Management of conditions other than multiple sclerosis in treatment of patients with ofamumab

Abstract

The present invention relates to the management of conditions other than multiple sclerosis in treatment of patients with Ofalimumab, and specifically provides methods of multiple sclerosis (MS) treatment that allow for the control of conditions other than MS, such as infections.

Description

TECHNICAL FIELD

[0001] The present application relates to ofatumumab for use in the treatment or prevention of relapsing forms of multiple sclerosis (RMS), wherein ofatumumab is for use in patients with a history of a previous or ongoing condition other than multiple sclerosis. BACKGROUND

[0002] Invasive viruses, bacteria or fungi employ various mechanisms to resist inactivation or destruction by the host. They sometimes produce toxins to impair the body's defense systems or change their shape or external structural proteins to mask evasion of recognition by the immune system (antigenic change). Some bacteria can produce adhesion factors that allow them to adhere to the mucosa and impede their destruction. As a result of these mechanisms, patients with a history of a condition, such as a previous or ongoing infection, can not tolerate or can be particularly sensitive to immunosuppressive therapy. However, certain diseases such as multiple sclerosis (MS) can require immunosuppressive therapy. Therefore, there is a need to provide MS therapy for patients with a history of a previous or ongoing infection condition.

[0003] These mechanisms of resistance to inactivation or destruction by the host are more likely to succeed in patients who are immunocompromised or immunosuppressed, such as patients who are undergoing treatment for MS. However, stopping immunosuppression is generally not an option as it is part of the treatment, such as treatment for MS. Therefore, there is a need to prevent, reduce or mitigate viral, bacterial or fungal infection while allowing immunosuppression, such as for the treatment of MS.

[0004] Importantly, immunosuppression is often incompatible with some prophylactic or therapeutic measures, such as vaccination. In some cases, this presents a dilemma for patients who are immunocompromised or immunosuppressed, such as patients undergoing treatment for MS. For example, lower urinary tract infections are a common adverse event in patients who are immunocompromised or immunosuppressed, such as patients undergoing treatment for MS. Viruses are increasingly recognized as a cause of lower urinary tract infections, especially hemorrhagic cystitis, in patients who are immunocompromised or immunosuppressed. BK virus, adenovirus, and cytomegalovirus are the primary pathogens associated with hemorrhagic cystitis. Cidofovir is emerging as a drug of choice for viral urinary tract infections because it is active against the most common viral pathogens. However, if these patients are already on therapy and / or are immunocompromised / immunosuppressed, such as MS patients undergoing treatment for MS, it can not be desirable to expose the patient, such as a patient undergoing treatment for MS, to a high drug load, including cidofovir. For example, cidofovir is known to cause adverse events, such as nephrotoxicity and neutropenia. For MS patients undergoing treatment for MS, such as with fingolimod, neutropenia can be dangerous because it exacerbates the leukopenia (lymphopenia) caused by fingolimod, thus being detrimental to the immune system. For MS patients undergoing treatment for MS, such as with fingolimod, nephrotoxicity can be dangerous because it impairs the body’s ability to excrete fingolimod and its metabolites, which can lead to fluid imbalance and related illnesses. Thus, there is a need to address adverse events in a different way. Specifically, there is a need for MS therapies that allow for vaccination during therapy.

[0005] Epstein-Barr virus (EBV) is one of the most successful human pathogens, with over 90% of the adult population persistently infected (Cesarman 2014, Cohen 2015). In immunodeficient individuals, EBV infection can be associated with a wide variety of diseases, including malignancies, including carcinoma (gastric or nasopharyngeal) or lymphoma (e.g. Hodgkin's lymphoma). In immunocompetent individuals, anti-viral T cell responses control the infection, but EBV remains latent in 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 suppress anti-EBV T cell responses, allowing EBV-induced B cell proliferation to run amok. Similarly, most individuals are infected with varicella zoster virus (VZV) in childhood, resulting in the onset of chickenpox. The immune system eventually eliminates the virus from most locations, but it remains dormant (or latent) in the ganglia adjacent to the spinal cord, called dorsal root ganglia, or in the cranial base trigeminal ganglion. The disease (shingles) results from the conversion of viral particles in a single sensory ganglion from their latent lytic cycle to their active lytic cycle. VZV infection has 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, causes the dreaded complication progressive multifocal leukoencephalopathy (PML). As with EBV and VZV, cells infected with JC virus are under the control of anti-viral T cells. Immunosuppressive agents that currently affect T cell function increase the risk of activating latent viruses like EB and JC. Thus, there is an urgent need for new therapies to modulate, prevent or inhibit viral infections, such as EBV or JCV infection, and related diseases in MS patients, who are particularly susceptible. SUMMARY

[0006] A method of treating multiple sclerosis (MS) in patients with a prior or ongoing condition other than MS is provided. Surprisingly, it was found that patients with a prior or ongoing condition other than multiple sclerosis and in need of treatment or prevention of relapsing multiple sclerosis can be successfully treated with ofatumumab without substantially impairing management of the condition other than MS. Furthermore, patients can be vaccinated during ofatumumab treatment. This is completely unexpected because ofatumumab is an anti-CD20 antibody and depletes lymphocytes. Therefore, ofatumumab was expected to negatively affect the immune system, so that a prior or ongoing condition (e.g. a prior or ongoing infection) cannot be successfully treated in patients treated with ofatumumab. In line with this expectation, Pescovitz et al. demonstrated that rituximab (another anti-CD20 antibody) leads to 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 DRAWINGS

[0007] Figure 1 The clinical trial setup according to Example 1 and the measurement of IgG and IgM are described.

[0008] Figure 2 The change in serum IgG levels relative to baseline is illustrated.

[0009] Figure 3 The change in serum IgM levels relative to baseline is illustrated.

[0010] Figure 4 The decrease in IgG levels after administration of a prior art anti-CD20 (ocrelizumab) is illustrated. Figure 4First published as part of 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.

[0011] Figure 5 shows that after two years (96 weeks), ocrevus treatment (combined with OPERA, see Figure 4 ) has led to a decrease of IgG levels of about 5%, while ofatumumab has led to an increase of about 3%.

[0012] Figure 6 shows the treatment groups of the study, in which a single dose of anti-CD20 antibody was given to mice by two different routes (intravenous (i.v.) or subcutaneous (s.c.)) to investigate the effect of B cell depletion on antibody-mediated immunity.

[0013] Figure 7 shows the B cell depletion and vaccination study design of Figure 6 in more detail.

[0014] Figure 8 and 9 shows the total B-cell population at day 14 of the one-dose vaccination study Figure 8 : B cell gated CD19+, CD3-, CD11b-, LygG / C-; Figure 9 : proportion and total number of B cells).

[0015] Figure 10 and 11 shows the B-cell subtypes at day 14 of the one-dose vaccination study Figure 10 : B cell gated; marginal zone CD23-CD21+; follicular: CD23+IgD+; germinal center: PNA+IgD-; Figure 11 : proportion and number of non-depleted B cells).

[0016] Figure 12 shows the B cell depletion at day 29 of the two-dose vaccination study using spleen homogenate.

[0017] Figure 13 B cell depletion at day 29 in the two-dose vaccination study is shown, highlighting the proportion, number and subtypes of B cells.

[0018] Figure 14 and 15 Pneumococcal-specific immunoglobulin levels (IgG / IgM) at day 16 and day 29 in the two-dose vaccination study are shown.

[0019] General definitions

[0020] The term "treatment" or "therapy" can be defined as the administration or application of ofatumumab to a patient with the objective to eliminate, reduce or alleviate the symptoms of a disease (e.g. multiple sclerosis (MS)). In particular, the term "treatment" includes achieving an effect that is of clinical significance to the patient, e.g. achieving a clinically meaningful reduction in annual relapse rate when treating RMS.

[0021] As used herein, a patient is "in need of" a treatment if such patient would benefit from such treatment medically or in terms of quality of life. The term "patient" as used herein can be a mammal, e.g. a primate, preferably a higher primate, particularly preferably a human (e.g. a patient having or at risk of having a disease as described herein). Preferably, the patient is adult.

[0022] As used herein, the term "administration" or "administering" of ofatumumab can mean providing ofatumumab to a patient in need of treatment. Administration "in combination" with one or more other therapeutic agents includes simultaneous (parallel) and consecutive administration in any order and by any administration route.

[0023] As used herein, "therapeutically effective amount" can mean an amount of ofatumumab effective, i.e. that achieves a clinically meaningful effect.

[0024] The term "adverse event" (AE) can relate to any untoward medical occurrence in a patient or clinical investigation in which a subject is, or has been exposed to a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Thus, an adverse event (AE) can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.

[0025] The phrase "treatment regimen" can mean a regimen for treating a disease or preventing a disease condition or disease progression, e.g. the dose used. A treatment regimen can include an induction regimen, a loading regimen and a maintenance regimen.

[0026] The phrase "loading regimen" or "loading dose" can refer to a treatment regimen (or portion of a treatment regimen) used for initial treatment of a disease. In some embodiments, the disclosed methods, uses, kits, processes, and regimens employ a loading regimen. In some cases, the loading phase is a period until maximum efficacy is achieved. The general goal of a loading regimen can be to provide a high level of drug to the patient in the initial phase of the treatment regimen. An induction regimen can employ (partially or entirely) a "loading regimen" or "loading dose," which can include administering a larger dose of drug than a physician would employ during a maintenance regimen, administering the drug more frequently than a physician would administer during a maintenance regimen, or both. Doses can be escalated during or after an induction regimen.

[0027] The phrase "maintenance regimen" or "maintenance dose" can refer to a treatment regimen (or portion of a treatment regimen) used to maintain a patient during treatment of a disease, e.g., to keep a patient in remission long periods of time (months or years) after an induction period. In some embodiments, the disclosed methods, uses, and regimens employ a maintenance regimen. A maintenance regimen can employ continuous treatment (e.g., administering a drug at regular intervals, e.g., weekly, monthly [every 4 weeks], yearly, etc.) or intermittent treatment (e.g., interrupted treatment, intermittent treatment, relapse treatment, or treatment until a particular predetermined criterion [e.g., pain, disease manifestation, etc.] is achieved). Doses can be escalated during a maintenance regimen.

[0028] The term "Multiple Sclerosis Impact Scale (MSIS-29)" is defined as follows: The MSIS-29 version 2 is a 29-item self-completion questionnaire that includes 2 domains: physical and psychological. Responses are recorded on a 4-point ordinal scale, ranging from 1 (not at all) to 4 (very much), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete and the questions are designed to determine the patient's perception of the impact of MS on their daily life over the past 2 weeks. Reference: 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.

[0029] The expression "patient with a prior medical history other than multiple sclerosis" can mean that the patient has or had a preexisting condition. A preexisting condition is defined as "a medical condition that occurred before a program of health benefits went into effect" ("Billing terminology". Pittsburgh: University of Pittsburgh Medical Center (UPMC). 2010. From a printout of the original on October 3, 2010. Retrieved on January 16, 2010). In the context of the present invention, the "program of health benefits" can relate to a therapy comprising the administration of ofatumumab. Thus, the preexisting condition occurred or started before the initiation of ofatumumab treatment. In a preferred embodiment, the ofatumumab therapy is for the treatment of (R)MS.

[0030] Vaccination can be the administration of a vaccine to help the immune system form a defense against a disease. Vaccines preferably contain a microorganism or virus in a weakened, live or dead state, or a protein or toxin from the organism. They help prevent disease caused by infectious agents in stimulating the body's adaptive immunity. When a large enough percentage of a population has been vaccinated, herd immunity results. Vaccination can be the most effective method of preventing infectious diseases. However, if a person is already receiving treatment to cure, modify or alleviate the symptoms of a first disease (e.g. MS), it can be difficult or impossible to vaccinate him against a second disease according to the art.

