(12):iii, ix-x, 1-177. NS RO to Hobart J, Lamping D, Fitzpatrick R, et al (2001), “The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure”, Brain; 124(Pt 5):962-73.

[0017] The expression "a patient having a history of past conditions other than multiple sclerosis" can mean that the patient has or 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. Retrieved January 16, 2010). In the context of the present invention, a "health benefit program" can be related to a therapy including the administration of ofatumumab. Thus, a pre-existing condition occurred or started before the initiation 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 defenses against diseases. A 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 a population is vaccinated, herd immunity results. Vaccination can be the most effective way to prevent infectious diseases. However, if a person has already received treatment to cure, modify, or alleviate the symptoms of a first disease (e.g., MS), then according to the research results in the art, it is difficult or impossible to vaccinate that person against a second disease.

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

[0020] RRMS Relapsing-remitting multiple sclerosis (MS) is defined as a new episode of neurological deficit or neurological worsening lasting longer than 24 hours, for example, in the absence of fever or infection, characterized by relapses.

[0021] There is no obvious progression of the disease during the remission period. RRMS can be further characterized at different time points as either active (evidence of relapse and / or new MRI activity) or inactive, and as either worsening (an increase in disability has been confirmed over a specified period after relapse) or not worsening, referring to Lublin 2014, Neurology. 2014 Jul 15; 83(3): 278-286.

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

[0023] Primary progressive MS (PPMS) PPMS is characterized by a 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 having activity (sporadic relapses and / or evidence of new MRI activity) or not having activity, and similarly, as either having progression (evidence that the disease is worsening with respect to an objective measure of change over time, regardless of the presence or absence of relapses or new MRI activity) or not having progression, referring to Lublin 2014.

[0024] Each person's experience of PPMS is unique. PPMS may have short periods during which the disease is stable, regardless of the presence or absence of MRI relapses or new activity, and similarly, may have periods during which an increase in disability occurs, regardless of the presence or absence of new relapses or lesions on MRI.

[0025] Secondary progressive MS (SPMS) SPMS occurs following the first relapse-remission phase. Most people diagnosed with RRMS will ultimately transition into a secondary progressive phase, in which there is a progressive worsening of neurological function over time (accumulation of disability). SPMS can be further characterized as being either active (evidence of relapses and / or new MRI activity) or inactive at different time points, and similarly, either progressive (evidence that the disease is worsening based on an objective measure of change over time regardless of the presence or absence of relapses) or non-progressive. Referring to Lublin 2014.

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

[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 suggest multiple sclerosis (MS). CIS symptoms can be either monophasic or polyphasic and typically can include 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.

[0028] T1 and T2 lesions T1 and T2 are related to different MRI methods used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time elapsed between the magnetic pulse and the recording of the image. These different methods are used to detect different structures or chemicals in the central nervous system. T1 and T2 lesions refer to whether a lesion is 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 of disease or lesion load (the total amount of old and new lesion areas).

[0029] Relapse Relapse can be defined as an episode of new neurological deficits or neurological worsening that preferably lasts longer than 24 hours. In other words, relapse can be considered as separate episodes of neurological dysfunction (also referred to in the art as "attacks", "flares" or "exacerbations") that preferably last at least 24 hours. Usually, relapse is followed by a period of remission during which there is no complete or partial recovery and no progression of symptoms or accumulation of disability.

[0030] Ocrelizumab: Ofatumumab is a human monoclonal antibody against the CD20 protein. Ofatumumab can specifically bind to both the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab can bind to the CD20 molecule, and the Fc domain mediates immune effector functions to cause 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. 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. 3284753. Further reference is made to the description 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 10022 N 1742 O 2020 S 44 and the average protein weight is about 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 in two ways: a non-target-dependent pathway as in the case of other IgG molecules, and a target-mediated pathway related to binding to B cells.

[0033] After repeated subcutaneous administration of a dose of 20 mg in particular, 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 is not involved in the regulation of the expression of drug-metabolizing enzymes.

[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 infectious diseases. Since some MS therapies have been found to reduce immunoglobulin levels, this raises concerns. In particular, treatment with B-cell depletion therapy has been reported to result in a decrease in the serum levels of immunoglobulin (Ig) G, IgM and / or IgA. Furthermore, since MS therapy is usually a lifelong therapy, MS patients have an increased risk of infectious diseases.

[0036] For example, ocrelizumab (brand name Ocrevus), an anti-CD20 antibody, can result in a higher infection rate in patients who receive this administration. Ocrevus is approved for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS) in the United States. Rituximab, another antibody similar to ocrelizumab, 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 ocrelizumab prescribing information and described the association between the decrease in immunoglobulins and severe infectious diseases as follows: "Treatment with Ocrevus induced mainly a decrease in IgM over a controlled experimental period, resulting in a decrease in total immunoglobulins. The clinical trial data show an association between a decrease in 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 the Risk of Infection", 09 / 12 / 19; 278212; P1010) reported that there was no evidence of a significant difference in IgM levels between MS patients treated with ocrelizumab who developed an infectious disease 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 infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their 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 increased rate of serious infections. This association was strongest for IgG, but less so for IgM or IgA. The reduction 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 serious infections.

[0040] Overall, in clinical trials, it has been reported that 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.

[0041] Therefore, it is entirely surprising that ofatumumab therapy is advantageous compared to other B-cell depletion therapies because it causes a lower degree of reduction in immunoglobulin (e.g., IgM). Consequently, the risk of serious infections is unexpectedly reduced in patients treated with ofatumumab. Furthermore, the lack of or improvement in adverse effects on the immune system has opened up new avenues for patients treated with ofatumumab. For example, these patients can receive vaccinations while on ofatumumab therapy. Additionally, 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 later in this specification.

[0042] In contrast, other immunomodulatory or immunosuppressive therapies (e.g., ocrelizumab) expose patients to a higher risk of a stronger immune response (e.g., due to activation of the complement system and / or reduction of interactions between B cells and T cells and / or changes in cytokine production and / or activation of bystanders). Furthermore, even if these other therapies allow or recommend vaccination, more caution must be exercised regarding the timing of vaccination (see Tobias Zrzavy et al.: Vaccination in Multiple Sclerosis: Friend or Foe?, FRONTIERS IN IMMUNOLOGY, vol. 10, 1 January 2019, page 1883).

