Ofatumumab for treating pediatric MS

Abstract

The present invention relates to ofatumumab for use in the treatment or prevention of pediatric multiple sclerosis (MS). According to the invention, ofatumumab is administered during a loading dosing schedule in weeks 0, 1 and 2 of the dosing schedule, and ofatumumab is administered during a maintenance dosing schedule starting in week 8 of the dosing schedule and continuing every 6 weeks thereafter.

Description

[Technical field]

[0001] The present invention relates to ofatumumab for use in the treatment of pediatric multiple sclerosis (MS). According to the invention, ofatumumab is administered during a loading dosing schedule at weeks 0, 1 and 2 of the dosing schedule, and ofatumumab is administered during a maintenance dosing schedule starting at week 8 of the dosing schedule and continuing every 6 weeks thereafter. [Background technology]

[0002] The burden of pediatric MS on patients and their families is great. Pediatric MS patients experience recurrent episodes of acute inflammatory activity and neurological abnormalities, which severely impact the quality of life of patients. Childhood onset of MS is associated with failure to achieve age-expected brain growth during childhood / early adolescence, and brain atrophy from mid-adolescence through adulthood. Ultimately, patients with childhood onset of MS have a poorer prognosis, are more disabled, and experience cognitive sequelae at an earlier age compared to patients with adult onset of MS. Unfortunately, current therapeutic avenues are very limited.

[0003] Thus, the unmet medical need in pediatric MS is high. Currently, fingolimod (Gilenya®) is the only therapy (based on PARADIGMS), which showed better efficacy than interferon beta-1a on disease activity. After PARADIGMS, TERIKIDS was conducted to investigate the efficacy and safety of teriflunomide in 166 pediatric patients. However, this study did not reach statistical significance of the primary endpoint of time to first clinical relapse. Thus, fingolimod is the only therapy approved for pediatric MS in the United States. In the European Union (EU), interferon beta agents may be used in pediatric patients (of various age ranges) according to the approved label of the drug. However, these EU-only approvals were not based on prospective randomized controlled clinical studies such as PARADIGMS or TERIKIDS. As a result, treatment options are not only limited but also lack sufficient support and data from clinical studies.

[0004] In addition to limited treatment options, this lack of data is problematic when treatment is interrupted or changed. In these situations, pediatric MS patients are particularly vulnerable, and therefore there is a need to reduce or minimize this vulnerability. Importantly, treatment interruptions or changes are not uncommon events in the care of pediatric patients. Reasons for treatment interruptions or changes include adverse effects, treatment failure, disease progression, disease regression, comorbidities, physiological and metabolic changes (e.g., menstruation), and evolving patient preferences.

[0005] Thus, there is a need for drugs that are not only effective but also safe and tolerable for patients with pediatric MS.

[0006] Monoclonal antibodies (mAbs) against proteins expressed by B cells, e.g., anti-CD20 antibodies such as ofatumumab, ocrelizumab, and rituximab, are highly effective disease-modifying therapies (DMTs) with a generally favorable safety profile (D'Amico et al., 2019).

[0007] Ofatumumab (OMB157) is a human IgG1κ mAb that targets CD20 expressed on a subset of B and T cells; unlike other anti-CD20 mAbs, ofatumumab binds to a distinct epitope on the CD20 molecule, a cell surface antigen present on pre-B and mature B lymphocytes, inducing potent B cell lysis and depletion. After cell surface binding to B lymphocytes, ofatumumab induces antibody-dependent cell lysis and complement-mediated lysis.

[0008] Ofatumumab (Kesimpta®) is approved in the United States and Europe for the treatment of relapsing MS in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Summary of the Invention

[0009] According to the present invention, it has unexpectedly been found that ofatumumab therapy is beneficial not only in pediatric MS patients but also in MS patients with low body weight up to 40 kg.

[0010] Thus, the present invention provides ofatumumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40 kg and / or aged between 5 and 17 years.

[0011] The invention further provides ofatumumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40 kg.

[0012] The invention further provides ofatumumab for use in the treatment or prevention of multiple sclerosis in a patient weighing a maximum of 40 kg and aged between 5 and 17 years.

[0013] Embodiment The present invention provides ofatumumab for use in the treatment or prevention, preferably the treatment, of multiple sclerosis in a patient weighing up to 40 kg and / or aged between 5 and 17 years.

[0014] In a preferred embodiment, the patient has a body weight of up to 40 kg. In another preferred embodiment, the patient has a body weight of at least 25 kg, preferably the patient has a body weight of at least 25 kg and up to 40 kg.

[0015] In a preferred embodiment, the patient is a pediatric patient. In a preferred embodiment, the patient is a child. In another preferred embodiment, the patient is an adolescent.

[0016] Preferably, the pediatric patient is aged between 5 and 17 years, more preferably between 10 and 17 years, i.e. between 10 and 18 years. In another embodiment, the pediatric patient is aged between 10 and 12 years. In another embodiment, the pediatric patient is aged between 5 and 14 years, preferably between 10 and 14 years. In another embodiment, the pediatric patient is aged between 15 and 17 years, i.e. between 14 and 18 years.

[0017] In a preferred embodiment, the pediatric patient has a body weight of up to 40 kg. It is even more preferred that the pediatric patient has a body weight of at least 25 kg, and more preferably the pediatric patient has a body weight of at least 25 kg and up to 40 kg.

[0018] In a further preferred embodiment the pediatric patient is between 5 and 17 years of age, preferably between 10 and 18 years of age, and weighs up to 40 kg, preferably between 25 and 40 kg.

[0019] In a preferred embodiment of the invention, ofatumumab is administered at a dose of 20 mg every 6 weeks, also referred to as the maintenance dose.

[0020] Preferably, ofatumumab is administered parenterally, for example by epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural or intrasternal injection or infusion. The preferred route of administration is subcutaneous injection (sc).

[0021] In a preferred embodiment of the invention, ofatumumab is administered in a loading dose. The term "loading dose" is defined below. In a preferred embodiment, three loading doses are preferably administered at weeks 0, 1 and 2 after the initiation of ofatumumab therapy. This means that the first loading dose at week 0 constitutes the start of treatment. In an alternative preferred embodiment, three loading doses are administered at days 1, 5-9, preferably 7, and 12-16, preferably 14, after the initiation of ofatumumab therapy. This means that the first loading dose at day 1 constitutes the start of treatment.