[0031] In a preferred embodiment, the vaccine is not 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.

[0032] RRMS

[0033] Relapsing-remitting multiple sclerosis (MS) is characterized by relapses, e.g., defined as new neurologic deficits or exacerbations of neurologic worsening lasting more than 24 hours, without fever or infection.

[0034] There is no clear disease progression during remissions. At different time points, RRMS can be further characterized as active (with evidence of relapses and / or new MRI activity) or not active, and worsening (with evidence of increasing disability within a specific time period after a relapse) or not worsening. Reference: Lublin 2014, Neurology. 2014 Jul 15;83(3):278-286.

[0035] RMS

[0036] The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS and clinically isolated syndrome (CIS).

[0037] Primary progressive MS (PPMS)

[0038] PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions. PPMS can be further characterized at different time points as active (with occasional relapses and / or evidence of new MRI activity) or not active, and progressive (evidence of worsening disease by objective measures over time, with or without relapses or new MRI activity) or not progressive. Reference: Lublin 2014.

[0039] Everyone’s experience with PPMS is unique. PPMS can have periods of short-lived disease stability, with or without relapses or new MRI activity, and periods when increasing disability occurs with or without new relapses or MRI lesions.

[0040] Secondary progressive MS (SPMS)

[0041] SPMS occurs after the initial relapsing-remitting course. Most people diagnosed with RRMS will eventually transition to a secondary progressive course, in which progressive worsening of neurologic function (accumulation of disability) occurs over time. SPMS can be further characterized at different time points as active (with evidence of relapses and / or new MRI activity) or not active, and progressive (evidence of worsening disease by objective measures over time, with or without relapses) or not progressive. Reference: Lublin 2014.

[0042] Everyone’s experience with SPMS is unique. SPMS occurs after relapsing-remitting MS. Disability gradually increases over time, with or without evidence of disease activity (relapses or MRI changes). In SPMS, occasional relapses can occur, as well as periods of stability.

[0043] Clinically isolated syndrome (CIS):

[0044] Clinically isolated syndromes (CIS) can refer to a single clinical episode of inflammatory demyelination in the central nervous system (CNS) suggestive of multiple sclerosis (MS). CIS manifestations can be either monofocal or multifocal, and can typically involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral hemisphere. Reference: Miller et al., Clinically isolated syndromes, Lancet Neurol. 2012; 11 : 157-169.

[0045] T1 and T2 lesions

[0046] T1 and T2 relate to different MRI methods used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time used between the magnetic pulse and the image recording. These different methods are used to detect different structures or chemical substances in the central nervous system. T1 and T2 lesions refer to whether a lesion was detected using a T1 or T2 method. T1 MRI images provide information about current disease activity by highlighting active inflammatory areas. T2 MRI images provide information about disease burden or lesion burden (total amount of new and old lesion areas).

[0047] Relapse

[0048] A relapse can be defined as a new neurologic deficit or an onset of neurologic worsening, preferably lasting more than 24 hours. In other words, a relapse can be considered as a discrete episode of neurologic dysfunction (also referred to in the art as "attack", "flare-up" or "exacerbation"), preferably lasting at least 24 hours. Typically, a relapse is followed by a period of complete or partial recovery and absence of symptom progression or disability accumulation (remission).

[0049] Ocrelizumab:

[0050] Ocrelizumab is a human monoclonal antibody directed against the CD20 protein. Ocrelizumab can bind specifically to the small and large extracellular loops of the CD20 molecule. The Fab domain of ocrelizumab can bind to the CD20 molecule, while the Fc domain mediates immune effector functions to cause B cell lysis in vitro. Specifically, ocrelizumab is a recombinant human monoclonal immunoglobulin Gl (IgGl) antibody that binds to human CD20 expressed on, for example, B cells. Ocrelizumab is produced in murine NS0 cell lines, consisting of two IgGl heavy chains and two kappa light chains, with a molecular weight of approximately 146 kDa.

[0051] Ocrelizumab is described in EP 1 558 648 B1 and EP 3 284 753 B1. Further reference is made to the description in drugbank.ca, accession number DB06650, and to WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the protein has the chemical formula C 6480 H 10022 N 1742 O 2020 S 44 and a weight average molecular weight of about 146100 Da.

[0052] The metabolic pathway of ocrelizumab can be degradation into small peptides and amino acids by ubiquitously present proteolytic enzymes. Ocrelizumab can be eliminated in two ways: a target-independent route as other IgG molecules and a target-mediated route involving binding to B cells.

[0053] The half-life of ocrelizumab can be about 16 days in the steady state, especially after repeated subcutaneous administration of a 20 mg dose.

[0054] Ocrelizumab preferably does not share a common elimination pathway with chemical drugs metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Preferably, ocrelizumab is not involved in the modulation of drug metabolizing enzyme expression. DETAILED DESCRIPTION

[0055] Long-term, low-levels of immunoglobulin G (IgG) and / or IgM are associated with an increased risk of infections. This raises concerns as several MS therapies were found to lower immunoglobulin levels. In particular, it was reported that treatment with B-cell-depleting therapies leads to reduced serum levels of immunoglobulin (Ig) G, IgM and / or IgA. Moreover, as MS therapies are usually life-long, MS patients are at an increased risk of infections.

[0056] For example, ocrelizumab (trade name Ocrevus), an anti-CD20 antibody, can lead to a higher infection rate in patients receiving its treatment. Ocrevus is approved in the United States for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS). Rituximab, another antibody similar to ocrelizumab, has been reported to be associated with a higher infection rate, especially in patients with low levels of IgM or IgG.

[0057] In June 2019, the European Commission updated the prescribing information for ocrelizumab describing the association between immunoglobulin reduction and serious infections as follows: “During the study control period, which was primarily driven by IgM reduction, treatment with Ocrevus resulted in total immunoglobulin reduction. Clinical trial data have shown an association between reduced IgG levels (but not IgM or IgA) and serious infections.”

[0058] K. Smoot et al. (“The Impact of Ocrelizumab on Immunoglobulin Levels and the Risk of Infection”, 09 / 12 / 19; 278212; P1010) investigated ocrelizumab-treated MS patients and reported that there was no evidence of a significant difference in IgM levels between patients with and without infections. However, they emphasized that infections were more common in patients with lower IgG levels.

[0059] 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 reduction in serum Ig levels which was significantly associated with an increased rate of serious infections. The association was strongest for IgG, but not for IgM or IgA. Serum Ig levels declined at an average rate of about 3-4% per year (see Figure 1 ). There was a significant association between reduced IgG levels and serious infections.

[0060] In summary, it is reported that one of the most common adverse events associated with B-cell-depleting therapies (such as ocrelizumab therapy) in clinical trials is a reduction in immunoglobulins (such as IgM) in the blood.

[0061] Thus, it is completely unexpected that ofatumumab therapy is advantageous compared to other B-cell-depleting therapies, as it leads to a smaller reduction of immunoglobulins (e.g. IgM). Thus, the risk of serious infections is unexpectedly reduced in patients treated with ofatumumab. Furthermore, the absence or improvement of negative effects on the immune system opens new ways for patients treated with ofatumumab. For example, they can be vaccinated during ofatumumab therapy. Furthermore, they can be treated with ofatumumab despite a prior or ongoing condition other than multiple sclerosis. This is an important clinical benefit, which is explained in detail below.

[0062] In contrast, other immunomodulatory or immunosuppressive therapies (e.g. ocrelizumab) put patients at a higher risk of a stronger immune response (e.g. due to activation of the complement system and / or a decrease in the interaction between B cells and T cells and / or altered production of cytokines and / or bystander activation). Furthermore, these other therapies require more caution in the timing of vaccination, if possible or fully recommended (see Tobias Zrzavy et al.: Vaccination in Multiple Sclerosis: Friend or Foe?, FRONTIERS IN IMMUNOLOGY, Vol. 10, January 1, 2019, p. 1883).

[0063] One aspect of the present application relates to ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis (RMS), wherein ofatumumab is used in patients with a history of a prior or ongoing condition other than multiple sclerosis. The expression "patients with a history of a prior condition other than multiple sclerosis" means that the patients have or had a pre-existing condition. A pre-existing condition is defined as "a medical condition that occurred before a program of health benefits went into effect" ("Billing terminology". Pittsburgh: University of Pittsburgh Medical Center (UPMC). 2010. From original printed copy archived on October 3, 2010. Retrieved on January 16, 2010). In the context of the present application, "program of health benefits" relates to a therapy comprising the administration of ofatumumab. Thus, the pre-existing condition occurred or started before the start of ofatumumab therapy.

[0064] The condition other than multiple sclerosis can be one or several of the following

[0065] Nasopharyngitis

[0066] Headache

[0067] Injection site reactions

[0068] Upper respiratory tract infection

[0069] Urinary tract infection

[0070] Back pain

[0071] Fatigue

[0072] Influenza

[0073] Nausea

[0074] Decreased immunoglobulin M or G

[0075] Hair loss

[0076] Joint pain

[0077] Diarrhea

[0078] Pain in extremities

[0079] Depression

[0080] Macular edema

[0081] Chickenpox (varicella)

[0082] Head cold

[0083] Increased gamma-glutamyl transferase

[0084] Abdominal pain

[0085] Skin cancer

[0086] Bradycardia

[0087] Hemorrhagic focal encephalitis

[0088] Herpes infection

[0089] Progressive multifocal leukoencephalopathy (PML)

[0090] Hypertension

[0091] Paresthesia.

[0092] These conditions other than multiple sclerosis can be caused by a virus, bacteria or other infection, as described below.

[0093] Alternatively, these conditions other than multiple sclerosis can be caused by drugs, such as immunosuppressive drugs. 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 chelators, such as fingolimod (Gilenya); biologies, 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.

[0094] As a further alternative, the condition other than multiple sclerosis can be caused by a disease, e.g. an autoimmune disease other than multiple sclerosis.

[0095] In a preferred embodiment of this aspect of the application, the prior or ongoing history of a condition other than multiple sclerosis is a prior or ongoing history of an infection. The expression "prior or ongoing history of an infection" means that the patient has or had a pre-existing infection. A pre-existing infection is defined analogously to the pre-existing condition described above. In the context of the present application, a "health benefit item" relates to a therapy comprising the administration of Ofatumumab. Thus, the pre-existing infection occurred or started prior to the start of Ofatumumab treatment.

[0096] Patients suffering from an infection are prone to more severe signs or symptoms if they receive an immunosuppressive therapy. It is completely unexpected that Ofatumumab, as an anti-CD20 antibody, does not trigger or contribute to more severe signs and symptoms, since anti-CD20 antibodies suppress the immune system.

[0097] The prior or ongoing infection can be caused by a virus or microorganism selected from the group consisting of:

[0098] Respiratory syncytial virus (RSV),

[0099] Influenza or parainfluenza virus,

[0100] Human polyomavirus (BK virus),

[0101] Adenovirus,

[0102] Rhinovirus,

[0103] Coronavirus, in particular SARS-CoV-2,

[0104] Human herpes virus, such as herpes simplex virus (HSV),

[0105] Varicella zoster virus (VZV),

[0106] Epstein-Barr virus (EBV),

[0107] Cytomegalovirus (CMV),

[0108] Beta polyomavirus, such as John Cunningham virus (JCV),

[0109] Bordetella pertussis,

[0110] Bordetella parapertussis,

[0111] Corynebacterium diphtheriae,

[0112] Escherichia coli,

[0113] Staphylococcus (e.g. Staphylococcus saprophyticus or Staphylococcus aureus),

[0114] Chlamydia trachomatis,

[0115] Haemophilus influenzae,

[0116] Meningococcus,

[0117] Klebsiella spec.,

[0118] Pseudomonas spec.,

[0119] Enterococcus spec.,

[0120] Streptococcus spec.,

[0121] Yeast (e.g. Candida albicans),

[0122] Pneumocystis (e.g. Pneumocystis murina),

[0123] Cryptococcus (e.g. Cryptococcus neoformans),

[0124] Aspergillus,

[0125] Mycoplasma genitalium.