[0043] One aspect of the invention relates to ofatumumab for use in the 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. The expression "patients having a history of past conditions other than multiple sclerosis" means that the patient has or 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, the "health benefit program" relates to a therapy including administration of ofatumumab. Thus, the pre-existing condition occurred or started before the initiation of ofatumumab therapy.

[0044] A condition other than multiple sclerosis is 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 (chickenpox) Common cold Increase in gamma-glutamyl transferase Abdominal pain Skin cancer Bradycardia Hemorrhagic encephalitis Herpes infection Progressive multifocal leukoencephalopathy (PML) Hypertension Paraesthesia May be one or more of the following.

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

[0046] Instead, these conditions other than multiple sclerosis can also result from drugs, such as immunosuppressive drugs. Examples of immunosuppressive drugs include corticosteroids, such as prednisone (Deltasone, Orasone), budesonide (Entocort EC), prednisolone (Millipred); 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 trapping agents, such as fingolimod (Gilenya); biologics, 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). In a preferred embodiment, the immunosuppressive drug is fingolimod (Gilenya), ocrelizumab (Ocrevus), natalizumab (Tysabri) or rituximab (Rituxan). Fingolimod (Gilenya) is particularly preferred.

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

[0048] In a preferred embodiment of this aspect of the invention, a history of past or ongoing conditions other than multiple sclerosis is a history of past or ongoing infections. The expression "history of past or ongoing infections" means that the patient has or had a pre-existing infection. A pre-existing infection 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 therapies including the administration of ocrelizumab. Thus, a pre-existing infection occurred or began prior to the initiation of ocrelizumab therapy.

[0049] Patients with an infection are more likely to exhibit more severe signs and symptoms when receiving immunosuppressive therapy. Since anti-CD20 antibodies suppress the immune system, it is entirely surprising that ocrelizumab, an anti-CD20 antibody, neither causes nor acts favorably on more severe signs and symptoms.

[0050] Past or ongoing infections include the following Respiratory syncytial virus (RSV), Influenza or parainfluenza virus, Human polyomavirus (BK virus), Adenovirus, Rhinovirus, Coronavirus, particularly 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, Escherichia coli (E.coli), It may be caused by a virus or microorganism selected from the group consisting of 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] Therefore, a history of past conditions other than multiple sclerosis may have been triggered by a viral infection, and the viruses that can cause the infection are, for example, respiratory syncytial virus (RSV), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, rhinovirus, coronavirus, human herpesviruses such as herpes simplex virus (HSV), varicella-zoster virus (VZV), EBV or cytomegalovirus (CMV) or beta polyomaviruses such as John Cunningham virus (JCV).

[0052] Three of the four types of influenza viruses affect humans: type A, type B, and type C. Type D is not known to infect humans but is thought to have the potential to do so. Usually, the virus spreads through the air via coughing or sneezing. The virus can also spread by touching a virus-contaminated surface and then touching the eyes, nose, or mouth. People can infect others before and during the period when they show symptoms. Annual influenza vaccination 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 six 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-CD20 antibodies suppress the immune system, it was completely surprising that ofatumumab, an anti-CD20 antibody, does not interfere with influenza virus vaccination.

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

[0054] Coronaviruses are a group of viruses that cause diseases in mammals and birds. In humans, coronaviruses usually cause respiratory infections that are mild, for example, in some cases of the common cold (among other major causes, mainly rhinoviruses), although rarer forms, such as SARS, MERS, and COVID-19 can be lethal. There are no vaccines or antiviral drugs yet to prevent or treat human coronavirus infections. Patients infected with a coronavirus, such as SARS-CoV-2, are assumed to be treatable or able to initiate 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, where it resides for life. Causes of recurrence can include a decrease in immune function, stress, and exposure to sunlight. Thus, patients are more likely to experience recurrence if they are undergoing immunosuppressive therapy. Since anti-CD20 antibodies suppress the immune system, it was entirely surprising that ofatumumab, an anti-CD20 antibody, neither causes nor favorably acts on recurrence.

[0056] The spread can also be reduced by an infected person taking antiviral drugs daily. There is no available vaccine, and once infected, it cannot be cured. Paracetamol (acetaminophen) and topical lidocaine can be used to help with symptoms. Treatment with antiviral drugs, such as acyclovir or valacyclovir, can reduce the severity of symptomatic episodes. It has surprisingly been found that the drugs can be used in patients treated with or initiating treatment with ofatumumab. Thus, aspects of the present invention are based on the surprising discovery that ofatumumab, in contrast to other anti-CD20 therapies, does not interfere with HSV control.

[0057] Human alpha herpesvirus 3 (HHV-3), commonly known as varicella-zoster virus (VZV), is one of nine known herpesviruses that infect humans. It causes chickenpox, a disease that most commonly 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 variety of symptoms. After the primary infection (chickenpox), the virus becomes latent within nerves, including the cranial ganglia, dorsal root ganglia, and autonomic ganglia. Years after this person has recovered from chickenpox, VZV can reactivate and cause a neurological condition. In the human body, this condition can be treated with several drugs and therapeutic agents, including acyclovir for chickenpox, famciclovir, valacyclovir, varicella-zoster immune globulin (ZIG), and vidarabine for shingles. VZV immune globulin is also a treatment. Acyclovir is frequently used as a generally preferred drug in primary VZV infections, and by starting its administration early, the duration of any symptoms can be significantly shortened. It has surprisingly been found that the said drugs and therapeutic agents can be used as VZV therapy in patients being treated with or starting treatment with ofatumumab. Patients can also receive further vaccination against VZV during ofatumumab therapy. 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 VZV control. Accordingly, the present disclosure relates to a method of preventing diseases associated with VZV in a patient, the method comprising administering a therapeutically effective dose of ofatumumab to the patient.