[0022] According to the invention, ofatumumab is administered during a loading dose regimen preferably comprising 20 mg ofatumumab in weeks 0, 1 and 2 of the dosing regimen, and ofatumumab is administered during a maintenance dose regimen preferably comprising 20 mg ofatumumab beginning in week 8 of the dosing regimen and continuing every 6 weeks thereafter.

[0023] Thus, in a preferred embodiment, ofatumumab is a) ofatumumab is administered, preferably as a loading dose comprising a sc injection of 20 mg ofatumumab at weeks 0, 1 and 2 of the dosing regimen; b) ofatumumab is administered according to a dosing regimen, preferably administered as a maintenance dose comprising an sc injection of 20 mg ofatumumab starting on week 8 of the regimen and continuing every 6 weeks thereafter.

[0024] It was quite surprising that this dosing regimen provided safe and effective treatment in patients as defined in the claims, particularly pediatric patients, because of age-related changes associated with distribution and / or absorption, turnover and / or elimination of monoclonal antibodies (mAbs).

[0025] First, based on recent reports pointing out several processes that undergo age-related changes and are related to mAb distribution, it is believed that the biodistribution of mAbs is subject to developmental changes. Thus, there are well-known differences in tissue water content in pediatric patients versus adult tissue water content. Thus, for hydrophilic macromolecules such as monoclonal antibodies (mAbs), the percentage of total body volume available for distribution is expected to be higher in pediatric patients. Furthermore, tissue perfusion rates in pediatric patients are usually higher than the corresponding tissue perfusion rates in adults. Furthermore, pediatric patients have a higher percentage of "leaky" organs and tissues (e.g., liver, kidney, and spleen) that have a larger capillary surface area per unit tissue volume and a higher capillary permeability relative to their body dimensions. In summary, pediatric patients are expected to have a faster extravasation and a lower concentration difference between the vascular and extravascular spaces compared to adults. Higher rates of mAb absorption are expected in pediatric patients based on the increased extracellular fluid volume in pediatric patients compared with adults, and the higher perfusion rates (approximately 0.2% of the plasma flow rate) that are assumed to be equally affected for plasma and lymph.

[0026] Second, general age-related differences in the efficiency of recycling processes (such as those involving the IgG receptor FcRn) and in lysosomal protein turnover may account for the differences in mAb clearance between pediatric patients and adults after correcting for size differences. In this context, it is noted that protein turnover, i.e., catabolism in general, appears to be substantially higher in pediatric patients compared to adults. The effect of pediatric age on these processes would have been expected to result in clinically detectable differences in mAb clearance.

[0027] For these reasons, it would have been expected that age-related dose adjustments would be necessary in the claimed patients, particularly pediatric patients, and therefore the fact that the claimed dosing regimens are similar to adult dosing regimens is entirely unexpected.

[0028] Moreover, it was surprising that the claimed dosing regimens could be safely and effectively administered subcutaneously (sc), since intravenous (IV) and, to a lesser extent, intramuscular (IM) administration is typically preferred for pediatric patients.

[0029] Furthermore, the absence of significant problems with immunogenicity and endogenous anti-drug antibodies (ADA) in pediatric patients was surprising.

[0030] It was unexpectedly found that the above-identified dosing regimen achieves depletion of B cells below a threshold of 8 cells per microliter. This was quite surprising, since significant differences exist between adult and pediatric patients. These differences relate to physiology, metabolism, and weight, among others. In this regard, it is also noted that since children have a higher baseline B cell count compared to adults, it would not have been expected that the claimed dosing regimen would be able to consistently deplete B cells in patients as defined in the claims.

[0031] Most of the changes in B cell subpopulations occur during childhood. The percentage and absolute number of naive B cells gradually decrease from 18 months of age. On the other hand, there is an increase in memory B cells. Switched memory B cells expressing CD27 have undergone somatic hypermutation and class switch recombination in germinal centers. The percentage of CD27+IgD- B cells increases until age 18 and into adulthood. The population of CD19+CD27+IgD+ cells is often called non-switched memory B cells and corresponds to circulating marginal zone B cells. These cells are involved in T-independent responses and play an important role in controlling infections by encapsulated bacteria. The percentage and absolute number of non-switched memory B cells gradually increase from early childhood to adolescence. Without being bound by theory, it is believed that ofatumumab reduces the usage of (subsets of) regulatory T cells or B cells, including marginal zone B cells. Therefore, it is reasonable to believe that the claimed dosing regimen ofatumumab will provide safe and effective treatment in patients as defined in the claims.

[0032] On the other hand, the subject matter defined in the claims was unexpected based on the prior art, because age-related changes such as those described above or those related to the maturation of regulatory T cells and other T lymphocyte populations lead to the expectation that there are significant differences between pediatric patients and adults in the maturation of immune system functionality and therefore in processes involving immune cells, such as immune reactivity. One exemplary process that may differ between pediatric patients and adults is "target-mediated drug disposition (TMDD)", which describes the elimination pathway based on the binding of a mAb to its target. The detection of these and other age-related differences and the assessment of their magnitude are complex and unpredictable, so success using the claimed dosing regimen was unexpected.

[0033] In general, the present invention relates to the treatment of multiple sclerosis. In one embodiment of the present invention, the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). In another embodiment of the present invention, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In a further embodiment of the present invention, the multiple sclerosis is secondary progressive multiple sclerosis (SPMS). In a further embodiment, the multiple sclerosis is clinically isolated syndrome (CIS). RRMS is most preferred.

[0034] In another embodiment, progressive forms of MS such as PPMS and SPMS are not included.

[0035] In the completed PARADIGMS study, fingolimod was compared to interferon (IFN) beta-1a (Avonex). Patients treated with IFN beta-1a experienced 120 MS relapses during 163 participant-exposure years, whereas patients treated with fingolimod experienced 25 MS relapses during 180 participant-exposure years. The annualized relapse rate (ARR) (i.e., number of MS relapses per year) was 0.122 in the fingolimod group and 0.675 in the IFN beta-1a group. This corresponds to an 81.9% reduction in the ARR for IFN beta-1a (p < 0.001) (Chitnis et al., 2018).