[0126] Thus, a prior history other than multiple sclerosis can be triggered by a viral infection, wherein the virus causing the infection is, for example, respiratory syncytial virus (RSV), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, rhinovirus, coronavirus, human herpes virus, such as herpes simplex virus (HSV), varicella zoster virus (VZV), EBV or cytomegalovirus (CMV), or a beta polyomavirus, such as John Cunningham virus (JCV).

[0127] Three of the four influenza virus types affect humans: Type A, Type B, and Type C. Type D has not been found to infect humans, but is believed to have the potential to do so. Typically, the virus is spread through the air by coughing or sneezing. It can also be spread by touching a surface contaminated with the virus and then touching the eyes, nose, or mouth. People can be contagious before and during the onset of symptoms. The World Health Organization (WHO) recommends that high-risk groups be vaccinated against influenza annually, and the Centers for Disease Control and Prevention (CDC) recommends that people 6 months and older be vaccinated against influenza annually. However, patients who are susceptible to or have initiated immunosuppressive therapy are generally not suitable for vaccination or do not respond to vaccination because their immune system is suppressed. Since anti-CD20 antibodies suppress the immune system, it is completely unexpected that ofatumumab, as an anti-CD20 antibody, does not impair vaccination against influenza virus.

[0128] Antiviral drugs such as oseltamivir and other neuraminidase inhibitors have been used to treat influenza. Surprisingly, it was found that the drugs can be used in patients who are receiving or have initiated treatment with ofatumumab. Thus, one aspect of the present application is based on the surprising finding that ofatumumab does not impair influenza control compared to other anti-CD20 therapies.

[0129] Coronaviruses are a group of viruses that cause diseases in mammals and birds. In humans, coronaviruses can cause mild respiratory tract infections, such as some cases of the common cold (among other possible causes, primarily rhinovirus), but more severe forms can be fatal, such as SARS, MERS, and COVID-19. There are currently no vaccines or antiviral drugs to prevent or treat human coronavirus infections. It is envisaged that patients infected with a coronavirus (e.g. SARS-CoV-2) can be treated with or initiate treatment with ofatumumab.

[0130] There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). HSV-1 more often causes infections around the mouth, while HSV-2 more often causes genital infections. They are spread by direct contact with the bodily fluids or sores of an infected individual. After infection, the virus is transported along sensory nerves to the nerve cell body, where it resides for life. Causes of recurrence can include low immune function, stress, and sun exposure. Thus, if a patient is receiving immunosuppressive therapy, it is easy for the patient to relapse. Since anti-CD20 antibodies suppress the immune system, it is completely unexpected that ofatumumab, as an anti-CD20 antibody, does not trigger or favor relapse.

[0131] Ingestion of antiviral medication by the infected person every day can also reduce transmission. There is no vaccine available and once infected, there is no cure. Paracetamol (acetaminophen) and topical lidocaine can be used to help (alleviate) symptoms. Treatment with antiviral medication (e.g. acyclovir or valacyclovir) can reduce the severity of the outbreak of symptoms. Surprisingly, it was found that the medication can be used for patients receiving or starting to receive ofatumumab treatment. Thus, one aspect of the present invention is based on the surprising finding that ofatumumab does not impair HSV control compared to other anti-CD20 therapies.

[0132] Human alpha herpesvirus 3 (HHV-3), commonly known as varicella zoster virus (VZV), is one of nine herpes viruses known to infect humans. It causes chickenpox (varicella), a disease most commonly affecting children, adolescents and young adults, and shingles (herpes zoster) in adults; shingles is rare in children. VZV replicates in the lungs, causing a variety of symptoms. After primary infection (chickenpox), the virus remains dormant in nerves, including cranial, dorsal root and autonomic ganglia. Years after recovery from chickenpox, VZV can reactivate, causing a neurological condition. In humans, it can be treated by a variety of drugs and therapeutic agents, including acyclovir for treating chickenpox, famciclovir, valaciclovir for treating shingles, zoster immune globulin (ZIG) and vidarabine. VZV immune globulin is also a therapy. Acyclovir is often used as a drug of choice for primary VZV infection, and early initiation of dosing can significantly shorten the duration of any symptoms. Surprisingly, it was discovered that the drugs and therapeutic agents can be used for VZV treatment in patients receiving or starting to receive ofatumumab treatment. Patients can even be vaccinated against VZV during ofatumumab treatment. Thus, one aspect of the present invention is based on the surprising finding that ofatumumab does not impair VSV control compared to other anti-CD20 therapies. Thus, the present invention relates to a method of preventing VZV-related disease in a patient comprising administering to said patient a therapeutically effective dose of ofatumumab.

[0133] In one embodiment of the present invention, ofatumumab is not administered to a patient having an active HBV infection.

[0134] Epstein-Barr virus (EBV) is a human herpesvirus type 4 (HHV4) belonging to the Lymphocryptovirus genus in the gamma herpesvirus subfamily. These viruses establish latent infections of their host cells and induce proliferation of latently infected cells (reviewed in Roizman B. Herpesviridae: general description, taxonomy and classification. In: Roizman B, ed. The herpesviruses. London: Plenum Press, 1996: 1 / 23.). EBV is associated with a growing list of clinical diseases, ranging from acute and chronic inflammatory diseases to lymphoid and epithelial malignancies. Epstein-Barr virus is associated with lymphoproliferative diseases, a disease in which different types of lymphocytes (such as T cells, B cells or natural killer (NK) cells) are infected with Epstein-Barr virus. The infected cells overproliferate, developing into various lymphoproliferative diseases (LPD, non-cancerous, pre-cancerous and cancerous). These LPD include infectious mononucleosis and the subsequent possible development of diseases. Non-LPD but EBV-associated diseases include malignancies, sarcomas, multiple sclerosis, systemic lupus erythematosus, Hodgkin's and non-Hodgkin's lymphoma, nasopharyngeal carcinoma, gastric carcinoma, leiomyosarcoma and "Alice in Wonderland syndrome" (Middeldorp et al., Critical Reviews in Oncology / Hematology 45 (2003) 1 / 36 2003).

[0135] One aspect of the present application is based on the surprising finding that ofatumumab does not impair EBV control in vitro compared to other anti-CD20 therapies. Therefore, the surprising finding that immunosuppressive anti-CD20 therapy does not impair EBV control is a prerequisite and basis for developing therapeutic approaches in patients at risk of developing EBV-associated diseases.

[0136] Cytomegalovirus (CMV) is a virus genus in the order Herpesvirales, the family Herpesviridae, the subfamily Betaherpesvirinae. Humans and monkeys are 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 infected with CMV are otherwise healthy and show few signs and symptoms. However, some congenitally CMV-infected infants who appear healthy at birth develop signs over time - sometimes not for months or years after birth. The most common of these late-developing signs are hearing loss and developmental delay. A small number of infants can also develop vision problems. In addition, people with weaker immune systems can experience more severe signs and symptoms, affecting:

[0137] the eye,

[0138] the lung,

[0139] the liver,

[0140] the esophagus,

[0141] the stomach,

[0142] the intestine,

[0143] the brain.

[0144] In a preferred embodiment, control of the viral infection (viral control) is possible, i.e. is performed without substantial or at least acceptable delay or limitation, despite (initial) ofatumumab treatment. The term viral control or control of the viral infection also refers to the above-mentioned treatment, wherein the viral load in the whole blood of the treated patient is below 5000 copies of the viral genome per pg DNA, below 4500 copies per pg DNA, below 4000 copies per pg DNA, below 3500 copies per pg DNA, below 3000 copies per pg DNA, below 2500 copies per pg DNA, below 2000 copies per pg DNA, below 1500 copies per pg DNA or below 1000 copies per pg DNA. In a preferred embodiment, the above-mentioned viral load in the whole blood 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 more after the transplant has been performed.

[0145] The term viral control or control of viral infection also refers to the above treatment wherein the viral load in the plasma is below 3000 copies / 100 μl, below 2500 copies / 100 μl, below 2000 copies / 100 μl, below 1500 copies / 100 μl or below 1000 copies / 100 μl. In a preferred embodiment, the above viral load in the plasma is maintained for at least 6 months, for at least 9 months, for at least 12 months, for at least 15 months, for at least 18 months, for at least 21 months, for at least 24 months, for at least 3 years, for at least 4 years, for at least 5 years, for at least 6 years, for at least 7 years, for at least 8 years or more after the transplantation has been performed.

[0146] Furthermore, the term viral control or control of viral infection as used herein also refers to the treatment of a patient with a therapeutically effective dose of ofatumumab, in particular wherein the patient is an MS patient, more particularly a patient in need of immunosuppression, wherein a reduced viral titer or viral load or viral infection status is obtained, wherein the viral load (e.g. viral DNA load) is reduced by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90% or by more than 90%. In a preferred embodiment, the reduced viral load is maintained for at least 6 months, for at least 9 months, for at least 12 months, for at least 15 months, for at least 18 months, for at least 21 months, for at least 24 months, for at least 3 years, for at least 4 years, for at least 5 years, for at least 6 years, for at least 7 years, for at least 8 years or more after the start of ofatumumab treatment.

[0147] In a preferred embodiment, the treatment according to the application allows to prevent viral associated diseases by providing appropriate measures (e.g. drugs or vaccinations) that are not usually used during immunosuppressive therapy. It is completely unexpected that due to the suppression of the immune system by the anti-CD20 antibody, ofatumumab does not impair the prevention of viral associated diseases. The terms "prevention" or "prevent" generally refer to prophylactic or preventative treatment; they concern the delay or prevention of the onset of the disease, disorder and / or its associated symptoms associated therewith. As used herein, the term "prevention of viral associated diseases" refers to the outcome of treating a patient with a therapeutically effective dose of ofatumumab, in particular wherein the patient is an MS patient, more particularly a patient in need of immunosuppression, wherein the patient does not develop a viral associated disease, in particular the patient does not develop a lymphoproliferative disease (LPD, non-cancerous, pre-cancerous and cancerous, including infectious mononucleosis and subsequently possible occurring diseases, or non-LPD but viral associated diseases, including malignancies, sarcomas, multiple sclerosis, systemic lupus erythematosus and "Alice in Wonderland syndrome". The term "prevention of viral associated diseases" also refers to the outcome of treating a patient as described above after starting ofatumumab treatment, wherein the patient does not develop a viral associated disease as described herein for at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years or more.

[0148] As mentioned before, the previous history of a disease other than multiple sclerosis can be triggered by a bacterial infection, wherein the bacteria causing the infection is, for example, Bordetella pertussis, Bordetella parapertussis, Corynebacterium diphtheriae, E. coli, Staphylococcus spec. (e.g. Staphylococcus saprophyticus or Staphylococcus aureus), Chlamydia trachomatis, Haemophilus influenzae, Meningococcus spec., Klebsiella spec., Pseudomonas spec., Enterococcus spec., Streptococcus spec.

[0149] Bordetella pertussis is a gram-negative coccobacillus, the causative agent of pertussis or whooping cough. Its virulence factors include pertussis toxin, adenylate cyclase toxin, filamentous hæmagglutinin, pertactin, fimbriae, and tracheal cytotoxin.

[0150] Diphtheria is an infection caused by Corynebacterium diphtheriae. Complications can include myocarditis, inflammation of the nerves, kidney problems, and bleeding problems due to low platelet levels. Myocarditis can cause abnormal heart rates, and inflammation of the nerves can cause paralysis.