[0058] In one embodiment of the invention, ofatumumab is not administered to patients having active HBV infection.

[0059] Epstein-Barr virus (EBV) is human herpesvirus 4 (HHV4) and belongs to the genus Lymphocryptovirus within the subfamily of gammaherpesviruses. These viruses establish latent infection of these host cells and induce the proliferation of latently infected cells (reviewed in Roizman B. Herpesviridae: general description, taxonomy and classification. In: Roizman B, editor. The herpesviruses. London: Plenum Press, 1996:1_ / 23). EBV is associated with an increasingly broad range of clinical disorders, ranging from acute and chronic inflammatory diseases to lymphoid and epithelial malignancies. Epstein-Barr virus is associated with lymphoproliferative diseases, diseases in which different types of lymphoid cells, such as T cells, B cells or natural killer (NK) cells, are infected with Epstein-Barr virus. Infected cells divide excessively and develop various lymphoproliferative disorders (LPDs, non-cancerous, pre-cancerous and cancerous). These LPDs include infectious mononucleosis and subsequent disorders that may occur later. Although not an LPD, diseases associated with EBV include malignancies, sarcomas, multiple sclerosis, systemic lupus erythematosus, Hodgkin and non-Hodgkin lymphomas, nasopharyngeal carcinoma, gastric carcinoma, leiomyosarcoma and "Alice in Wonderland syndrome" (Middeldorp et al., Critical Reviews in Oncology / Hematology 45 (2003) 1- / 36 2003).

[0060] 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 basis for the development of therapeutic methods in patients at risk of developing diseases associated with EBV.

[0061] Cytomegalovirus (CMV) is a genus of viruses in the order Herpesvirales, family Herpesviridae, subfamily Betaherpesvirinae. Humans and monkeys function as natural hosts. Human betaherpesvirus 5 (HCMV, human cytomegalovirus, HHV-5) is the species that infects humans. Diseases associated with HHV-5 include mononucleosis and pneumonia. Most people who are infected with CMV, although healthy otherwise, experience little, if any, signs and symptoms. However, a small number of infants born with congenital CMV, who appear healthy at birth, may develop symptoms over time (sometimes months or even years after birth). The most common of these late-onset symptoms are hearing loss and developmental delay. A small number of infants may also develop visual impairment. In addition, people with weakened immune systems may experience more severe signs and symptoms that affect the following: Eye, Lung, Liver, Esophagus, Stomach, Intestine, Brain.

[0062] In a preferred embodiment, control of the viral infection (viral control) is possible, i.e., it proceeds without substantial or at least acceptable delay or limitation despite the initiation of ofatumumab therapy. The term control of the virus or control of the viral infection also refers to the treatment described above, and the amount of virus in the whole blood of the treated patient is less than 5000 copies / μg DNA of the viral genome, less than 4500 copies / μg DNA, less than 4000 copies / μg DNA, less than 3500 copies / μg DNA, less than 3000 copies / μg DNA, less than 2500 copies / μg DNA, less than 2000 copies / μg DNA, less than 1500 copies / μg DNA or less than 1000 copies / μg DNA. In a preferred embodiment, the amount of virus in the 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 control of the virus or control of the viral infection also refers to the treatment described above, and the amount of virus in the plasma is less than 3000 copies / 100 μl, less than 2500 copies / 100 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 amount of virus in the plasma 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.

[0064] Furthermore, the term controlling a virus or controlling a viral infection, as used herein, also refers to treating a patient, particularly where the patient is an MS patient, and more particularly where the patient requires immunosuppression and a therapeutically effective dose of ocrelizumab results in a reduction in viral titer or viral amount or viral infection status, and the viral amount (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 90% or more. In preferred embodiments, the reduced viral amount 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 the initiation of ocrelizumab therapy.

[0065] In a preferred embodiment, the treatment according to the invention enables the prevention of virus-associated diseases by providing suitable means (such as medication or vaccination) not commonly used during immunosuppressive treatment. Since anti-CD20 antibodies suppress the immune system, it is completely surprising that ofatumumab, 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 diseases, disorders and / or associated symptoms. 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 ofatumumab, particularly when the patient is a patient with MS, more specifically a patient in need of immunosuppression, and the patient does not develop a virus-associated disease, particularly the patient does not develop a lymphoproliferative disorder (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 a period of 12 months, at least a period of 18 months, at least a period of 24 months, at least a period of 3 years, at least a period of 4 years, at least a period of 5 years, at least a period of 6 years, at least a period of 7 years, at least a period of 8 years or longer after the start of ofatumumab therapy.

[0066] As described previously, a medical history of past conditions other than multiple sclerosis may be triggered by bacterial infections, and the bacteria that cause the infections are, for example, Bordetella pertussis, Bordetella parapertussis, Corynebacterium diphtheriae, Escherichia coli, Staphylococcus spec. (such as Staphylococcus saprophyticus or Staphylococcus aureus), Chlamydia trachomatis, Haemophilus influenzae, Meningococcus spec., Klebsiella spec., Pseudomonas spec., Enterococcus spec., Streptococcus 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, fimbria, and tracheal cytotoxin.

[0068] Diphtheria is an infectious disease caused by the bacterium Corynebacterium diphtheriae. Complications can include myocarditis, neural inflammation, kidney damage, and bleeding disorders due to low levels of platelets. Myocarditis can result in abnormal heart rate, and neural inflammation can result in 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 lead to food contamination incidents. Toxic E. coli strains can cause gastroenteritis, urinary tract infections, neonatal meningitis, hemorrhagic colitis, and Crohn's disease. Common signs and symptoms include severe abdominal cramps, diarrhea, hemorrhagic colitis, vomiting, and sometimes fever. In rare cases, toxic strains are also involved in intestinal necrosis (tissue death) and perforation that do not progress to hemolytic uremic syndrome, peritonitis, mastitis, sepsis, and Gram-negative pneumonia.

[0070] Some strains of 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 behind lesions that result in the hemorrhagic diarrhea that is a symptom of Shiga toxin-producing E. 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.