[0036] In one embodiment of the invention, ofatumumab is non-inferior to interferon in terms of annual relapse rate, in particular in terms of maintaining the annual relapse rate, preferably in terms of reducing the annual relapse rate. In other words, the annual relapse rate under ofatumumab treatment is at most the annual relapse rate under interferon, i.e., the annual relapse rate of an average patient under ofatumumab treatment is at most the annual relapse rate of an average patient under interferon.

[0037] In a preferred embodiment, ofatumumab is non-inferior to interferon beta, specifically an interferon beta selected from the group consisting of interferon beta 1a, interferon beta 1b, and pegylated forms thereof, in terms of annualized relapse rate.

[0038] Specifically, the annual relapse rate (ARR) (ie, the number of MS relapses per year) is less than 0.67, preferably less than 0.50, more preferably less than 0.25, and even more preferably less than 0.15.

[0039] Preferably, ofatumumab provides a reduction in the ARR versus IFNβ-1a of at least 26% (p<0.001), more preferably the reduction in the ARR is at least 63%, more preferably at least 78%, particularly at least 82%.

[0040] In a preferred embodiment of the invention, ofatumumab is non-inferior to fingolimod in terms of annualized relapse rate, in particular in terms of maintaining the annualized relapse rate, preferably in terms of reducing the annualized relapse rate, in other words, the annualized relapse rate under ofatumumab treatment is at most the annualized relapse rate under fingolimod, i.e., the annualized relapse rate of an average patient under ofatumumab treatment is at most the annualized relapse rate of an average patient under fingolimod.

[0041] Preferably, the ARR is at most 0.12. Preferably, the ARR is less than 0.10, more preferably less than 0.08.

[0042] In another embodiment of the invention, ofatumumab is non-inferior to siponimod in terms of annual relapse rate, in particular in terms of maintaining the annual relapse rate, preferably in terms of reducing the annual relapse rate. In other words, the annual relapse rate under ofatumumab treatment is at most the annual relapse rate under siponimod, i.e., the annual relapse rate of an average patient under ofatumumab treatment is at most the annual relapse rate of an average patient under siponimod.

[0043] In one embodiment of the present invention, ofatumumab is no worse than fingolimod in terms of ARR (i.e., non-inferior), using a non-inferiority margin of 2. Non-inferiority is evaluated based on the estimated ARR ratio (ofatumumab / fingolimod). In other words, the ARR ratio of ofatumumab / fingolimod is less than 2, preferably less than 1.

[0044] In the PARADIGMS study, the ARR ratio (fingolimod / interferon) was 0.18 (95% CI: 0.11; 0.30) (Chitnis et al. 2018). Taking the upper limit of the confidence interval as a conservative estimate, the ARR was 3.3 times higher for interferon versus fingolimod.

[0045] The margin of 2 over fingolimod provides evidence of superiority of ofatumumab over interferon.

[0046] Optionally, as an additional criterion, the primary objective will be met only if the posterior median ARR for ofatumumab is less than 0.3. This additional criterion prevents declaring non-inferiority in situations where the ARR is not substantially lower than that of interferon, which may otherwise occur if the ARR of the comparator (fingolimod) is higher than expected.

[0047] A still further embodiment of the invention is ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein ofatumumab is non-inferior to fingolimod in terms of annualized T2 lesion rate, in other words the annualized T2 lesion rate under ofatumumab is at most the annualized T2 lesion rate under fingolimod, preferably the annualized T2 lesion rate under ofatumumab is reduced compared to fingolimod.

[0048] A still further embodiment of the present invention is ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein ofatumumab is non-inferior to fingolimod in terms of neurofilament light chain (NfL) serum concentration. In other words, axonal damage measured by NfL serum concentration under ofatumumab treatment is up to as severe as under fingolimod treatment, and preferably axonal damage measured by NfL serum concentration under ofatumumab treatment is reduced compared to fingolimod treatment.

[0049] In a preferred embodiment, the invention relates to ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein neuroaxonal damage as measured by NfL serum concentration is reduced compared to fingolimod.

[0050] Another embodiment of the invention is ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein ofatumumab meets the following criteria in terms of safety and tolerability relative to fingolimod: - frequency and severity of treatment-emergent adverse events (TEAEs); - Columbia-Suicide Severity Rating Scale (C-SSRS), - 12-lead ECG, - laboratory and ophthalmological data, - Pulmonary function tests, - Non-inferiority as determined by at least one vital sign.

[0051] Another embodiment of the invention relates to ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein ofatumumab is non-inferior to fingolimod in terms of immunogenicity and endogenous anti-drug antibodies (ADA).

[0052] In a preferred embodiment of the present invention, ofatumumab for use in treating MS is used for long-term treatment.The term long-term treatment indicates that ofatumumab is used for a long period of time.For example, ofatumumab can be used for more than 2 years, 3 years, 4 years, 5 years, 10 years.Ofatumumab can be used for up to 5 years, 10 years, 15 years, 20 years, or lifelong.

[0053] In a preferred embodiment of the invention, ofatumumab is administered at a dose of 20 mg every 6 weeks in patients weighing up to 40 kg, or in patients weighing up to 40 kg and aged between 5 and 17 years old. When the patient reaches a weight greater than 40 kg, or when the patient reaches the age of 18 and a weight greater than 40 kg, the dosing regimen is simply switched to a dose of 20 mg every 4 weeks.

[0054] This allows MS treatment to continue even with changing conditions such as age or weight gain, by only slightly modifying the treatment protocol, without the need to switch disease-modifying drugs, which is particularly advantageous since switching disease-modifying drugs may require washout periods and / or may be associated with the occurrence of adverse events.

[0055] In a preferred embodiment of the invention, a premedication is administered to the patient before the first dose of ofatumumab is administered. Preferably, the premedication comprises a compound selected from acetaminophen, an antihistamine, and a steroid. Methylprednisolone may be a preferred steroid. 100 mg iv may be a preferred dose. Preferably, the premedication is administered 30-60 minutes prior to the ofatumumab injection.

[0056] In a particularly preferred embodiment, no premedication is administered prior to the first dose of ofatumumab.

[0057] In a preferred embodiment of the invention, ofatumumab is administered as the only active ingredient for treating MS, in other words, ofatumumab is preferably the only disease-modifying drug administered.

[0058] In general, side effects and adverse events associated with B cell depleting therapy such as ocrelizumab therapy are reported to be associated with a decrease in immunoglobulin (e.g., IgG). In the present invention, it has surprisingly been found that ofatumumab therapy is advantageous compared to other B cell depleting therapies, since it does not cause a decrease in immunoglobulin (e.g., IgG) in the long term, thus opening up new avenues for patients under long-term treatment.