[0151] Escherichia coli, also known as E. coli, is a gram-negative bacterium commonly found in the lower intestine of humans and other animals. Most strains of E. coli are harmless, but some serotypes can cause severe food poisoning in their hosts, occasionally leading 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 cramping, diarrhea, hemorrhagic colitis, vomiting, and sometimes fever. In rare cases, toxic strains can also cause necrosis (tissue death) and perforation of the intestine, not developing into hemolytic-uremic syndrome, peritonitis, mastitis, sepsis, and gram-negative pneumonia.

[0152] Some strains of E. coli, such as O157:H7, can produce Shiga toxin (classified as a bioterrorism agent). Shiga toxin causes an inflammatory response in target cells in the intestine, leaving lesions that cause bloody diarrhea, a symptom of Shiga toxin-producing E. coli (STEC) infection. This toxin further causes premature destruction of red blood cells, which then clog the body's filtration system (kidneys), leading in some rare cases (usually in children and the elderly) to hemolytic-uremic syndrome (HUS), which can lead to kidney failure and even death.

[0153] 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 a variety of ways.

[0154] Enterotoxigenic E. coli (ETEC) is the most common cause of traveler's diarrhea, with up to 840 million cases per year in developing countries worldwide. This bacterium is usually spread through contaminated food or drinking water, adheres to the inner lining of the intestine, where it secretes either of two types of enterotoxins, causing watery diarrhea.

[0155] Certain strains of E. coli are a major cause of foodborne illness. Enterohemorrhagic E. coli (EHEC) bacteria cause hemolytic uremic syndrome (HUS), a medical emergency requiring urgent treatment.

[0156] Staphylococcus is a genus of Gram-positive bacteria of the family Staphylococcaceae in the order Bacillales. Staphylococci can cause a variety of diseases in humans and animals by producing toxins or by permeation. Staphylococci are a common cause of food poisoning, as they can be produced by bacteria that grow in food due to improper storage. The most common sialadenitis is caused by Staphylococci, such as bacterial infections.

[0157] Chlamydial infection is a sexually transmitted infection caused by the bacterium Chlamydia trachomatis. Most people infected with it have no symptoms. Symptoms do appear can take several weeks after infection occurs. Infection can spread to the upper genital tract in women, causing pelvic inflammatory disease, which can lead to infertility or ectopic pregnancy. Untreated repeated eye infections can lead to trachoma, which is a common cause of blindness in the third world. Chlamydia can be transmitted during vaginal, anal or oral sex and can be passed from an infected mother to her baby during childbirth.

[0158] In a preferred embodiment, bacterial infection control (bacterial control) is possible, i.e. is performed without substantial or at least acceptable delay or limitation, despite (initial) ofatumumab treatment. The term bacterial control or control of bacterial infection also refers to the above-mentioned treatment, wherein bacteremia is prevented or reduced. Bacteremia is most often diagnosed by blood culture, wherein a blood sample taken from a vein by needle puncture is allowed to incubate with a culture medium that promotes bacterial growth. If bacteria are present in the bloodstream at the time the sample is taken, this bacteria will multiply and thus be detected.

[0159] In another embodiment, the prior medical history other than multiple sclerosis can be caused by a fungal infection, wherein the fungus causing the infection is: a yeast (e.g., Candida albicans), Pneumocystis spec. (e.g., Pneumocystis murina), Cryptococcus spec. (e.g., Cryptococcus neoformans), and Aspergillus spec.

[0160] Candida albicans is an opportunistic pathogenic yeast that is a common member of the human intestinal flora. It is usually a commensal organism, but under a variety of conditions, it can become pathogenic in immunocompromised individuals. It is one of the few species of Candida that causes candidiasis in humans, which is caused by excessive growth of the fungus. For example, candidiasis is frequently observed in HIV-infected patients. C. albicans is the most common fungal species isolated from biofilms formed on (permanent) implanted medical devices or human tissue. C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata together cause 50-90% of human cases of candidiasis. Mortality rates of 40% have been reported for patients with systemic candidiasis caused by C. albicans. Recent studies have shown that C. albicans can cross the blood-brain barrier.

[0161] Pneumocystis spec. represents a related group of fungal species that are members of the Ascomycota, subphylum Taphrinomycotina, class Pneumocystidii, order Pneumocystidiales, and family Pneumocystidiae. A group of cases of Pneumocystis pneumonia (PCP) have been reported in immunocompromised patients. Pneumocystis infection has a global distribution in humans, with most individuals showing serological evidence of infection by the age of 2 years. The incidence of PCP is related to the degree of immunosuppression, particularly impairment of cell-mediated immune function, as evidenced by the frequent occurrence of PCP in AIDS patients.

[0162] In a preferred embodiment, fungal infection control (fungal control) is possible despite (initial) ofatumumab treatment, i.e. without substantial or at least acceptable delay or limitation.

[0163] In another embodiment, a prior medical history other than multiple sclerosis can be triggered by a Mycoplasma infection, wherein the Mycoplasma causing the infection is Mycoplasma genitalium.

[0164] Mycoplasmas are a genus of bacteria that lack a cell wall around their cell membrane. This property makes them naturally resistant to antibiotics that target cell wall synthesis, such as beta-lactam antibiotics. Mycoplasma genitalium is a sexually transmitted, small pathogenic bacterium that lives on the skin cells of the urinary and reproductive tracts of humans. It can cause negative health effects in both men and women.

[0165] Furthermore, different organisms require different incubation times (latency) from the time they enter the body to the time symptoms appear. Some common pathogens of the upper respiratory tract and their respective latency times are as follows:

[0166] Rhinovirus, 1-5 days;

[0167] Streptococcus A, 1-5 days;

[0168] Influenza and parainfluenza viruses, 1-4 days;

[0169] Respiratory syncytial virus (RSV), 7 days;

[0170] Whooping cough (pertussis), 7-21 days;

[0171] Diphtheria, 1-10 days; and

[0172] Epstein-Barr virus (EBV), 4-6 weeks.

[0173] Therefore, a portion of these pathogens allow for intervention up to several weeks after entering the body, before they cause disease. Therefore, treatment strategies can be changed during the latency period.

[0174] Thus, in another aspect of the disclosure, there is provided a method of preventing, reducing or mitigating adverse events in a patient at risk of developing such adverse events, such as a patient with MS, comprising administering ofatumumab to said patient, wherein the patient is a multiple sclerosis (MS) patient who has received a disease-modifying therapy treatment other than ofatumumab. In one embodiment, the ofatumumab treatment is initiated when the patient is exposed to a risk of viral, bacterial or fungal infection. Alternatively, the ofatumumab treatment is initiated when there is evidence of viral, bacterial or fungal infection, such as DNA, but the patient has not yet shown any symptoms. The adverse event can be one or several of the following: injection-related reactions, nasopharyngitis, headache, injection site reactions, upper respiratory tract infection, urinary tract infection, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, arthralgia, diarrhea, extremity pain, depression, macular edema, Chickenpox (varicella), head cold, increased gamma-glutamyl transferase, abdominal pain, skin cancer, bradycardia, hemorrhagic focal encephalitis, herpes infection, progressive multifocal leukoencephalopathy (PML), hypertension, paresthesia.

[0175] In another embodiment, the method according to the disclosure is a method wherein the patient at risk of developing an infection-related disease is immunosuppressed or is receiving an immunomodulatory drug. In one embodiment, the method according to the disclosure is a method wherein the adverse event is cancer or a lymphoproliferative disease.

[0176] In a preferred embodiment of this aspect of the application, the patient treated with ofatumumab is vaccinated during the ofatumumab treatment. In another embodiment of the application, the patient treated with ofatumumab is vaccinated during the ofatumumab treatment, said patient having no prior or ongoing history of a condition other than multiple sclerosis.

[0177] The vaccination can be against any one of

[0178] a thinovirus,

[0179] a respiratory syncytial virus (RSV),

[0180] an influenza or parainfluenza virus,

[0181] a human polyomavirus (BK virus),

[0182] an adenovirus,

[0183] a human herpes virus, such as herpes simplex virus (HSV),

[0184] varicella zoster virus (VZV),

[0185] Epstein-Barr virus (EBV),

[0186] Cytomegalovirus (CMV),

[0187] beta polyomavirus, such as John Cunningham virus (JCV),

[0188] Bordetella pertussis,

[0189] Bordetella parapertussis,

[0190] Corynebacterium diphtheriae,

[0191] Escherichia coli,

[0192] Staphylococcus saprophyticus,

[0193] Staphylococcus aureus,

[0194] Chlamydia trachomatis,

[0195] Klebsiella spec.,

[0196] Pseudomonas spec.,

[0197] Enterococcus spec.,

[0198] Streptococcus spec.,

[0199] Yeast (e.g., Candida albicans),

[0200] Pneumocystis (e.g., Pneumocystis murina),

[0201] Cryptococcus (e.g., Cryptococcus neoformans),

[0202] Aspergillus,

[0203] Mycoplasma genitalium,

[0204] Coronaviruses, especially SARS-CoV-2.

[0205] Because ofamumab is an anti-CD20 antibody and depletes lymphocytes, it was entirely unexpected that vaccination would be successful in patients treated with ofamumab. Therefore, it was anticipated that ofamumab would have a negative impact on the immune system, such as immunoglobulins, which are essential for acquiring immunity after vaccination. Consistent with this expectation, Pescovitz et al. demonstrated that rituximab (another anti-CD20 antibody) led to a decrease in IgM levels; see Pescovitz et al., “B-lymphocyte depletion with rituximab and β-cell function: two-year results”, Diabetes Care, Feb 2014; 37(2); 453-9.

[0206] Therefore, surprisingly, vaccination can be administered during oframumab treatment. Vaccination can be administered in patients with or without a history of a pre-existing or ongoing condition other than multiple sclerosis. Therefore, another subject of the invention is oframumab for the treatment or prevention of relapsing-remitting multiple sclerosis, wherein vaccination is administered during oframumab treatment. Generally, embodiments described for vaccination in patients with a history of the disease (e.g., the amount and dosage regimen of oframumab) can also be applied to patients without a history of the disease.

[0207] In another embodiment of this aspect of the invention, a patient with a history of a previous or ongoing condition other than multiple sclerosis may have a history of transient ischemic attack (TIA).

[0208] History of cerebral infarction, with no residual defects;

[0209] History of thrombotic stroke, with no lasting impact;

[0210] History of thrombotic stroke, with no residual defects;

[0211] History of transient ischemic attack;

[0212] History of ischemic stroke, with no residual defects;

[0213] History of non-atherosclerotic stroke with no residual defects;

[0214] History of parietal lobe cerebrovascular accident;

[0215] History of cerebrovascular accident, with no residual defects;

[0216] History of embolic stroke, no defect;

[0217] History of embolic stroke, no persistent effects;

[0218] History of embolic transient ischemic attack;

[0219] History of hemorrhagic cerebrovascular accident, no residual defect;

[0220] History of atherosclerotic cerebrovascular accident, no residual defect;

[0221] History of cardiac embolic stroke.

[0222] Herein, the expression "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 a program of health benefits went into effect" ("Billing terminology". Pittsburgh: University of Pittsburgh Medical Center (UPMC). 2010. From a printout of the original on October 3, 2010. Retrieved on January 16, 2010). In the context of the present application, "program of health benefits" relates to a therapy comprising the administration of ofatumumab. Thus, a pre-existing condition (e.g. TIA) occurred or started before the start of ofatumumab treatment.

[0223] It is envisaged that patients with a history of a condition other than multiple sclerosis are treated to cure, reduce or eliminate the condition before the start of ofatumumab treatment. The treatment can include the administration of glucocorticoids, such as cortisone 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.