[0071] Uropathogenic E. coli (UPEC) is one of the main causes of urinary tract infections. It is part of the normal microbiota in the intestine and can be introduced in many ways.

[0072] Enterotoxigenic 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 enterotoxins there, resulting in watery diarrhea.

[0073] A certain strain of Escherichia coli (E. coli) is a major cause of food poisoning. Enterohemorrhagic E. coli (EHEC) bacteria can lead to 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. Since these diseases can be caused by bacteria that grow in improperly stored food products, 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 reproductive 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 without substantial or at least acceptable 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, incubating a blood sample taken from a vein by needle puncture 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 been triggered by 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 microbiota. It is a normally commensal organism but can become pathogenic in immunocompromised individuals under various conditions. Candida albicans is one of several species of the genus Candida that cause human candidiasis, a fungal overgrowth infection. Candidiasis is observed, for example, frequently in patients infected with HIV. C. albicans is the most common fungal species isolated from biofilms formed on implanted medical devices or human tissues (permanently). 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 due to C. albicans. 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 Pneumocystidomycetes, 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 global distribution among humans, and most individuals show serological evidence of infection by the age of two. As demonstrated by the frequent occurrence of PCP in patients with AIDS, the incidence of PCP is related to the degree of immunosuppression, particularly dysfunction in cellular immunity.

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

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

[0082] Mycoplasma is a genus of bacteria that lack a cell wall around their cell membranes. Due to this characteristic, Mycoplasma are 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.

[0083] 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 tract infections and 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 from when they enter the body until they cause disease. Thus, treatment strategies can be changed during the incubation time.

[0085] Accordingly, in accordance with another aspect of the present disclosure, a method of preventing, reducing or alleviating a harmful event in a patient (e.g., an MS patient) at risk of developing such a harmful event, the method comprising administering ofatumumab to the patient, wherein the patient is a patient with multiple sclerosis (MS) being treated with a disease-modifying therapy other than ofatumumab, is provided. In one embodiment, the ofatumumab treatment is initiated when the patient is exposed to the risk of viral, bacterial or fungal infections. Alternatively, the ofatumumab treatment is initiated when signs (e.g., DNA) of a viral, bacterial or fungal infection are detected, but the patient has not yet shown any symptoms. The harmful event may be one or more of an injection-related reaction, nasopharyngitis, headache, injection site reaction, upper respiratory tract infection, urinary tract infection, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, arthralgia, diarrhea, limb pain, depression, macular edema, varicella, common cold, increased gamma-glutamyl transfer, abdominal pain, skin cancer, bradycardia, hemorrhagic necrotizing encephalitis, herpes infection, progressive multifocal leukoencephalopathy (PML), hypertension, and paresthesia.

[0086] In another embodiment, the method according to the present disclosure is a method in which a patient at risk of developing a disease associated with an infection is immunosuppressed or receiving administration of an immunomodulatory drug. In one embodiment, the method according to the present disclosure is a method in which the harmful 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 the ofatumumab therapy. In another embodiment of the invention, a patient being treated with ofatumumab receives vaccination during the 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 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, Escherichia coli (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 was expected to have a negative impact on the immune system and such immunoglobulins necessary for immune acquisition after vaccination. Consistent with this expectation, Pescovitz et al. demonstrated that rituximab, another anti-CD20 antibody, results in a decrease in IgM levels. See Pescovitz et al., “B-lymphocyte depletion with rituximab and β-cell function: two-year results”, Diabetes Care, 2014 Feb; 37(2); 453-9.

[0090] Surprisingly, therefore, vaccination can be performed during ofatumumab therapy. Vaccination can be performed on patients regardless of the presence or absence 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 for patients being vaccinated with a history (e.g., the amount and dosing regimen of ofatumumab administration) can also be applied to patients without a 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 History of ischemic stroke without residual defects; History of non-atherosclerotic stroke without residual defects; History of parietal cerebrovascular attack; History of cerebrovascular attack without residual defects; History of embolic stroke without defects; History of embolic stroke without persistent effect; History of embolic transient cerebral ischemic attack; History of hemorrhagic cerebrovascular attack without residual defects; History of atherosclerotic cerebrovascular attack without residual defects; History of cardiogenic cerebral embolism may have.

[0092] Here, the expression "a patient with a history of ~" means that the patient has or had a pre-existing condition (e.g., TIA). 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, the "health benefit program" relates to therapies including the administration of ofatumumab. Therefore, a pre-existing condition (e.g., TIA) occurred or started before the initiation of ofatumumab therapy.

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

[0094] In a preferred embodiment of this aspect of the present 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 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.

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

[0097] In a preferred embodiment of this aspect of the invention, the medical history of past or ongoing conditions other than multiple sclerosis is a hospital admission history. The expression "hospital admission history" means that the patient was admitted to or had been admitted to the hospital prior to the initiation of ocrelizumab therapy. In particular, the hospital admission history is envisioned to include a history of intensive care 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 agents can be selected from the group consisting of glucocorticoids (e.g., cortisone, prednisone, dexamethasone, and hydrocortisone), antimetabolites (e.g., methotrexate, anthracyclines, mitomycin C, bleomycin, mitramycin), antibodies (e.g., basiliximab (Simulect) and daclizumab (Zenapax)), or drugs that act on immunophilins (e.g., tacrolimus and cyclosporine).

[0098] Alternatively, the medical history of a past condition other than multiple sclerosis may be a surgical history. The expression "surgical history" means that the patient has undergone or had undergone surgical treatment intervention prior to the initiation of ocrelizumab therapy. Patients with a surgical history can be treated with immunosuppressive agents other than ocrelizumab. The immunosuppressive agents can be selected from the group consisting of glucocorticoids (e.g., cortisone, prednisone, dexamethasone, and hydrocortisone), antimetabolites (e.g., methotrexate, anthracyclines, mitomycin C, bleomycin, mitramycin), antibodies (e.g., basiliximab (Simulect) and daclizumab (Zenapax)), or drugs that act on immunophilins (e.g., tacrolimus and cyclosporine).

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

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

[0101] In a preferred embodiment of this aspect of the invention, the condition other than multiple sclerosis is cancer or a lymphoproliferative disorder.