[0059] Thus, in a preferred embodiment of the invention, ofatumumab is used to treat MS, where ofatumumab is administered to patients with known risk factors for malignancies. In another preferred embodiment of the invention, ofatumumab is used to treat MS, where ofatumumab is administered to patients who are being actively monitored for recurrence of malignancies. In an alternative embodiment of the invention, ofatumumab is used to treat MS, where ofatumumab is administered to patients with known active malignancies.

[0060] The MSIS-29 (see definition below) is a clinically useful and scientifically sound measure of the impact of MS from the patient's perspective, suitable for clinical and epidemiological studies. It is considered to be a reliable, valid, and responsive PRO (patient-reported outcome) measure that complements other indicators of disease severity used to improve understanding of the impact of MS.

[0061] In the present invention, it has unexpectedly been found that administration of ofatumumab results in a beneficial reduction in the MS Impact Scale MSIS-29, as defined below.

[0062] In this regard, a further subject of the invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, in which ofatumumab reduces the MSIS-29 score. Preferably, ofatumumab reduces the MSIS-29 score by at least 1.5, more preferably by at least 2.0, even more preferably by at least 2.5 within 24 months. This reduction may be up to 3.0 or 3.5 or 4.0.

[0063] In one embodiment of the present invention, the ofatumumab composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where appropriate, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to reduce pain at the injection site. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example as a lyophilized powder or water-free concentrate, in a hermetically sealed container, such as an ampoule or sachet indicating the quantity of active agent.

[0064] Where the composition is to be administered by infusion, particularly by subcutaneous injection (sc), it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.

[0065] Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0066] In one embodiment, the formulation of ofatumumab can be formulated according to the formulations disclosed in WO2009 / 009407.

[0067] In one embodiment, ofatumumab is formulated in an antibody formulation, wherein ofatumumab is present in an amount of about 20-300 mg / mL, 50-300 mg / mL, 100-300 mg / mL, 150-300 mg / mL, 200-300 mg / mL, or 250-300 mg / mL, preferably 50 mg / ml.

[0068] In one embodiment, ofatumumab is formulated in an antibody formulation, where the formulation contains 10-100 mM sodium acetate, 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0.2 mM EDTA, 0.01-0.2% polysorbate 80, and is adjusted to a pH of 5.0-7.0. Preferably, the ofatumumab formulation contains 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, 0.02% polysorbate 80, and is adjusted to a pH of 5.5.

[0069] The preferred dosing regimen for ofatumumab is as follows: A loading dose or 20 mg subcutaneous injection at weeks 0, 1, and 2, followed by A follow-on or maintenance dose of 20 mg administered by subcutaneous injection starting on week 8 of the dosing regimen and continuing every 6 weeks thereafter.

[0070] If an injection of ofatumumab is missed, it should be administered as soon as possible, preferably without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended interval.

[0071] In one embodiment, the ofatumumab formulation is provided in a prefilled syringe or autoinjector, preferably a single dose prefilled syringe or a single dose prefilled autoinjector. Preferably, a prefilled autoinjector designed for sc administration is used.

[0072] In a preferred embodiment, ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each 20 mg / 0.4 mL prefilled pen or syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg ofatumumab and arginine (4 mg), edetate disodium (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg), and water for injection (USP pH 5.5). Hydrochloric acid may be added to adjust the pH.

[0073] In a preferred embodiment, the ofatumumab formulation is for patient self-administration, preferably by subcutaneous injection.

[0074] In a preferred embodiment, the formulation is administered subcutaneously to the abdomen, thigh, or outer upper arm. In a preferred embodiment, the formulation is not administered to pigmented birthmarks, scars, or areas where the skin is tender, bruised, reddened, hard, or not intact.

[0075] In one embodiment, the first injection of the ofatumumab formulation can be administered under the supervision of a medical professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Prior to administration, the pen or prefilled syringe is preferably removed from the refrigerator and allowed to reach room temperature, for example, for about 15-30 minutes. In a preferred embodiment, the ofatumumab formulation of the present invention is a clear to slightly opalescent and colorless to slightly brownish yellow solution available as follows: Injection: Single dose prefilled pen, e.g. 20 mg / 0.4 mL in Sensoready® pen Injection: 20 mg / 0.4 mL in a single-dose prefilled syringe.

[0076] In a preferred embodiment of the present invention, administration of ofatumumab is delayed in patients with active infection, such as COVID-19, until the infection is resolved. Alternatively, ofatumumab can be administered during infection, such as COVID-19 infection. Thus, administration of ofatumumab can be continued during infection, such as COVID-19 infection.

[0077] In another preferred embodiment of the invention, immunoglobulin levels are monitored at the initiation of, during, and after discontinuation of treatment with ofatumumab as clinically indicated until B-cell repletion. Discontinuation of ofatumumab treatment is considered if immunoglobulin levels indicate immunocompromise or if the patient develops serious opportunistic or recurrent infections.

[0078] In one embodiment of the invention, ofatumumab is used in patients who have been treated with a disease-modifying therapy other than ofatumumab, where the prior disease-modifying therapy drug is selected from ocrelizumab, rituximab, fingolimod, teriflunomide, interferon beta, and glatiramer acetate.

[0079] A further subject of the invention is ofatumumab for use in the treatment of pediatric multiple sclerosis, wherein the treatment is a long-term treatment and the serum IgG concentration is maintained within a certain range, said range being essentially the same as in untreated patients.

[0080] In the context of the present invention, a "treatment-naive patient" refers to a pediatric patient diagnosed with MS or clinically isolated syndrome (CIS) who is not receiving a B-cell and / or T-cell inhibitor. In a preferred embodiment, the treatment-naive patient exhibits an IgG concentration in the range of 600-2500 mg / dl.

[0081] Another subject of the invention is ofatumumab for use in the treatment of pediatric multiple sclerosis, in which pediatric patients with reduced serum IgG concentrations are treated.

[0082] Yet another subject of the invention is ofatumumab for use in the treatment of multiple sclerosis, in which pediatric patients are treated having risk factors linked to serum Ig concentrations, in particular serum IgG concentrations.