[0224] In a preferred embodiment of this aspect of the application, the pre-existing or persistent condition is an autoimmune disease other than multiple sclerosis. The autoimmune disease other than multiple sclerosis can be selected from

[0225] Type 1 diabetes mellitus,

[0226] Rheumatoid arthritis (RA),

[0227] Psoriasis / psoriatic arthritis,

[0228] Systemic lupus erythematosus (SLE),

[0229] Inflammatory bowel disease,

[0230] Addison's disease,

[0231] Graves' disease,

[0232] Sjogren's syndrome,

[0233] Hashimoto's thyroiditis,

[0234] Myasthenia gravis,

[0235] Autoimmune vasculitis,

[0236] Pernicious anaemia,

[0237] Celiac disease.

[0238] Thus, the autoimmune disease can be rheumatoid arthritis (RA). In this case, the rheumatoid arthritis (RA) can be treated with a disease-modifying antirheumatic drug (DMARD) selected from the group consisting of methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-a inhibitors (certolizumab, infliximab and etanercept), abatacept, anakinra, rituximab and tocilizumab.

[0239] Alternatively, the autoimmune disease can be psoriasis. Psoriasis can be treated with methotrexate, cyclosporin, hydroxyurea, fumarates such as dimethyl fumarate, retinoids, anti-TNF therapies such as infliximab, adalimumab, golimumab and certolizumab pegol, etanercept, ixekizumab, ustekinumab, guselkumab, efalizumab and afelimtamab.

[0240] In a preferred embodiment of this aspect of the application, the prior or ongoing history of a condition other than multiple sclerosis is a history of hospitalization. The expression "history of hospitalization" means that the patient has been hospitalized prior to the start of the treatment with ofatumumab. In particular, it is envisaged that the history of hospitalization includes a history of intensive care and / or a history of surgery. Preferably, the term "history of hospitalization" does not include childbirth. The patient with a history of surgery can be treated with an immunosuppressant other than ofatumumab. The immunosuppressant can be selected from the group consisting of glucocorticoids (e.g. cortisone, prednisone, dexamethasone and hydrocortisone), cytostatic agents (e.g. methotrexate, anthracyclines, mitomycin C, bleomycin, mithramycin), antibodies (e.g. basiliximab (Simulect) and daclizumab (Zinbryta) or drugs acting on immunophilins (e.g. tacrolismus and cyclosporine).

[0241] Alternatively, the prior history of a condition other than multiple sclerosis can be a history of surgery. The expression "history of surgery" means that the patient has undergone or is undergoing a surgical intervention prior to the start of the treatment with ofatumumab. The patient with a history of surgery can be treated with an immunosuppressant other than ofatumumab. The immunosuppressant can be selected from the group consisting of glucocorticoids (e.g. cortisone, prednisone, dexamethasone and hydrocortisone), cytostatic agents (e.g. methotrexate, anthracyclines, mitomycin C, bleomycin, mithramycin), antibodies (e.g. basiliximab (Simulect) and daclizumab (Zinbryta) or drugs acting on immunophilins (e.g. tacrolismus and cyclosporine).

[0242] Ofatumumab can be used for the treatment or prevention of relapsing multiple sclerosis (RMS) in elderly patients. The elderly patients can have age-related macular degeneration (AMD) or Alzheimer's disease or atherosclerosis or benign prostatic hyperplasia (BPH).

[0243] Ofatumumab can be used for the treatment or prevention of relapsing multiple sclerosis (RMS) in pediatric patients.

[0244] In a preferred embodiment of this aspect of the application, the condition other than multiple sclerosis is cancer or a lymphoproliferative disease.

[0245] In all embodiments described so far, ofatumumab is administered when serum neurofilament light chain (NfL) concentration is 4-13 pg / mL. Neurofilament light chain is a neurofilament protein encoded by the NEFL gene in humans. Neurofilament light chain is a biomarker that can be measured in cerebrospinal fluid and plasma with immunoassays and reflects axonal damage in various neurological diseases. Surprisingly, it turned out to be a useful marker for disease monitoring in multiple sclerosis. This has been shown in the ASCLEPIOS I and II studies. 1,882 patients with MS, aged 18 to 55 years, with an Expanded Disability Status Scale (EDSS) score of 0-5.5 were enrolled. The study was conducted at over 350 sites in 37 countries. Other secondary endpoints included confirmed disability improvement at 6 months, serum levels of neurofilament light chain (NfL), and rate of brain volume loss.

[0246] In general, the dosing regimen of ofatumumab described in WO 2018 / 033841 can be applied in the present application.

[0247] MSIS-29 (see above for definition) is a clinically useful and scientifically sound measure of MS impact from the patient perspective, suitable for use in clinical research and epidemiological studies. It is considered a reliable, valid, and responsive PRO (Patient Reported Outcomes) measure that can complement other disease severity measures to improve our understanding of the impact of MS.

[0248] In the present application, it was surprisingly found that administration of ofatumumab leads to a favorable reduction of the MS Impact Scale MSIS-29 as defined below.

[0249] In this respect, another subject of the present application 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, still more preferably by at least 2.5 within 24 months. The reduction can be up to 3.0 or 3.5 or 4.0.

[0250] 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 maintenance dose.

[0251] In a preferred embodiment, ofatumumab is administered irrespective of body weight, gender, age, race or baseline B-cell count. For example, a 35 year old female weighing 60 kg receives the same dose as a 50 year old male weighing 90 kg. In particular, body weight, gender, age, race or baseline B-cell count have no clinically significant impact on the pharmacokinetics of ofatumumab.

[0252] In a preferred embodiment, ofatumumab is administered to patients who have discontinued an early DMT (such as anti-CD20 therapy) due to side effects (e.g. severe infusion-related reactions or recurrent infections).

[0253] Ofatumumab can be administered by injection. In a preferred embodiment, it is administered subcutaneously. Surprisingly, subcutaneous injection is advantageous compared to other parenteral forms of administration, e.g. compared to intravenous injection.

[0254] In a preferred embodiment, ofatumumab can be administered in a loading dose. A loading dose can be regarded as an initial higher dose of a drug given at the beginning of a course of treatment, followed by a lower maintenance dose. In a preferred embodiment, 20 mg ofatumumab is administered as a loading dose on day 1, day 7 and day 14. In a particularly preferred embodiment, 20 mg ofatumumab is administered as a loading dose on week 0, week 1 and week 2.

[0255] In a preferred embodiment of the application, the loading dose is 10-30 mg, preferably 20 mg ofatumumab.

[0256] A preferred dose of ofatumumab is:

[0257] • 20 mg initially administered by subcutaneous injection on weeks 0, 1 and 2, followed by

[0258] • 20 mg administered by subcutaneous injection monthly from week 4 onwards.

[0259] If an injection of ofatumumab is missed, it is preferred to administer it as soon as possible and not to wait until the next scheduled administration. Subsequent doses should be given at the recommended intervals.

[0260] Alternatively, ofatumumab is not administered as a loading dose.

[0261] In a preferred embodiment of the application, ofatumumab is administered to patients who have been treated with a disease-modifying therapy other than ofatumumab.

[0262] In a particularly preferred embodiment, the disease-modifying therapy other than ofatumumab is dimethyl fumarate (DMF). Preferably, DMF is administered in a daily dose of 120 mg to 480 mg, in particular 480 mg. In a particularly preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is laquinimod. Preferably, laquinimod is administered in a daily dose of 0.2 to 1.0 mg, preferably 0.6 mg.

[0263] In a particularly preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is teriflunomide. Preferably, teriflunomide is administered in a daily dose of 6 to 18 mg, preferably 14 mg.

[0264] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is administered by injection. Examples of suitable DMTs are natalizumab, rituximab, ocrelizumab, alemtuzumab, daclizumab and glatiramer acetate.

[0265] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is natalizumab. Preferably, natalizumab is administered by intravenous injection in a dose of 100 to 500 mg, preferably 300 mg, every 4 weeks.

[0266] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is daclizumab. Preferably, daclizumab is administered subcutaneously once a month in a dose of 50 to 250 mg, preferably 150 mg.

[0267] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is glatiramer acetate. Preferably, glatiramer acetate is administered by subcutaneous injection in a dose of 20 mg / mL once a day or 40 mg / mL three times a week.

[0268] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is rituximab. Preferably, rituximab is administered in a dose of 500 or 1,000 mg every 6-12 months, in particular intravenously.

[0269] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is ocrelizumab. Preferably, ocrelizumab is administered in a dose of 600 mg every 6 months, in particular intravenously.

[0270] Preferably, the patient has previously received at least 2 (e.g. 2-5) consecutive courses of intravenous ocrelizumab or rituximab treatment. The last dose can be given, e.g. 4-9 months prior to the ofatumumab administration.

[0271] According to the present application, ofatumumab maintains efficacy in RMS patients transitioning from intravenous anti-CD20 treatment.

[0272] In a preferred embodiment, ofatumumab is administered to patients who have had a poor response to anti-CD20 treatment (e.g. relapse, > 2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, clinical worsening) in the past 6 months and / or patients who have discontinued anti-CD20 treatment due to adverse events (e.g. serious infusion-related reactions or recurrent infections).

[0273] In a preferred embodiment of the present application, the disease-modifying therapy other than ofatumumab is alemtuzumab. Preferably, alemtuzumab is administered at a dose of 12 mg / day, administered as an intravenous infusion.

[0274] In a preferred embodiment of the present application, ofatumumab is administered at a dose of 10-30 mg every 4 weeks, preferably 20 mg every 4 weeks. Preferably, ofatumumab is administered by subcutaneous injection (s.c.).

[0275] Ofatumumab can be administered in the form of a pharmaceutical formulation, e.g. as described in WO 2009 / 009407.

[0276] In a preferred embodiment, the ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each 20 mg / 0.4 mL pre-filled pen or pre-filled syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg of ofatumumab and arginine (4 mg), edetate disodium (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg) and water for injection, USP at a pH of 5.5. Hydrochloric acid can be added to adjust the pH.

[0277] In a preferred embodiment, the ofatumumab formulation is intended for patient self-administration, preferably by subcutaneous injection.

[0278] 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 to areas with moles, scars or areas of skin that are soft, bruised, red, hard or incomplete.

[0279] In one embodiment, the first injection of the ofatumumab formulation can be performed under the guidance of a medical service professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Prior to administration, the pen or pre-filled syringe is preferably taken out of the refrigerator and allowed to reach room temperature, e.g. for about 15 to 30 minutes. In a preferred embodiment, the ofatumumab formulation of the present application is a clear to slightly opalescent and colorless to slightly brownish yellow solution, obtainable as follows:

[0280] • Injection: 20 mg / 0.4 mL in a single-dose pre-filled pen, e.g. Sensoready® pen

[0281] • Injection: 20 mg / 0.4 mL in a single-dose pre-filled syringe.

[0282] In a preferred embodiment, a subcutaneous ofatumumab dose of 20 mg every 4 weeks results in a mean AUC tau of about 400-550, more preferably 450-500, e.g. 483 mcg h / mL and / or a mean C 最大值 of 1.0-2.5, more preferably 1.2-1.7, e.g. 1.43 mcg / mL at steady state. In a preferred embodiment, the volume of distribution at steady state can be 4.5-6.5, more preferably 5.0-6.0, e.g. 5.42 L after repeated subcutaneous administration of ofatumumab at a dose of 20 mg.

[0283] After subcutaneous administration, ofatumumab is absorbed via the lymphatic system.

[0284] In all embodiments described so far, the relapsing form of multiple sclerosis can be selected from relapsing remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Currently, the National Multiple Sclerosis Society and the International Federation of Multiple Sclerosis describe four types of MS (revised in 2013):

[0285] Clinically isolated syndrome (CIS)

[0286] Relapsing-remitting MS (RRMS)

[0287] Primary progressive MS (PPMS)

[0288] Secondary progressive MS (SPMS)

[0289] In a preferred embodiment of the application, ofatumumab is administered to treat relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease, preferably in adults.