[0102] In all embodiments described so far, ocrelizumab can be administered when the serum neurofilament light chain (NfL) concentration is between 4 and 13 pg / mL. Neurofilament light chain is a human neurofilament 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 disease monitoring in multiple sclerosis. This has been demonstrated by the ASCLEPIOS I and II trials. 1,882 patients with MS between the ages of 18 and 55 with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 were enrolled. The trials were 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 the rate of brain volume loss.

[0103] Generally, the dosing regimen of ocrelizumab 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 considered a reliable, valid, and responsive PRO (patient-reported outcome) assessment criterion that complements other indicators of disease severity used to improve understanding of the impact of MS.

[0105] In the present invention, it has unexpectedly been found that administration of ofatumumab results in a beneficial reduction of the MS Impact Scale MSIS-29 as defined below.

[0106] In this context, a further subject of the 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 - 30 mg every 4 weeks, 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 woman weighing 60 kg is preferably administered the same dose as a 50-year-old man 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 a 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, for example compared to intravenous injection.

[0111] In a preferred embodiment, ofatumumab can be administered as a loading dose. A loading dose can be considered as an initial higher dose of a drug that can be administered at the start of a 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 can be administered as a loading dose at week 0, week 1, and week 2.

[0112] In a preferred embodiment of the present invention, the loading dose is 10 - 30 mg, preferably 20 mg of 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 monthly starting from week 4 is.

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

[0115] Alternatively, ofatumumab can be administered without a loading dose.

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

[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 to 1.0 mg, preferably 0.6 mg.

[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, particularly intravenously.

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

[0126] Preferably, the patient has been previously treated with at least two courses, for example 2 to 5 consecutive courses, of intravenous ocrelizumab or rituximab. The last dose may have been 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 six months (e.g., recurrence, ≥2 active gadolinium-enhanced [Gd+] lesions, any new / enlarging T2 lesions, clinical worsening) and / or patients who have interrupted 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 is 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 four weeks, preferably 20 mg every four weeks. Preferably, ofatumumab is administered by subcutaneous injection (s.c.).

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

[0132] In a preferred embodiment, the ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each filled pen or filled syringe of 20 mg / 0.4 mL delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg of ofatumumab and arginine (4 mg), disodium edetate (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg) and water for injection, USP at pH 5.5. Hydrochloric acid can also be added to adjust the pH.

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

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

[0135] In one embodiment, the first injection of the ofatumumab formulation can be performed under the guidance of a healthcare professional. Symptomatic treatment is recommended if injection-related reactions occur. Before administration, the pen or filled syringe is preferably removed from the refrigerator and allowed to return to room temperature, for example, over about 15 - 30 minutes. In a preferred embodiment, the ofatumumab formulation of the present invention is a clear to slightly milky white and colorless to slightly yellowish brown solution and is available as follows: - Injection: 20 mg / 0.4 mL, single-dose filled pen, for example, Sensoready® pen - Injection: 20 mg / 0.4 mL, single-dose filled syringe.

[0136] In a preferred embodiment, the subcutaneous ofatumumab dose of 20 mg every 4 weeks has an average AUC tau of about 400 - 550, more preferably 450 - 500, for example 483 mcg h / mL, and / or an average C maxIt provides a steady state of 1.0 to 2.5, more preferably 1.2 to 1.7, for example 1.43 mcg / mL. In a preferred embodiment, after subcutaneous administration of a dose of 20 mg of ofatumumab repeated, the steady state volume of distribution can be 4.5 to 6.5, more preferably 5.0 to 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) Relapsing-Remitting MS (RRMS) Primary Progressive MS (PPMS) Secondary Progressive MS (SPMS)

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

[0140] Relapsing-remitting MS is characterized by unpredictable relapses followed by relatively quiet (remission) periods of months to years without new signs of disease activity. Due to the deficits that occur during attacks, the disability may disappear or remain, 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. When the deficits always disappear during attacks, 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. The relapsing-remitting subtype usually begins with clinically isolated syndrome (CIS). In CIS, people have attacks suggestive of demyelination but do 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] Primary progressive MS occurs in approximately 10 - 20% of individuals without remission after initial symptoms. It is characterized by no remission and improvement, or only occasional and minor remission and improvement, with progressive disability from the start. The usual age of onset of the primary progressive subtype is later than that of the relapsing-remitting subtype. Secondary progressive usually occurs around age 40 and is similar to the age of onset in relapsing-remitting MS.

[0142] Secondary progressive MS occurs in about 65% of people with 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.

[0143] Atypical variants of MS are described; these include tumefactive multiple sclerosis, Baló concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. There is debate as to whether these are variants of MS or different diseases. Some diseases that were previously thought to be variants of MS, such as Devic's disease, are now considered to be outside the MS spectrum.

[0144] For all embodiments described heretofore, a premedication can be administered to the patient before the first dose of ofatumumab is given. The premedication can include acetaminophen, an antihistamine, and / or a steroid. It can be administered 30 to 60 minutes before the ofatumumab injection.

[0145] Alternatively, no premedication can be administered before the first dose of ofatumumab.

[0146] The effect of past or ongoing conditions, such as the prevention of diseases associated with infectious diseases, can be evaluated by standard, predefined 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 applicable to the purposes described above. For example, the viral load or infectious disease state 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. A person skilled in the art is aware of the techniques for analyzing the viral load and infectious disease state in a patient. The viral DNA load can be evaluated by analyzing the expression of viral genes.

[0147] The present disclosure further relates to a method of 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 treatment of the patient, and more particularly, when the patient is a patient with MS, and more specifically, 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 may include one or more of 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, nasal cold, increased gamma-glutamyl transfer, abdominal pain, skin cancer, bradycardia, hemorrhagic necrotizing encephalitis, herpes infections, progressive multifocal leukoencephalopathy (PML), hypertension, and paresthesia.

Example

[0148] [Example 1] Design / Method APLIOS was a 12-week, open-label, Phase 2 bioequivalence study. Patients received an ofatumumab 20 mg (0.4 mL) s.c. loading dose on days 1, 7, and 14, and maintenance doses from week 4 onwards every 4 weeks via a prefilled syringe or 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.