[0083] In one embodiment of the invention, ofatumumab is not administered to pediatric patients with active HBV infection, particularly those with active HBV infection confirmed by positive Hepatitis B surface antigen [HBsAg] and anti-HBV tests. Ofatumumab may or may not be administered to pediatric patients who are HBsAg negative and Hepatitis B core antibody [HBcAb+] positive or who are carriers of HBV [HBsAg+].

[0084] In another embodiment of the invention, ofatumumab is not administered to pediatric patients with acute or chronic hepatitis A, hepatitis B, hepatitis C, and / or hepatitis E infection.

[0085] In another embodiment of the invention, ofatumumab is not administered to pediatric patients who have received a live or live-attenuated vaccine (including for varicella zoster virus or measles) within 4 weeks prior to the first intended dose of ofatumumab.

[0086] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising administering ofatumumab to a patient in need thereof, wherein the patient is i) weighs a maximum of 40kg; and / or ii) Age is between 5 and 17 years old.

[0087] A further subject of the invention is a process for the manufacture of a medicament for use in the above-mentioned treatment.

[0088] definition The term "treatment" or "treating" can be defined as the application or administration of, for example, ofatumumab, to a patient for the purpose of eliminating, reducing or alleviating the symptoms of a disease, such as multiple sclerosis (MS). In particular, the term "treatment" includes achieving a clinically significant benefit to the patient, for example, achieving a clinically significant reduction in the annual relapse rate when treating RMS. The term further includes preventing the transition to a progressive form of MS.

[0089] The term "patient" preferably refers to a human patient, e.g., a patient having or at risk of having a disorder as described herein. Preferably, the patient is a pediatric patient. In accordance with the present invention, the treatments described herein are suitable for individual patients as well as patient populations.

[0090] The term "pediatric patient" encompasses patients up to 18 years of age, and thus includes adolescents as well as children. Preferably, pediatric patients are aged between 5 and 17 years, more preferably between 10 and under 18 years (i.e., these patients have not yet reached their 18th birthday). More preferably, pediatric patients weigh up to 40 kg. It is even more preferred that pediatric patients weigh at least 25 kg, and more preferably, pediatric patients weigh at least 25 kg and up to 40 kg.

[0091] More preferably, the pediatric patient is aged between 5 and 17 years and weighs a maximum of 40 kg, preferably 25 to 40 kg.

[0092] As used herein, the term "child" refers to an individual between the ages of 5 and 12, and the term "adolescent" refers to an individual between the ages of 13 and less than 18.

[0093] The term "adverse event" (AE) may refer to any undesirable medical occurrence in a patient or clinical study where a subject is administered a medicinal product that does not necessarily have a causal relationship to the treatment. Thus, an adverse event (AE) may be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a medicinal product (investigational product), whether or not it is related to the medicinal product (investigational product).

[0094] RRMS Relapsing-remitting multiple sclerosis (RRMS) can be characterized by relapses, defined as episodes of new neurological deficits or neurological deterioration lasting longer than 24 hours, preferably in the absence of fever or infection.

[0095] During periods of remission, there may be no apparent progression of the disease. At different times, RRMS may be further characterized as either active (with relapses and / or evidence of new MRI activity) or inactive, and either worsening (confirmed increase in disability over a specified period of time following a relapse) or non-worsening. See Lublin, Neurology. 2014 Jul 15;83(3):278-286.

[0096] RMS The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS, and clinically isolated syndrome (CIS).

[0097] Primary progressive MS (PPMS) PPMS may be characterized by a worsening of neurological function (accumulation of disability) from symptom onset without early relapses or remission. PPMS may be further characterized at various time points as either active (with occasional relapses and / or evidence of new MRI activity) or inactive, and either progressing (evidence of disease worsening based on objective measures of change over time, with or without relapses or new MRI activity) or not progressing. See Lublin 2014.

[0098] The experience of each individual with PPMS will be unique. PPMS may have short periods of stable disease with or without relapses or new MRI activity and periods of increased disability with or without new relapses or lesions on MRI.

[0099] Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people diagnosed with RRMS eventually transition to a secondary progressive course in which there is a progressive deterioration of neurological function over time (accumulation of disability). SPMS can be further characterized at various times as either active (with relapses and / or evidence of new MRI activity) or inactive, and either progressing (evidence of disease worsening based on objective measures of change over time, with or without relapses) or not. See Lublin 2014.

[0100] Each individual's experience with SPMS will be unique. SPMS follows relapsing-remitting MS. Disability increases gradually over time with or without evidence of disease activity (relapses or changes on MRI). Occasional relapses and periods of stability can occur in SPMS.

[0101] Siponimod, sold under the trade name Mayzent®, is an oral selective sphingosine-1-phosphate receptor modulator used for multiple sclerosis (MS).

[0102] recurrence Relapse can be defined as a new neurological deficit or an episode of neurological deterioration that preferably lasts for more than 24 hours. In other words, relapse can be considered as a separate episode of neurological dysfunction (also referred to in the art as a "attack", "flare-up", or "exacerbation") that preferably lasts for at least 24 hours. Relapse is usually followed by a period of complete or partial recovery and no progression of symptoms or accumulation of disability (remission).

[0103] The term "Annual Relapse Rate" (ARR) relates to the number of MS relapses per year, specifically the number of MS relapses of the average patient per year. As used herein, the term "average patient" relates to the average behavior of a treated patient population.

[0104] As used herein, B cells may refer to a type of white blood cell of the lymphocyte subtype. B cells function in the humoral immune component of the adaptive immune system by secreting antibodies such as immunoglobulins (e.g., IgG). In addition, B cells may present antigens and secrete cytokines. B cells, unlike T cells and natural killer cells, express a B cell receptor (BCR) on their cell membrane. The BCR allows B cells to bind to specific antigens against which they initiate an antibody response.

[0105] As used herein, T cells may refer to a type of lymphocyte that develops in the thymus. T cells may be distinguished from other lymphocytes by the presence of T cell receptors on the cell surface.

[0106] Clinically isolated syndrome (CIS): Clinically isolated syndrome (CIS) may refer to a single clinical attack of inflammatory demyelinating symptoms in the central nervous system (CNS) suggestive of multiple sclerosis (MS). CIS presentations may be unifocal or multifocal and typically affect the optic nerves, brainstem, cerebellum, spinal cord, or cerebral hemispheres. See Miller et al, Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169.