[0290] Relapsing-remitting MS is characterized by unpredictable relapses, followed by months to years of relative quiet (remission) with no signs of new disease activity. Deficits occurring during an episode can resolve or leave problems, the latter occurring in about 40% of episodes and being more common the longer a person has been ill. This describes the initial course of 80% of individuals with MS. When deficits always resolve between episodes, this is sometimes referred to as benign MS, although over the long term, people still accumulate some degree of disability. On the other hand, the term malignant multiple sclerosis is used to describe MS patients who have reached a significant level of disability in the short term. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an episode of demyelination suggestive of multiple sclerosis, but does not meet the criteria for the disease. 30-70% of people who experience CIS later develop MS. Thus, a patient with CIS can be a patient as described herein, i.e., a patient in need of treatment or prevention of relapsing forms of multiple sclerosis.

[0291] Primary progressive MS occurs in about 10-20% of individuals, with no remission after initial symptoms. It is characterized by progressive disability from the outset, with no or only occasional and minor remissions and improvements. The usual age of onset of the primary progressive subtype is later than the relapsing-remitting subtype. It is similar to the age at which the secondary progressive form usually begins, about 40 years.

[0292] Secondary progressive MS occurs in about 65% of initially relapsing-remitting MS patients, who have a progressive neurologic decline between acute episodes, without any clear remission periods. Occasionally, relapses and minor remissions occur. The most common length of time between disease onset and the transition from relapsing-remitting to secondary progressive MS is 19 years.

[0293] Atypical variants of MS have been described; these include tumefactive multiple sclerosis, Balo concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. There is controversy as to whether they are variants of MS or different diseases. Some diseases previously thought to be variants of MS, such as Devic's disease, are now thought to be outside the MS spectrum.

[0294] In all of the embodiments described thus far, the patient is given premedication prior to administration of the first dose of ofatumumab. The premedication can include acetaminophen, antihistamines, and / or steroids. It can be given 30 to 60 minutes prior to the ofatumumab injection.

[0295] Alternatively, no premedication can be given prior to the first dose of ofatumumab.

[0296] The effect of preventing a prior or ongoing condition (e.g., an infection-related disease) can be assessed by standard routine health checks performed by physicians and other technical personnel using state-of-the-art assays and techniques to diagnose and monitor the disease. Those of skill in the art are aware of the various state-of-the-art existing diagnostic techniques that can be used for the above purposes. For example, viral load or infection status can be analyzed by, e.g., assays that measure viral DNA load, where viral DNA quantification can be analyzed in whole blood, plasma, and / or B cells. Those of ordinary skill in the art are aware of techniques to analyze viral load and infection status of a patient. Viral DNA load can be assessed by analyzing expression of viral genes.

[0297] The present disclosure also relates to a method of reducing the likelihood that a patient will develop an adverse event, comprising administering to the patient a therapeutically effective dose of ofatumumab. As used herein, the term "reducing the likelihood" in the context of development of an adverse event refers to the patient's therapeutic outcome, particularly where the patient is an MS patient, more particularly where the patient is in need of immunosuppression with a therapeutically effective dose of ofatumumab, wherein the patient has a reduced risk of developing an adverse event. The adverse event can be one or several of the following: injection-related reactions, nasopharyngitis, headache, injection site reactions, upper respiratory tract infection, urinary tract infection, back pain, fatigue, influenza, nausea, decreased blood immunoglobulin M or G, alopecia, arthralgia, diarrhea, extremity pain, depression, macular edema, Chickenpox (varicella), head cold, increased gamma-glutamyl transferase, abdominal pain, skin cancer, bradycardia, hemorrhagic focal encephalitis, herpes infection, progressive multifocal leukoencephalopathy (PML), hypertension, paresthesia.

[0298] Example of an implementation project

[0299] The following embodiments are provided in the application:

[0300] 1. Ofatumumab for use in the treatment or prevention of relapsing forms of multiple sclerosis (RMS), wherein ofatumumab is for use in a patient with a history of a condition other than multiple sclerosis.

[0301] 2. Ofatumumab for use according to item 1, wherein the condition other than multiple sclerosis is one or more of

[0302] injection-related reactions,

[0303] nasopharyngitis,

[0304] headache,

[0305] injection site reactions,

[0306] upper respiratory tract infections,

[0307] urinary tract infections,

[0308] back pain,

[0309] fatigue,

[0310] influenza,

[0311] nausea,

[0312] reduced blood immunoglobulin M,

[0313] alopecia,

[0314] joint pain,

[0315] diarrhea,

[0316] pain in extremities,

[0317] depression,

[0318] hypertension,

[0319] paresthesia.

[0320] 3. Ofatumumab for use according to item 1 or 2, wherein the history of a condition other than multiple sclerosis is a history of an infection.

[0321] 4. Ofatumumab for use according to item 3, wherein the history of an infection is an infection caused by a virus or microorganism selected from the group consisting of

[0322] respiratory syncytial virus (RSV),

[0323] influenza or parainfluenza virus,

[0324] human polyomavirus (BK virus),

[0325] adenovirus,

[0326] rhinovirus,

[0327] coronavirus,

[0328] human herpes viruses, such as herpes simplex virus (HSV),

[0329] varicella zoster virus (VZV),

[0330] Epstein-Barr virus (EBV),

[0331] cytomegalovirus (CMV),

[0332] beta polyomavirus, such as John Cunningham virus (JCV),

[0333] Bordetella pertussis,

[0334] Bordetella parapertussis,

[0335] Corynebacterium diphtheriae,

[0336] Escherichia coli,

[0337] Staphylococcus (e.g. S. saprophyticus or S. aureus),

[0338] Chlamydia trachomatis,

[0339] Haemophilus influenzae,

[0340] Meningococcus,

[0341] Klebsiella,

[0342] Pseudomonas,

[0343] Enterococcus,

[0344] Streptococcus

[0345] yeast (e.g. Candida albicans),

[0346] Pneumocystis (e.g. Pneumocystis murina),

[0347] Cryptococcus (e.g. Cryptococcus neoformans),

[0348] Aspergillus,

[0349] Mycoplasma genitalium.

[0350] 5. Ofatumumab for use according to any of the preceding items, wherein the patient is vaccinated during ofatumumab treatment.

[0351] 6. Ofatumumab for use as claimed in item 5, wherein the vaccination is against any one of:

[0352] a rhinovirus,

[0353] respiratory syncytial virus (RSV),

[0354] influenza or parainfluenza virus,

[0355] human polyomavirus (BK virus),

[0356] an adenovirus,

[0357] a human herpes virus, such as herpes simplex virus (HSV),

[0358] varicella zoster virus (VZV),

[0359] Epstein-Barr virus (EBV),

[0360] cytomegalovirus (CMV),

[0361] a betapolyomavirus, such as John Cunningham virus (JCV),

[0362] Bordetella pertussis,

[0363] Bordetella parapertussis,

[0364] Corynebacterium diphtheriae,

[0365] Escherichia coli,

[0366] S. saprophyticus,

[0367] S. aureus,

[0368] Chlamydia trachomatis,

[0369] Klebsiella,

[0370] Pseudomonas,

[0371] Enterococcus,

[0372] Streptococcus,

[0373] a yeast (e.g., Candida albicans),

[0374] Pneumocystis (e.g., Pneumocystis murina),

[0375] Cryptococcus (e.g., Cryptococcus neoformans),

[0376] Aspergillus,

[0377] Mycoplasma genitalium.

[0378] 7. Ofatumumab for use according to any of the preceding items, wherein the patient with a history of a condition other than multiple sclerosis that is either past or ongoing has:

[0379] a history of transient ischemic attack (TIA);

[0380] a history of cerebral infarction without residual deficit;

[0381] a history of thrombotic stroke without persistent impact;

[0382] a history of thrombotic stroke without residual deficit;

[0383] a history of transient ischemic attack;

[0384] a history of ischemic stroke without residual deficit;

[0385] a history of non-atherosclerotic stroke without residual deficit;

[0386] a history of parietal lobe cerebrovascular accident;

[0387] a history of cerebrovascular accident without residual deficit;

[0388] a history of embolic stroke without deficit;

[0389] a history of embolic stroke without persistent impact;

[0390] a history of embolic transient ischemic attack;

[0391] a history of hemorrhagic cerebrovascular accident without residual deficit;

[0392] a history of atherosclerotic cerebrovascular accident without residual deficit;

[0393] a history of cardiac embolic stroke.

[0394] 8. Ofatumumab for use according to any of the preceding items, wherein the patient with a history of a condition other than multiple sclerosis that is either past or ongoing is treated to cure, reduce or eliminate the condition prior to initiation of ofatumumab treatment.

[0395] 9. Ofatumumab for use according to item 8, wherein the treatment comprises administration of a glucocorticoid, such as cortisone 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.

[0396] 10. Ofatumumab for use according to any of the preceding items, wherein the condition that is either past or ongoing is an autoimmune disease other than multiple sclerosis.

[0397] 11. Ofatumumab for use according to item 10, wherein the autoimmune disease other than multiple sclerosis is selected from the group consisting of:

[0398] Type 1 diabetes,

[0399] Rheumatoid arthritis (RA),

[0400] Psoriasis / psoriatic arthritis,

[0401] Systemic lupus erythematosus (SLE),

[0402] Inflammatory bowel disease,

[0403] Addison's disease,

[0404] Graves' disease,

[0405] Sjogren's syndrome,

[0406] Hashimoto's thyroiditis,

[0407] Myasthenia gravis,

[0408] Autoimmune vasculitis,

[0409] Pernicious anemia,

[0410] Celiac disease.

[0411] 12. Ofatumumab for use according to item 10, wherein the autoimmune disease is rheumatoid arthritis (RA).

[0412] 13. Ofatumumab for use according to item 12, wherein the rheumatoid arthritis (RA) is treated with a disease-modifying antirheumatic drug (DMARD) selected from the group consisting of methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-a inhibitors (certolizumab, infliximab and etanercept), abatacept, anakinra, rituximab and tocilizumab.

[0413] 14. Ofatumumab for use according to item 10, wherein the autoimmune disease is psoriasis.

[0414] 15. Ofatumumab for use according to item 14, wherein the psoriasis is treated with methotrexate, cyclosporin, hydroxyurea, fumarates such as dimethyl fumarate, retinoids, anti-TNF therapies such as infliximab, adalimumab, golimumab and PEGylated certolizumab, etanercept, ixekizumab, ustekinumab, guselkumab, efalizumab and apremilast.

[0415] 16. Ofatumumab for use according to any of the preceding items, wherein the history of a condition other than multiple sclerosis is a history of hospitalization.

[0416] 17. Ofatumumab for use according to any of the preceding items, wherein the history of a condition other than multiple sclerosis is a history of surgery.

[0417] 18. Ofatumumab for use according to item 16 or 17, wherein the patient is treated with an immunosuppressive agent other than ofatumumab.

[0418] 19. Ofatumumab for use according to item 18, wherein the immunosuppressive agent is selected from the group consisting of glucocorticoids (e.g. cortisone, prednisone, dexamethasone and hydrocortisone), cytostatic agents (e.g. methotrexate, anthracyclines, mitomycin C, bleomycin, mithramycin), antibodies (e.g. basiliximab (Simulect) and daclizumab (Zinbryta) or drugs acting on the immunophilins (e.g. tacrolimus and cyclosporine).

[0419] 20. Ofatumumab for use according to any of the preceding items, wherein the patient is an elderly patient.

[0420] 21. Ofatumumab for use according to item 20, wherein the elderly patient has age-related macular degeneration (AMD).

[0421] 22. Ofatumumab for use according to item 20, wherein the elderly patient has Alzheimer’s disease.