[0149] Results Ofatumumab 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. Naive B cells (CD19+CD45+IgD+CD27-CD38 dimMore efficient depletion of memory B cells (CD19+CD45+CD27+) was observed compared to

[0150] Conclusion Ofatumumab 20 mg s.c. resulted in rapid and sustained depletion of both CD20+B and CD20+T cells in patients with RMS. 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 ofatumumab in the pathophysiology of MS.

[0151] [Example 2] Background Ofatumumab, the first fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy compared to teriflunomide in the ASCLEPIOS I / II trial, phase 3. See ECTRIMS Online Library, Hauser S.et.al. 09 / 13 / 19;279581;336. MS patients treated with ofatumumab had annualized relapse rates (ARR) that were reduced by 50.5% (0.11 vs 0.22) and 58.5% (0.10 vs 0.25), respectively, compared to Aubagio® * (teriflunomide) (p<0.001 for both trials). Ofatumumab showed a highly significant suppression of gadolinium (Gd) T1 lesions and demonstrated strong suppression of new inflammatory activity compared to Aubagio®. In a pre-specified pooled analysis, ofatumumab 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 compared to Aubagio®.

[0152] Objective To determine serum immunoglobulin (Ig) levels and examine the relationship between IgG or IgM levels and novel treatment options, 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 trials. Patients were randomized (1:1) to receive either ocrelizumab 20 mg sc injection every 4 weeks (after an initial loading regimen of 20 mg sc doses on days 1, 7, and 14) or teriflunomide 14 mg orally once daily for up to 30 months. The trial had a flexible duration with a core treatment period that could be stopped according to pre-specified criteria. Patients aged 18 to 55 years, with an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at screening (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444-52), who had experienced ≥1 relapse within the past year or ≥2 relapses within the past 2 years, or who had a positive gadolinium-enhanced (Gd+) MRI scan during the year prior to randomization were included.

[0154] 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 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.

[0155] Results regarding IgG and IgM levels

[0156]

Table 1

[0157] The change from the baseline of serum IgG level is shown in Figure 2. The change from the baseline of serum IgM level 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 tendency of decreasing IgG level reverses, and finally, starting from about week 72, IgG results in a net increase.

[0159] 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 rate of infectious diseases was found.

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

[0162] [Example 3] Method In a 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 a reduction of approximately 5% in IgG level, while ofatumumab resulted in an increase of about 3%. See Figure 2.

[0164] Conclusion Ofatumumab can result in a long-term persistence and even an increase in IgG level, while ocrelizumab can rather result in a continuous reduction in IgG level.

[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 who do not have injection-related reactions and have not received hydrocortisone treatment. Overall, no signs of immunosuppression or toxicity are expected with 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.) to examine the effect of B cell depletion on antibody-mediated immunity against Streptococcus pneumoniae. B cells were depleted by administration of 50 μg / mouse of anti-CD20 (mIgG1, n = 8 per group) via either the i.v. or s.c. route of administration. Mice without B cell depletion received administration of an isotype control antibody (s.c.) at the same concentration. Mice were vaccinated with the 13-valent pneumococcal 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 an administration of PBS (phosphate buffered saline) (i.p.) (see Fig. 6).

[0169] Evaluation Serum pneumococcal-specific IgG levels were measured on day 16 (after the first vaccination) and day 29 (endpoint) by whole cell ELISA on plates coated with pneumococci (TIGR4 strain) (see Fig. 7).

[0170] Pneumococcal bacteria 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 Fig. 7).

[0171] On day 14, the spleen and lymph nodes were analyzed to observe the effect on blood and B cell repertoire levels. 14 days after anti-CD20 antibody treatment, the number of B cells was still approximately 20% of the B cell count in the untreated group (see Figs. 8 and 9).

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

[0173] Two-vaccination test: Depletion of B cells on day 29 - Four weeks after anti-CD20 treatment, only 60% of the B cell population was reconstituted (see Fig. 12). - No significant differences in B cell subtypes were observed between the s.c. and i.v. anti-CD20 treatment groups (see Fig. 13). - Pneumococcal-specific immunoglobulin levels (IgG / IgM) · The levels of IgG 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 (see day 16, Figure 14). · No significant difference in IgG levels was observed between the s.c. and i.v. anti-CD20 treatment groups (see Figure 14). · The accumulation of antibodies on the bacterial surface suggested lower levels of IgG binding to pneumococcus in the anti-CD20 treatment group (depleted samples) compared to vaccinated samples; however, IgM levels were equivalent (see Figure 15).

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

[0175] b) Clinical trials One hundred patients with relapsing-remitting MS receive subcutaneous ofatumumab

[0176] - During the loading dose regimen, it includes administering 20 mg of ofatumumab on days 0, 7, and 14 of the dosing regimen; and - During the maintenance dose regimen, it includes starting the administration of 20 mg of ofatumumab from the 4th week of the dosing regimen and continuing every 4 weeks thereafter for the duration of the treatment protocol.

[0177] 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 two months by radioactive examinations (MRI) and health check-ups.

[0178] In patients with an infectious disease as an adverse event, blood samples are collected for laboratory analysis. If an infectious disease caused by Staphylococcus aureus is confirmed by the analysis, each patient is treated with oral trimethoprim-sulfamethoxazole. Ofatumumab treatment is continued.

[0179] During treatment with trimethoprim-sulfamethoxazole, blood samples are collected every other day. From the analysis of these samples, it is expected that the IgG levels against Staphylococcus aureus in patients treated with ofatumumab will be shown to be equivalent to the IgG levels reported in the literature for infected subjects without MS and not treated with ofatumumab, as proven by meta-analysis. Furthermore, patients treated with ofatumumab are expected to recover more rapidly from the infectious disease when compared to past clinical trials.