[0107] Gd+ lesions Gadolinium ("contrast") is a chemical compound that is injected into an individual's veins during an MRI scan. Gadolinium normally cannot pass from the bloodstream to the brain or spinal cord due to the blood-brain barrier. However, during active inflammation in the brain or spinal cord, such as during an MS relapse, the blood-brain barrier is broken down, allowing gadolinium to pass. Gadolinium can then enter the brain or spinal cord and leak into an MS lesion, lighting it up and producing a highlighted spot on the MRI. Such MS lesions are called gadolinium-enhancing lesions or Gd+ lesions.

[0108] T1 and T2 Lesions T1 and T2 refer to the different MRI methods used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time taken between the magnetic pulse and the recording of the image. These different methods are used to detect different structures or chemicals in the central nervous system. T1 and T2 lesion refers to whether a lesion was detected using either the T1 or T2 method. T1 MRI images provide information about current disease activity by highlighting sites of active inflammation. T2 MRI images provide information about disease burden or lesion burden (the total amount of lesion sites, both old and new).

[0109] The term "annualized T2 lesion rate" relates to the number of new or newly enlarging T2 lesions on MRI per year.

[0110] EDSS The Expanded Disability Status Scale (EDSS) is a way to quantify disability in multiple sclerosis and to monitor changes in the level of disability over time.

[0111] The EDSS scale ranges from 0 to 10, with 0.5 unit increments representing higher levels of impairment. Scoring is based on examination by a neurologist.

[0112] EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any assistance and are based on a measure of impairment in the following eight functional systems (FS): Cones (weakness or difficulty moving the limbs) Cerebellum (ataxia, loss of balance, loss of coordination, or tremors) Brain stem (problems with speech, swallowing, and nystagmus) Sensory (numbness or loss of sensation) Bowel and bladder function Visual function (vision problems) Cerebral function (thinking and memory problems) · others.

[0113] A functional system (FS) represents a network of neurons in the brain that is responsible for a specific task. Each FS is scored on a scale from 0 (no impairment) to 5 or 6 (more severe impairment). See Kurtzke JF. Rating Neurologic Impairment in Multiple Sclerosis: An Expanded Disability Status Sclale (EDSS). Neurology. 1983, Nov; 33(11): 1444-52.

[0114] Multiple Sclerosis Impact Scale (MSIS-29). The MSIS-29 version 2 is a 29-item self-administered questionnaire that includes two domains: physical and psychological. Responses are captured on a 4-point ordinal scale ranging from 1 (not at all) to 4 (extremely), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete, and the questions are designed to assess the patient's own view of the impact of MS on their daily life during the past 2 weeks. See 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.

[0115] Ofatumumab: Ofatumumab is a human monoclonal antibody against the CD20 protein. Ofatumumab can specifically bind to both the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab can bind to the CD20 molecule, and the Fc domain mediates immune effector function to cause B cell lysis in vitro. Specifically, ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed, for example, on B cells. Ofatumumab is produced in a mouse NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains, with a molecular weight of approximately 146 kDa.

[0116] Ofatumumab is described in EP1558648B1 and EP3284753B1. Further reference is made to the description in drugbank.ca accession number DB06650 and WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the chemical formula of the protein is 6480 H 10022 N 1742 O 2020 S 44 and the average protein weight is approximately 146100 Da. In the United States, ofatumumab is marketed under the trade name Kesimpta®.

[0117] The metabolic pathway of ofatumumab may be degradation by ubiquitous proteolytic enzymes into small peptides and amino acids. Ofatumumab may be cleared in two ways: a target-independent pathway similar to other IgG molecules, and a target-mediated pathway associated with binding to B cells.

[0118] The half-life of ofatumumab at steady state may be approximately 16 days, especially following repeated subcutaneous administration of 20 mg doses.

[0119] Ofatumumab preferably does not share common clearance pathways with chemicals metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Preferably, ofatumumab is not involved in regulating the expression of drug metabolizing enzymes.

[0120] loading dose A loading dose is an initial dose of a drug, preferably an initial higher dose, that may be given at the beginning of treatment (e.g., DMT) before transitioning to a maintenance dose that is preferably administered at a lower or longer interval than the loading dose.

[0121] Disease Modifying Therapy (DMT) There is still no cure for multiple sclerosis (MS), but several disease-modifying drugs (DMDs) have been approved for MS, hence the term "disease-modifying therapy". In general, DMTs for RMS reduce the frequency and / or severity of relapses. Thus, DMTs are not a cure for RMS patients, but they can reduce the number of relapses and their severity that some have. DMTs include, but are not limited to, treatment with DMDs such as interferon beta, glatiramer acetate, teriflunomide, mitoxantrone, dimethyl fumarate, cladribine, fingolimod, siponimod, ponesimod, alemtuzumab, daclizumab, natalizumab, ofatumumab, ocrelizumab, and rituximab. EXAMPLES

[0122] A Phase 3 Clinical Study Comparing the Efficacy and Safety of Ofatumumab and Siponimod Versus Fingolimod in Pediatric Patients with Multiple Sclerosis The objective and rationale of this study was to demonstrate the efficacy and evaluate the safety / tolerability of ofatumumab and siponimod versus fingolimod in pediatric patients (aged 10 to <18 years) with multiple sclerosis (MS).

[0123] the purpose The primary objective is to demonstrate non-inferiority of ofatumumab and / or siponimod compared with fingolimod, as assessed by annualized relapse rate (ARR), in targeted pediatric MS participants treated for up to two years.

[0124] Secondary objectives specifically include demonstrating the superiority of ofatumumab and / or siponimod compared with historical interferon beta-1a data, as assessed by annualized relapse rate (ARR of confirmed relapse).

[0125] Secondary objectives further include: - To examine the effect of ofatumumab and / or siponimod versus fingolimod on the number of new or newly enlarging T2 lesions, as assessed by the number of new or newly enlarging T2 lesions on MRI per year (annualized T2 rate) - To examine the effect of ofatumumab and / or siponimod versus fingolimod on neurofilament light chain (NfL) concentrations, as assessed by NfL serum concentrations. - To evaluate the pharmacokinetic (PK) properties of ofatumumab and siponimod (and their metabolite M17) in pediatric patients with MS, as assessed by plasma concentrations of ofatumumab and siponimod (and their metabolite M17). - To assess immunogenicity (ofatumumab) as assessed by the proportion of participants with anti-ofatumumab antibodies - To assess the safety and tolerability of ofatumumab and siponimod as assessed by adverse events, Columbia-Suicide Severity Rating Scale (C-SSRS), ECG, laboratory and ophthalmologic data, pulmonary function tests, and vital signs.