[0422] 23. Ofatumumab for use according to item 20, wherein the elderly patient has atherosclerosis.

[0423] 24. Ofatumumab for use according to item 20, wherein the elderly patient has benign prostatic hyperplasia (BPH).

[0424] 25. Ofatumumab for use according to any of items 1-19, wherein ofatumumab is administered to a pediatric patient.

[0425] 26. Ofatumumab for use according to any of the preceding items, wherein the condition other than multiple sclerosis is a cancer or a lymphoproliferative disease.

[0426] 27. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered when the serum neurofilament light chain (NfL) concentration is 4-13 pg / mL.

[0427] 28. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered at a dose of 10-30 mg every 4 weeks, preferably 20 mg every 4 weeks.

[0428] 29. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered subcutaneously.

[0429] 30. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered as a loading dose.

[0430] 31. Ofatumumab for use according to item 30, wherein as a loading dose, 20 mg ofatumumab is administered on day 1, day 7 and day 14 or preferably on week 0, week 1 and week 2.

[0431] 32. Ofatumumab for use according to any of items 1-31, wherein ofatumumab is not administered as a loading dose.

[0432] 33. Ofatumumab for use according to any of the preceding items, wherein the relapsing form of multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS).

[0433] 34. Ofatumumab for use according to any of the preceding items, wherein prior to administration of said first dose of ofatumumab, a premedication is administered to said patient.

[0434] 35. Ofatumumab for use according to item 34, wherein said premedication comprises acetaminophen, an antihistamine and / or a steroid.

[0435] 36. Ofatumumab for use according to item 34 or 35, wherein said premedication is administered 30-60 minutes prior to the ofatumumab injection.

[0436] 37. Ofatumumab for use according to any of items 1-33, wherein no premedication is administered prior to the first dose of ofatumumab.

[0437] 38. Ofatumumab for use in the treatment or prevention of a relapsing form of multiple sclerosis, wherein vaccination is performed during ofatumumab treatment.

[0438] 39. Ofatumumab for use according to item 38, wherein said vaccination is against any one of

[0439] a rhinovirus,

[0440] respiratory syncytial virus (RSV),

[0441] Influenza or parainfluenza virus,

[0442] Human polyomavirus (BK virus),

[0443] Adenovirus,

[0444] Human herpes viruses, such as herpes simplex virus (HSV),

[0445] Varicella zoster virus (VZV),

[0446] Epstein-Barr virus (EBV),

[0447] Cytomegalovirus (CMV),

[0448] Beta polyomavirus, such as John Cunningham virus (JCV),

[0449] Bordetella pertussis,

[0450] Parapertussis Bordetella,

[0451] Corynebacterium diphtheriae,

[0452] Escherichia coli,

[0453] S. saprophyticus,

[0454] S. aureus,

[0455] Chlamydia trachomatis,

[0456] Klebsiella,

[0457] Pseudomonas,

[0458] Enterococcus,

[0459] Streptococcus

[0460] Yeast (e.g., Candida albicans),

[0461] Pneumocystis (e.g., Pneumocystis murina),

[0462] Cryptococcus (e.g., Cryptococcus neoformans),

[0463] Aspergillus

[0464] Mycoplasma genitalium

[0465] Coronavirus, in particular SARS-CoV-2.

[0466] 40. Ofatumumab for use according to any of the preceding items, wherein the patient is neurologically stable within one month prior to the first administration of ofatumumab.

[0467] 41. Ofatumumab for use according to any of the preceding items, wherein the patient has an EDSS score of 1-4 prior to the first administration of ofatumumab.

[0468] 42. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered at a dose of 10-30 mg every 4 weeks, preferably 20 mg every 4 weeks.

[0469] 43. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered subcutaneously.

[0470] 44. Ofatumumab for use according to any of the preceding items, wherein ofatumumab is administered as a loading dose.

[0471] 45. Ofatumumab for use according to item 44, wherein as a loading dose, 20 mg ofatumumab is administered on day 1, day 7 and day 14 or preferably on week 0, week 1 and week 2.

[0472] 46. Ofatumumab for use according to any of items 1-43, wherein ofatumumab is not administered as a loading dose.

[0473] 47. Ofatumumab for use according to any of the preceding items, wherein the relapsing form of multiple sclerosis is selected from relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS).

[0474] 48. Ofatumumab for use according to any of the preceding items, wherein the patient is administered premedication prior to the administration of the first dose of ofatumumab.

[0475] 49. Ofatumumab for use according to item 48, wherein the premedication comprises acetaminophen, an antihistamine and / or a steroid.

[0476] 50. Ofatumumab for use according to item 48 or 49, wherein the premedication is administered 30-60 minutes prior to the injection of ofatumumab.

[0477] 51. Ofatumumab for use according to any of items 38-47, wherein no premedication is administered prior to the first dose of ofatumumab.

[0478] 52. Use of ofatumumab for the manufacture of a medicament for the treatment or prevention of a relapsing form of multiple sclerosis (RMS), wherein ofatumumab is used as defined in any of the preceding items.

[0479] 53. A method of treating or preventing relapsing forms of multiple sclerosis (RMS) by administering ofatumumab as defined in any of the preceding items.

[0480] Examples

[0481] Example 1

[0482] Design / Methods

[0483] APLIOS was a 12-week, open-label, phase 2 bioequivalence study. Patients received a loading dose of ofatumumab 20 mg (0.4 mL) subcutaneously on days 1, 7, and 14, and a maintenance dose every 4 weeks starting at week 4 via prefilled syringe or autoinjector pen (SensoReady). Changes in B- and T-cell subsets were analyzed longitudinally in blood samples from a subset of patients using fluorescence-activated cell sorting (FACS).

[0484] Results

[0485] Ofatumumab treatment showed rapid and sustained depletion of total B cells (CD19+ CD45+) measured on days 4 and 7. Median total B-cell levels decreased to <5 cells / µL by day 7 to 14 of the loading regimen and remained unchanged throughout the remainder of the study. More efficient depletion was observed for memory B cells (CD19+ CD45+ CD27+) compared with naive B cells (CD19+ CD45+ IgD+ CD27- CD38dim). Specific subsets of CD20+ CD3+ T cells were also rapidly and efficiently depleted, consistent with previously reported findings in primates.

[0486] Conclusions

[0487] Subcutaneous administration of ofatumumab 20 mg in patients with RMS resulted in rapid and sustained depletion of CD20+ B cells and CD20+ T cells. The differential effects on specific subsets, i.e., depletion of memory B cells while sparing naive B cells, can be relevant to the efficacy and long-term safety of ofatumumab in the pathophysiology of MS.

[0488] Example 2

[0489] Background

[0490] The efficacy of ofatumumab (the first fully-human anti-CD20 monoclonal antibody) was demonstrated to be superior to teriflunomide in the phase 3 ASCLEPIOS I / II trial, see ECTRIMS Online Library. Hauser S. et al. 09 / 13 / 19; 279581;336. In the ASCLEPIOS I and II studies, annualized relapse rates (ARR) were reduced by 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25), respectively, in MS patients treated with ofatumumab compared with Aubagio® (teriflunomide) (p<0.001 for both studies). Ofatumumab showed highly significant suppression of gadolinium (Gd) T1 lesions compared with Aubagio®, demonstrating significant suppression of new inflammatory activity. In the pre-specified pooled analysis, ofatumumab demonstrated a 34.4% reduction in the relative risk of confirmed disability progression (CDP) within 3 months (p=0.002) and a 32.5% reduction in the relative risk of CDP within 6 months (p=0.012) compared with Aubagio®.

[0491] Objectives

[0492] To determine serum immunoglobulin (Ig) levels and investigate the association between IgG or IgM levels and new treatment options, multiple sclerosis patients received ofatumumab treatment.

[0493] Methods

[0494] ASCLEPIOS I and II were double-blind, double-dummy, active comparator-controlled, parallel-group, innovative, adaptive design, multicenter trials. Patients were randomized (1 : 1) to receive subcutaneous injections of ofatumumab 20 mg every 4 weeks (after an initial loading regimen of 20 mg subcutaneous doses on days 1, 7, and 14) or teriflunomide 14 mg once daily orally for up to 30 months. The study had a flexible duration and terminated at the end of the blinded core treatment period according to pre-specified criteria. Patients aged 18-55 years with an Expanded Disability Status Scale (EDSS) score (according to Kurtzke, Neurology. 1983 Nov; 33(11): 1444-52) of 0-5.5 at screening who experienced >1 relapse in the previous year or >2 relapses in the previous 2 years, or a positive gadolinium-enhancing (Gd+) MRI scan within the year prior to randomization were enrolled.

[0495] Serum IgG / IgM levels were monitored at baseline, week 4 (W), W12, and every 12 weeks, see Figure 1The lower limit of normal (LLN) was defined as IgG, 7 g / L and IgM, 0.4 g / L. Outcomes included the proportion of patients with particularly low IgG / IgM levels, and the association between particularly low IgG / IgM levels and incidence of infections. Reference Figure 1 .

[0496] Results on IgG and IgM levels

[0497]

[0498] - Base = Baseline; Change = Post Baseline - Baseline.

[0499] - At each visit-window, only patients with values at baseline and at the visit-window were included.

[0500] The change from baseline in serum IgG levels is shown in Figure 2 . The change from baseline in serum IgM levels is shown in Figure 3 .

[0501] In patients treated with ofatumumab, IgG levels did not decrease at week 72 and beyond. Furthermore, there was a turning point at week 36, when the trend of decreasing IgG levels reversed, ultimately leading to a net increase in IgG starting around week 72.

[0502] The decrease in IgG was less pronounced and shorter in patients treated with ofatumumab compared to patients treated with teriflunomide.

[0503] Results infections: A favourable low incidence of infections was found.

[0504] Conclusion:

[0505] Ig levels, in particular IgG levels, were unexpectedly high, and the incidence of infections was favourably low.

[0506] Example 3

[0507] Methods

[0508] In the pooled analysis, the results of Example 3 were compared to the results obtained by Derfuss et al., see Figure 5 .

[0509] Results

[0510] After two years (96 weeks), Ocrevus treatment (combined with OPERA, see Figure 4 ) has led to a decrease in IgG levels of about 5%, while ofatumumab has led to an increase of about 3%, see Figure 2 .

[0511] Conclusions

[0512] Ocrelizumab can lead to a rather persistent decrease in IgG levels, whereas ofatumumab long-term maintenance even increases IgG levels.

[0513] Example 4

[0514] Ofatumumab is administered subcutaneously to patients with RRMS. If injection-related reactions occur, symptomatic treatment is provided. For patients experiencing pain, redness, or itching, hydrocortisone cream is applied after injection to help alleviate itching, redness, and swelling. Analgesics can also be used.

[0515] Observations

[0516] The levels of (total) IgG in ofatumumab-treated patients with injection-related reactions are expected to be comparable to those in ofatumumab-treated patients without injection-related reactions and without hydrocortisone treatment. In summary, no evidence of combined immunosuppression or toxicity of ofatumumab and hydrocortisone is expected.

[0517] With ofatumumab treatment, a significant reduction in follicular B-cell subsets is expected to be observed, whereas marginal zone and germinal center B-cell subsets are expected to be less affected.

[0518] Example 5

[0519] a) Animal study

[0520] A single dose of anti-CD20 antibody (mIgGl) was administered to mice (C57BL / 6 female mice, 6 weeks old) by two different routes of administration (intravenous or subcutaneous) to investigate the effect of B-cell depletion on antibody-mediated immune responses to Streptococcus pneumonia. B-cells were depleted by administering 50 μg of anti-CD20 (mIgGl, n=8 per group) to each mouse by either intravenous or subcutaneous route of administration. Mice without B-cell depletion received the same concentration of isotype control antibody (subcutaneous). Mice were vaccinated with the 13-valent pneumococcal conjugate vaccine Prevnar® (20 μΐ^ / mouse, administered intraperitoneally (i.p.)):

[0521] One-dose vaccination study: One-dose Prevnar®

[0522] Two-dose vaccination study: Two-dose Prevnar®

[0523] Control animals (neither depleted nor vaccinated) received PBS (phosphate-buffered saline) (i.p.) (see Figure 6 ).