[0180] [Example 6] a) Animal tests In mice (C57BL / 6 female mice, 6 weeks old), the middle cerebral artery (MCA) was occluded using an endovascular filament model (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 recovered rapidly. A 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 a subset of mice in both groups (MCA occlusion group and sham group). B cells were depleted by administering 50 μg / mouse of anti-CD20 mIgG1 to n = 8 per group. Mice without B cell depletion received administration of an isotype control antibody (s.c.) at the same concentration.

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

[0183] Recovery after MCA occlusion (including tissue repair) appeared to be unaffected by anti-CD20 treatment.

[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 placed inside 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, etc.), - Fosfomycin (Monurol), - Nitrofurantoin (Macrodantin, Macrobid), - Cephalexin (Keflex) or - Ceftriaxone and treated with one of them.

[0185] The second group of patients consisted of MS patients treated with ocrelizumab. Subgroup patients develop adverse events including urinary tract infections. These infections are the following - Trimethoprim / sulfamethoxazole (Bactrim, Septra, etc.), - Fosfomycin (Monurol), - Nitrofurantoin (Macrodantin, Macrobid), - Cephalexin (Keflex) or - Ceftriaxone is treated with one of the following.

[0186] Conclusion - A significant decrease in follicular B cell subtype 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 difference is expected regarding the response to urinary tract infections. - The correlation of the data suggests that ofatumumab can be safely administered even after adverse events such as urinary tract infections occur after stroke.

[0187] [Example 7] Treat MS patients with either ofatumumab or ocrevus (ocrelizumab). Selected 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) and are therefore treated with one of the immunosuppressive agents, namely

[0188] - Azathioprine (Imuran, Azasan) or - Cyclosporine (Gengraf, Neoral, Sandimmune)

[0189] Findings: ​​The level of IgG in patients treated with ofatumumab is expected to be significantly higher than that in patients treated with ocrevus.

[0190] A significant decrease in follicular B cell subtypes was expected with ofatumumab treatment, while the marginal zone and germinal center B cell subtypes appeared to be less affected.

[0191] Significantly more adverse events (e.g., infections) are expected in the ocrevus group after treatment with immunosuppressive agents.