[0126] research design The study will randomize approximately 180 participants in a 1:1:1 randomization allocation ratio (60 participants randomized to sc ofatumumab, 60 to oral siponimod, and 60 to oral fingolimod), with a target enrollment of at least 5 participants with a body weight (BW) ≤40 kg and at least 5 participants aged 10-12 years in each of the ofatumumab and siponimod treatment arms.

[0127] This study consists of three parts: - Core portion including screening period and double-blind treatment period - Extension portion including transition period with double-blind treatment - Followed by an open-label treatment period - Post-treatment follow-up section

[0128] analysis Efficacy assessment included evaluation of the following: - MS relapse - EDSS -MRI - Neurofilament light chain (NfL) serum concentration - Symbol Digit Modalities Test (SDMT) - B cells

[0129] The primary endpoint of the study was the annualized relapse rate (ARR), defined as the mean number of confirmed relapses per year (i.e., the total number of confirmed relapses divided by the total number of days on study, multiplied by 365.25).

[0130] Secondary objective endpoints included annualized relapse rate (ARR of confirmed relapse), number of new or newly enlarging T2 lesions on MRI per year (annualized T2 lesion rate), neurofilament light chain (NfL) serum concentrations, plasma concentrations of ofatumumab and siponimod and (metabolite M17), proportion of participants with anti-ofatumumab antibodies, adverse events, Columbia-Suicide Severity Rating Scale (C-SSRS), ECG, laboratory and ophthalmologic data, pulmonary function tests, and vital signs.

[0131] ARR will be analyzed using a Bayesian primary analysis model including only confirmed recurrences.

[0132] Secondary endpoint analyses will include efficacy and / or pharmacodynamic endpoints, e.g., annualized rate of new / newly enlarging T2 lesions, compared with historical interferon data.

[0133] PK / PD Relationship of Ofatumumab and Siponimod A preliminary PK / PD analysis of absolute B cell counts will be performed if deemed relevant following evaluation of the primary outcome of the study.

[0134] No evidence of disease activity The proportion of participants with no clinical and MRI disease activity (no evidence of disease activity; NEDA-3) will be analyzed cross-sectionally at years 1 and 2 in logistic regression models adjusted for treatment, T2 lesion volume, and age at baseline. NEDA-3 will be defined as no 3mCDW, no confirmed MS relapse, and no new or enlarging T2 lesions on any MRI scan compared to baseline. Analyses will consider only participants followed up to the time of analysis assessment (e.g., only participants followed for ≥12 months at the 12-month assessment of disease freedom, etc.). Intermediate missing values ​​(e.g., due to missing MRI assessments) will be considered as not free of disease activity.

[0135] Worsening disability lasting 3 months 3-month confirmed disability worsening (3mCDW) is defined as an increase from baseline in EDSS that is sustained for at least 3 months. This means that after a scheduled or unscheduled visit where the patient meets the criteria for disability worsening at that time, all EDSS assessments (scheduled or unscheduled) must also meet the criteria for worsening until the worsening ("event") can be confirmed at or after the first scheduled visit, which occurs 3 months after the onset of the exacerbation. All participants who do not experience a 3mCDW event during the study are censored (censoring is also done for participants who had a "tentative" disability worsening that could not be confirmed due to early discontinuation or any other reason). Censoring time is defined as the time from the first dose to the last available EDSS assessment.

[0136] Further evaluated are target-reported outcomes including: - Pediatric Health Utility 9D (CHU9-D) - Pediatric Quality of Life Inventory (PedsQL) - PedsQL Multidimensional Fatigue Scale

[0137] The invention further features the following embodiments. 1.i) weighs a maximum of 40kg; and / or ii) Ofatumumab for use in the treatment or prevention of multiple sclerosis in patients between 5 and 17 years of age.

[0138] 2. Ofatumumab for use in the treatment or prevention of multiple sclerosis in patients weighing up to 40 kg.

[0139] 3.i) weighs a maximum of 40 kg; and ii) Ofatumumab for use in the treatment or prevention of multiple sclerosis in patients between 5 and 17 years of age.

[0140] 4. Ofatumumab for use according to any one of the preceding embodiments, wherein said patient is a pediatric patient.

[0141] 5. Ofatumumab for use according to any one of the preceding embodiments, wherein the patient is aged between 10 and 17 years.

[0142] 6.a) ofatumumab is administered as a loading dose at weeks 0, 1, and 2 of the dosing schedule; b) ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is administered according to said dosing regimen, wherein ofatumumab is administered as a maintenance dose starting on week 8 of said dosing regimen and continuing every 6 weeks thereafter.

[0143] 7. Ofatumumab for use according to embodiment 6, wherein said loading dose and said maintenance dose comprise a sc injection of 20 mg ofatumumab.

[0144] 8. Ofatumumab for use according to any one of the preceding embodiments, wherein said treatment or prevention achieves B-cell depletion below a threshold of 8 cells per microliter.

[0145] 9. Ofatumumab for use according to any one of the preceding embodiments, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS).

[0146] 10. Ofatumumab for use according to any one of the preceding embodiments, wherein the multiple sclerosis is clinically isolated syndrome (CIS).

[0147] 11. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to fingolimod in terms of annualized relapse rate.

[0148] 12. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to fingolimod in maintaining said annualized relapse rate, preferably in reducing said annualized relapse rate.

[0149] 13. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to interferon in terms of annualized relapse rate.

[0150] 14. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to interferon in maintaining said annual relapse rate, preferably in reducing said annual relapse rate.

[0151] 15. Ofatumumab for use according to embodiment 13 or 14, wherein the interferon is interferon beta, in particular interferon beta selected from the group consisting of interferon beta 1a, interferon beta 1b, and pegylated forms thereof.

[0152] 16. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to siponimod in terms of annualized relapse rate.

[0153] 17. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to siponimod in maintaining said annualized relapse rate, preferably in reducing said annualized relapse rate.

[0154] 18. Ofatumumab for use according to any one of the preceding embodiments, wherein said annualized relapse rate for the average patient is less than 0.67.