[0524] Evaluation

[0525] Serum pneumococcal-specific IgG levels were measured by whole cell ELISA on pneumococci (TIGR4 strain)-coated plates at day 16 (after the first dose of vaccine) and day 29 (end point) (see Figure 7 ).

[0526] Pneumococci were incubated with mouse sera (day 29) and the antibody binding to the surface of pneumococci was measured by flow cytometry (FACS); pneumococcal-specific IgG and IgM levels were measured by the serum deposition test (see Figure 7 ).

[0527] Blood, spleen and lymph nodes were analyzed to observe the effect on B-cell repertoire levels at day 14. The number of B cells was still about 20% of the number of B cells in the non-treated group 14 days after anti-CD20 antibody treatment (see Figure 8 and 9 ).

[0528] One dose vaccination study: B-cell subsets at day 14

[0529] A clear reduction of follicular B-cell subsets was observed in both intravenous and subcutaneous anti-CD20 treatment groups (see Figure 10 and 11 ).

[0530] Two dose vaccination study: B-cell depletion at day 29

[0531] - Only 60% of the B-cell population was reconstituted after 4 weeks of anti-CD20 treatment (see Figure 12 ).

[0532] - No significant difference in B-cell subsets was observed between the subcutaneous and intravenous anti-CD20 treatment groups (see Figure 13 ).

[0533] - Pneumococcal-specific immunoglobulin levels (IgG / IgM)

[0534] o At day 16 (after the first dose of vaccine, see Figure 14 ), IgG levels against pneumococci in anti-CD20 treated mice (intravenous and subcutaneous) were comparable to the vaccinated groups.

[0535] o No significant difference in IgG levels was observed between the subcutaneous and intravenous anti-CD20 treatment groups (see Figure 14 ).

[0536] o In the anti-CD20 treated group (depleted samples) compared to the vaccinated samples, the deposition of antibodies on the surface of the bacteria indicates lower levels of IgG bound to pneumococci; however, IgM levels are comparable (see Figure 15 ).

[0537] Conclusions

[0538] - The route of administration does not affect the non-depleted B cell population.

[0539] - With anti-CD20 treatment, a clear reduction in the follicular B cell subset is observed, while the marginal zone and germinal center B cell subsets seem to be less affected.

[0540] - After 4 weeks of anti-CD20 treatment, the B cell population is not completely reconstituted.

[0541] - B cell depletion reduces pneumococcal-specific IgG levels, while the reduction in IgM levels is much smaller.

[0542] b) Clinical trial

[0543] 100 patients with relapsing-remitting MS received subcutaneous administration of ofatumumab.

[0544] - during the loading dose regimen, which comprises administration of 20 mg ofatumumab on day 0, day 7 and day 14 of the dose regimen; and

[0545] - during the maintenance dose regimen, comprising administration of 20 mg ofatumumab starting from week 4 of the dose regimen and continuing every 4 weeks for the duration of the treatment regimen.

[0546] The general clinical status of the patients was investigated weekly by physical and laboratory examinations. The disease status and changes in disease progression were assessed every 2 months by radiological examination (MRI) and physical examination.

[0547] For those patients who suffered from an adverse event of infection, blood samples will be collected for laboratory analysis. If the analysis confirms a Staphylococcus aureus infection, the corresponding patient will receive oral trimethoprim-sulfamethoxazole treatment. The ofatumumab treatment will continue.

[0548] Blood samples were collected every other day during treatment with trimethoprim-sulfamethoxazole. Analysis of these samples, as evidenced by the comprehensive analysis, was expected to reveal levels of IgG against Staphylococcus aureus in the ofatumumab-treated patients comparable to those reported in the literature for infected subjects not suffering from MS and not treated with ofatumumab. In addition, ofatumumab-treated patients were expected to recover more quickly from the infection compared to previous trials.

[0549] Example 6

[0550] a) Animal study

[0551] In mice (C57BL / 6 female mice, 6 weeks old), the intravascular filament model was used to occlude the middle cerebral artery (MCA) (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). It is well known that occlusion leads to infarction of the MCA territory. After reperfusion by withdrawal of the occlusion filament, blood flow rapidly recovers. The control group received a sham MCA occlusion.

[0552] One week later, a subpopulation of mice from both groups (MCA occlusion and sham) was given a single dose of anti-CD20 antibody (mlgGl) subcutaneously. B cells were depleted by administering 50 μg of anti-CD20 mlgGl per mouse, n=8 per group. Mice without B cell depletion received the same concentration of isotype control antibody (subcutaneously).

[0553] With anti-CD20 treatment (both groups), a clear reduction of the follicular B cell subtype was observed, while the marginal zone and germinal center B cell subtypes appeared to be less affected.

[0554] Recovery after MCA occlusion (including tissue repair) appeared to be unaffected by anti-CD20 treatment.

[0555] b) Clinical trial

[0556] A first group of patients was monitored after ischemic stroke. A subset of patients was expected to have urinary incontinence or difficulty emptying the bladder completely due to muscle weakness. For these reasons, a urinary catheter was placed in the bladder. However, there was an increased risk of urinary tract infection associated with the use of a urinary catheter. These infections were treated with one of the following

[0557] Trimethoprim / sulfamethoxazole (Bactrim, Septra, etc.),

[0558] Fosfomycin (Monurol),

[0559] Nitrofurantoin (Macrodantin, Macrobid),

[0560] Cephalexin (Keflex), or

[0561] Ceftriaxone.

[0562] A second group of patients consisted of MS patients treated with ofatumumab. A subset of patients developed adverse events, including urinary tract infections. These infections were treated with one of the following

[0563] Trimethoprim / sulfamethoxazole (Bactrim, Septra, etc.),

[0564] Fosfomycin (Monurol),

[0565] Nitrofurantoin (Macrodantin, Macrobid),

[0566] Cephalexin (Keflex), or

[0567] Ceftriaxone.

[0568] Conclusion

[0569] With ofatumumab treatment, a significant reduction in the follicular B cell subset was expected to be observed, while the marginal zone and germinal center B cell subsets were expected to be less affected.

[0570] - No significant difference in the management of urinary tract infections was expected.

[0571] - The relevance of the data indicated that ofatumumab can be safely given after stroke even after the occurrence of an adverse event, such as urinary tract infection.

[0572] Example 7

[0573] MS patients are treated with ofatumumab or Ocrevus (ocrelizumab). Selected patients with psoriatic arthritis are monitored under a special study program. Subgroups of patients have more severe disease activity and / or do not respond well to NSAIDs. Some of them cannot take disease-modifying antirheumatic drugs (DMARDs), such as

[0574] Leflunomide (Arava),

[0575] Methotrexate (Otrexup, Rasuvo, Rheumatrex, Trexall) or

[0576] Sulfasalazine (Azulfidine).

[0577] Therefore, they are treated with immunosuppressants, i.e. one of the following

[0578] Azathioprine (Imuran, Azasan) or

[0579] Cyclosporine (Gengraf, Neoral, Sandimmune).

[0580] Observation:

[0581] It is expected that the levels of IgG are significantly higher in patients treated with ofatumumab than in Ocrevus-treated patients.

[0582] With ofatumumab treatment, the follicular B-cell subset is expected to be significantly reduced, while the marginal zone and germinal center B-cell subsets seem to be less affected.

[0583] After treatment with immunosuppressants, it is expected that there will be significantly more adverse events (e.g. infections) in the Ocrevus group.

[0584] It is expected that the management of psoriatic arthritis is comparable in both groups.

[0585] References

[0586] Diabetes Care. 2014 Feb;37(2):453-9. doi: 10.2337 / dc13-0626. Epub 2013 Sep 11. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Pescovitz MD1, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, Moran A, Raskin P, Rodriguez H, Schatz DA, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Anti-CD20 Study Group.

[0587] Cohen et al., New England Journal of Medicine 2010; 362: 402-15: Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis.

[0588] Cesarman E (2014). Gammaherpesviruses and lymphoproliferative disorders. Annu Rev Pathol, 9(349-372).

[0589] Cohen JI (2015). Primary Immunodeficiencies Associated with EBV Disease. Curr Top Microbiol Immunol, 390(Pt 1):241-265.

Claims

1. Ofatumumab for use in the treatment or prevention of relapsing forms of multiple sclerosis (RMS), wherein, Ofatumumab for use in patients with a history of or ongoing conditions other than multiple sclerosis.

2. Ofatumumab for use according to claim 1, wherein the condition other than multiple sclerosis is one or more of injection-related reactions, nasopharyngitis, headache, injection site reactions, upper respiratory tract infection, urinary tract infection, back pain, fatigue, flu, nausea, decreased blood immunoglobulin M, alopecia, arthralgia, diarrhea, pain in extremities, depression, hypertension, paresthesia.

3. Ofatumumab for use according to claim 1 or 2, wherein the history of or ongoing conditions other than multiple sclerosis is a history of infections.

4. Ofatumumab for use according to claim 3, wherein the history of or ongoing infections is caused by a virus or microorganism selected from the group consisting of respiratory syncytial virus (RSV), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, rhinovirus, coronavirus, human herpes virus, 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, Staphylococcus (e.g. S. saprophyticus or S. aureus), Chlamydia trachomatis, Haemophilus influenzae, Meningococcus, Klebsiella, Pseudomonas, Enterococcus, Streptococcus yeast (e.g. Candida albicans), Pneumocystis (e.g. Pneumocystis murina), Cryptococcus (e.g. Cryptococcus neoformans), Aspergillus, Mycoplasma genitalium.

5. Ofatumumab for use according to any of the preceding claims, wherein the patient is vaccinated during ofatumumab treatment.

6. Ofatumumab for use according to claim 5, wherein the vaccination is against any one of rhinovirus, respiratory syncytial virus (RSV), influenza or parainfluenza virus, human polyomavirus (BK virus), adenovirus, human herpes virus, 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, S. saprophyticus, S. aureus, Chlamydia trachomatis, Klebsiella, Pseudomonas, Enterococcus, Streptococcus, yeast (e.g. Candida albicans), Pneumocystis (e.g. Pneumocystis murina), Cryptococcus (e.g. Cryptococcus neoformans), Aspergillus, Mycoplasma genitalium.

7. Ofatumumab for use according to any of the preceding claims, wherein the patient with a history of or ongoing conditions other than multiple sclerosis has a history of transient ischemic attack (TIA); a history of cerebral infarction without residual deficit; a history of thrombotic stroke without ongoing impact; a history of thrombotic stroke without residual deficit; a history of transient ischemic attack; a history of ischemic stroke without residual deficit; No history of non-atherosclerotic stroke with no residual deficit; History of parietal lobar cerebral vascular accident; History of cerebral vascular accident with no residual deficit; History of embolic stroke with no deficit; History of embolic stroke with no persistent effects; History of embolic transient ischemic attack; History of hemorrhagic cerebral vascular accident with no residual deficit; History of atherosclerotic cerebral vascular accident with no residual deficit; History of cardiac embolic stroke.

8. Ofatumumab for use according to any one of the preceding claims, wherein the patient with a history of a past or ongoing condition other than multiple sclerosis is treated to cure, reduce or eliminate the condition prior to initiation of ofatumumab treatment.

9. Ofatumumab for use according to claim 8, wherein the treatment comprises administration of a glucocorticoid, such as cortisone 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 the preceding claims, wherein the past or ongoing condition is an autoimmune disease other than multiple sclerosis.

Images