[0192] Equivalent responses in psoriatic arthritis are expected in both groups. The present invention includes the following aspects. <1> Ocrelizumab for use in the treatment or prevention of relapsing multiple sclerosis (RMS), wherein the ocrelizumab is used in patients having a history of past or ongoing conditions other than multiple sclerosis. <2> Said conditions other than multiple sclerosis are Injection-related reactions, Nasopharyngitis, Headache, Reactions at the injection site, Upper respiratory tract infections, Urinary tract infections, Back pain, Fatigue, Influenza, Nausea, Decrease in blood immunoglobulin M, Alopecia, Arthralgia, Diarrhea, Pain in the extremities, Depression, Hypertension, Paraesthesia One or more of, the ocrelizumab for use according to <1>. <3> Said history of past or ongoing conditions other than multiple sclerosis is a history of past infectious diseases, the ocrelizumab for use according to <1> or <2>. <4> Said past or ongoing infectious diseases are Respiratory syncytial virus (RSV), Influenza or parainfluenza virus, Human polyomavirus (BK virus), Adenovirus, Rhinovirus, Coronavirus, 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, Escherichia coli (E.coli), Staphylococcus species (e.g., Staphylococcus saprophyticus or Staphylococcus aureus), Chlamydia trachomatis, Haemophilus influenzae, Meningococcus species, Klebsiella species, Pseudomonas species, Enterococcus species, Streptococcus species, Yeast (e.g., Candida albicans), Pneumocystis species (e.g., Pneumocystis murina), Cryptococcus species (e.g., Cryptococcus neoformans), Aspergillus species, Mycoplasma genitalium Ofatumumab for use according to <3>, caused by a virus or microorganism selected from the group consisting of. <5> Ofatumumab for use according to any of <1> to <4>, wherein the patient receives vaccination during ofatumumab therapy. <6> The vaccination is 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, Escherichia coli (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 An ofatumumab for use according to <5>, which is directed against any one of the above. <7> A patient having a history of past or ongoing conditions other than multiple sclerosis History of transient ischemic attack (TIA); History of cerebral infarction without residual defect; History of thrombotic stroke without persistent effect; History of thrombotic stroke without residual defect; History of transient ischemic attack; History of ischemic stroke without residual defect; History of non-atherosclerotic stroke without residual defect; History of cerebrovascular attack in the vertex; 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; Cardioembolism An ofatumumab for use according to any one of <1> to <6>, which has the above. <8> An ofatumumab for use according to any one of <1> to <7>, wherein a patient having a history of past or ongoing conditions other than multiple sclerosis follows a treatment to cure, relieve or eliminate the condition before starting ofatumumab therapy. <9> Ofatumumab for use according to <8>, wherein said treatment comprises administration of a glucocorticoid, such as cortisol, and / or a non-steroidal anti-inflammatory drug (NSAID), such as ibuprofen (Motrin, Advil) and naproxen (Naprosyn) or a COX-2 inhibitor, such as celecoxib, and / or an immunosuppressive drug. <10> Ofatumumab for use according to any one of <1> to <9>, wherein said past or ongoing condition is an autoimmune disease other than multiple sclerosis. <11> Said autoimmune disease other than multiple sclerosis is 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 Ofatumumab for use according to <10>, selected from <12> Ofatumumab for use according to <10>, wherein said autoimmune disease is rheumatoid arthritis (RA). <13> Ofatumumab for use according to <12>, wherein said rheumatoid arthritis (RA) is treated with a disease-modifying anti-rheumatic drug (DMARD) selected from the group consisting of methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-alpha inhibitors (certolizumab, infliximab and etanercept), abatacept, anakinra, rituximab and tocilizumab. <14> Ofatumumab for use according to <10>, wherein said autoimmune disease is psoriasis. <15> Ofatumumab for use according to <14>, wherein said psoriasis is 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, efalizumab and alefacept. <16> Ofatumumab for use according to any one of <1> to <15>, wherein the medical history of said past or ongoing condition other than multiple sclerosis is a medical history of hospitalization. <17> Ofatumumab for use according to any one of <1> to <16>, wherein the medical history of said past or ongoing condition other than multiple sclerosis is a medical history of surgery. <18> Ofatumumab for use as described in <16> or <17>, wherein the patient is treated with an immunosuppressant other than ofatumumab. <19> Ofatumumab for use as described in <18>, wherein the immunosuppressant is selected from the group consisting of glucocorticoids (e.g., cortisone, prednisone, dexamethasone, and hydrocortisone), cytostatic agents (e.g., methotrexate, anthracyclines, mitomycin C, bleomycin, mitramycin), antibodies (e.g., basiliximab (Simulect) and daclizumab (Zenapax)), and drugs acting on immunophilins (e.g., tacrolimus and cyclosporine). <20> Ofatumumab for use as described in any one of <1> to <19>, wherein the patient is an elderly patient. <21> Ofatumumab for use as described in <20>, wherein the elderly patient has age-related macular degeneration (AMD). <22> Ofatumumab for use as described in <20>, wherein the elderly patient has Alzheimer's disease. <23> Ofatumumab for use as described in <20>, wherein the elderly patient has atherosclerosis. <24> Ofatumumab for use as described in <20>, wherein the elderly patient has benign prostatic hyperplasia (BPH). <25> Ofatumumab for use as described in any one of <1> to <19>, wherein ofatumumab is administered to a pediatric patient. <26> Ofatumumab for use as described in any one of <1> to <25>, wherein the condition other than multiple sclerosis is cancer or a lymphoproliferative disorder. <27> Ofatumumab for use as described in any one of <1> to <26>, wherein it is administered when the serum neurofilament light chain (NfL) concentration is 4 - 13 pg / mL. <28> Ofatumumab for use as described in any one of <1> to <27>, wherein it is administered at a dose of 10 - 30 mg every 4 weeks, preferably 20 mg every 4 weeks. <29> Ofatumumab for use as described in any one of <1> to <28>, wherein it is administered subcutaneously. <30> Ofatumumab for use as described in any one of <1> to <29>, wherein it is administered as a loading dose. <31> Ofatumumab for use as described in <30>, wherein 20 mg of ofatumumab is administered as a loading dose on day 1, day 7, and day 14, or preferably on week 0, week 1, and week 2. <32> Ofatumumab for use as described in any one of <1> to <31>, wherein it is administered without a loading dose. <33> Ofatumumab for use as claimed in any one of <1> to <32>, wherein the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). <34> Ofatumumab for use as claimed in any one of <1> to <33>, wherein a premedication is administered to the patient before the first dose of ofatumumab is administered. <35> Ofatumumab for use as claimed in <34>, wherein the premedication comprises acetaminophen, an antihistamine and / or a steroid. <36> Ofatumumab for use as claimed in <34> or <35>, wherein the premedication is administered 30 to 60 minutes before an ofatumumab injection. <37> Ofatumumab for use as claimed in any one of <1> to <33>, wherein no premedication is administered before the first dose of ofatumumab. <38> Ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, wherein vaccination is carried out during ofatumumab therapy. <39> The vaccination is - 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, - Escherichia coli (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 Ofatumumab for use as described in <38>, which is directed against any one of coronavirus, particularly SARS-CoV-2. <40> Ofatumumab for use as described in any one of <1> to <39>, wherein the patient has been neurologically stable for one month prior to the first administration of ofatumumab. <41> Ofatumumab for use as described in any one of <1> to <40>, wherein the patient has an EDSS score of 1 to 4 prior to the first administration of ofatumumab. <42> Ofatumumab for use as described in any one of <1> to <41>, which is administered at a dose of 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks. <43> Ofatumumab for use as described in any one of <1> to <42>, which is administered subcutaneously. <44> Ofatumumab for use as described in any one of <1> to <43>, which is administered as a loading dose. <45> Ofatumumab for use as described in <44>, wherein 20 mg of ofatumumab is administered as a loading dose on day 1, day 7, and day 14, or preferably on week 0, week 1, and week 2. <46> Ofatumumab for use as described in any one of <1> to <43>, which is administered without a loading dose. <47> Ofatumumab for use as described in any one of <1> to <46>, wherein the relapsing multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). <48> Ofatumumab for use as described in any one of <1> to <47>, wherein the pre-medication is administered to the patient prior to the administration of the first dose of ofatumumab. <49> Ofatumumab for use as described in <48>, wherein the pre-medication comprises acetaminophen, an antihistamine, and / or a steroid. <50> Ofatumumab for use as described in <48> or <49>, wherein the pre-medication is administered 30 to 60 minutes before the ofatumumab injection. <51> Ofatumumab for use as described in any one of <38> to <47>, wherein the pre-medication is not administered before the first dose of ofatumumab. <52> Use of ofatumumab for the manufacture of a medicament for the treatment or prevention of relapsing-remitting multiple sclerosis (RMS), wherein ofatumumab is used as described in any one of <1> to <51>. <53> A method for treating or preventing relapsing-remitting multiple sclerosis (RMS) by administering ofatumumab as defined in any one of <1> to <52>.

[0193] References

[0194]

Table 2

Claims

1. A pharmaceutical composition comprising ofatumumab for use in a method of treating multiple sclerosis (MS), wherein the method comprises administering a therapeutically effective amount of ofatumumab to a patient in need thereof, wherein the method does not interfere with the prevention of virus-associated diseases by vaccination, and the patient receives vaccination during ofatumumab treatment. A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the multiple sclerosis (MS) is relapsing multiple sclerosis (RMS).

3. The pharmaceutical composition according to claim 2, wherein the relapsing multiple sclerosis (RMS) is relapsing-remitting multiple sclerosis (RRMS), active secondary progressive multiple sclerosis (SPMS), or clinically isolated syndrome (CIS).

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient is an adult.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the prevention delays or prevents the onset of virus-associated diseases, disorders, and / or symptoms associated therewith.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient does not develop a virus-associated disease.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient does not develop a virus-associated disease 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 ofatumumab therapy.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the vaccination is against influenza virus.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the vaccination is against varicella-zoster virus (VZV).

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein ofatumumab is administered subcutaneously.

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