[0155] 19. Ofatumumab for use according to any one of the preceding embodiments, wherein said annualized relapse rate for the average patient is at most 0.12.

[0156] 20. Ofatumumab for use according to any one of the preceding embodiments, wherein the ARR is reduced by at least 26% compared to interferon, more preferably wherein the reduction in ARR is at least 63%, more preferably at least 78%, particularly at least 82%.

[0157] 21. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is used in a patient who has been treated with a disease-modifying therapy other than ofatumumab, said prior disease-modifying therapy drug being selected from ocrelizumab, rituximab, fingolimod, teriflunomide, interferon beta, and glatiramer acetate.

[0158] 22. Ofatumumab for use according to any one of the preceding embodiments, wherein the treatment is a long-term treatment.

[0159] 23. Ofatumumab for use according to any one of the preceding embodiments, wherein premedication is administered to said patient before the first dose of ofatumumab is administered.

[0160] 24. Ofatumumab for use according to any one of the preceding embodiments, wherein said premedication comprises acetaminophen, an antihistamine, and / or a steroid.

[0161] 25. Ofatumumab for use according to any one of the preceding embodiments, wherein said premedication is administered 30 to 60 minutes prior to ofatumumab injection.

[0162] 26. Ofatumumab for use according to any one of the preceding embodiments, wherein premedication is not administered prior to the first dose of ofatumumab.

[0163] 27. Ofatumumab for use according to any one of the preceding embodiments, wherein patients acutely or previously infected with COVID-19 are treated.

[0164] 28. Ofatumumab for use according to any one of the preceding embodiments, wherein said treatment is continued during COVID-19 infection.

[0165] 29. Ofatumumab for use according to any one of the preceding embodiments, wherein said treatment is interrupted during COVID-19 infection and continued after said infection has been resolved.

[0166] 30. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to fingolimod in terms of annualized T2 disease rate.

[0167] 31. Ofatumumab for use according to any one of the preceding embodiments, wherein the annualized T2 lesion rate is reduced compared to fingolimod.

[0168] 32. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to fingolimod in terms of neurofilament light chain (NfL) serum concentrations.

[0169] 33. Ofatumumab for use according to any one of the preceding embodiments, wherein neuroaxonal damage as measured by NfL serum concentration is reduced compared to fingolimod.

[0170] 34.Ofatumumab meets the following criteria in terms of safety and tolerability compared to fingolimod: - frequency and severity of treatment-emergent adverse events (TEAEs); - Columbia-Suicide Severity Rating Scale (C-SSRS), - 12-lead ECG, - laboratory and ophthalmological data, - Pulmonary function tests, ofatumumab for use according to any one of the preceding embodiments, wherein the ofatumumab is non-inferior as determined by at least one of the following:

[0171] 35. Ofatumumab for use according to any one of the preceding embodiments, wherein the mean number of Gd-enhancing T1 lesions per year is reduced compared to fingolimod.

[0172] 36. Ofatumumab for use according to any one of the preceding embodiments, wherein the risk of 3-month sustained disability worsening (3mCDW) is reduced compared to fingolimod.

[0173] 37. Ofatumumab for use according to any one of the preceding embodiments, wherein the risk of 6-month sustained disability worsening (6mCDW) is reduced compared to fingolimod.

[0174] 38. Ofatumumab for use according to any one of the preceding embodiments, wherein ofatumumab is non-inferior to fingolimod in terms of immunogenicity and endogenous anti-drug antibodies (ADA).

[0175] 39. A method for treating multiple sclerosis, the treatment comprising administering ofatumumab to a patient in need thereof, wherein the patient is i) weighs a maximum of 40kg; and / or ii) The above method, wherein the age is 5 to 17 years old.

[0176] 40. A method for producing a medicament for use in the treatment of multiple sclerosis, comprising: i) weighs a maximum of 40kg; and / or ii) The above method, wherein the age is 5 to 17 years old.

Claims

1. i) weighs up to 40 kg; and / or ii) are between 5 and 18 years of age; A pharmaceutical composition comprising ofatumumab for use in the treatment of multiple sclerosis in a pediatric patient.

2. 1. A pharmaceutical composition comprising ofatumumab for use in the treatment of multiple sclerosis in a pediatric patient weighing up to 40 kg.

3. i) weighs a maximum of 40 kg; and ii) are between 5 and 18 years of age; A pharmaceutical composition comprising ofatumumab for use in the treatment of multiple sclerosis in a pediatric patient.

4. a) ofatumumab is administered as a loading dose at weeks 0, 1, and 2 of the dosing regimen; b) ofatumumab is administered according to a dosing regimen in which ofatumumab is administered as a maintenance dose starting at week 8 of said dosing regimen and continuing every 6 weeks thereafter; The pharmaceutical composition according to any one of claims 1 to 3.

5. 5. The pharmaceutical composition of claim 4, wherein the loading dose and the maintenance dose comprise a s.c. injection of 20 mg ofatumumab.

6. a) 20 mg ofatumumab is administered during a loading dose regimen at weeks 0, 1, and 2 of the dosing regimen; b) 20 mg ofatumumab is administered during a maintenance dosing regimen starting on week 8 of the dosing regimen and continuing every 6 weeks thereafter; The pharmaceutical composition according to claim 3.

7. The pharmaceutical composition of claim 6, wherein ofatumumab is administered by subcutaneous administration.

8. A pharmaceutical composition described in claim 1, 2, 3 or 6, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.

9. The pharmaceutical composition described in claim 1, 2, 3 or 6, wherein the patient is aged 10 years or older but less than 18 years.

10. The administration regimen i) when the patient reaches a weight of more than 40 kg; or ii) When the patient reaches the age of 18 years and a weight of more than 40 kg; 7. The pharmaceutical composition of claim 6, which is switched to a dose of 20 mg every four weeks.

11. 10. The pharmaceutical composition of claim 1, 2, 3, or 6, wherein ofatumumab is non-inferior to fingolimod, siponimod, or interferon beta in maintaining annualized relapse rate.

12. The pharmaceutical composition described in claim 11, wherein ofatumumab is non-inferior to fingolimod, siponimod, or interferon beta in reducing the annual relapse rate.

13. 10. The pharmaceutical composition of claim 1, 2, 3 or 6, wherein the average patient annual relapse rate is less than 0.

67.

14. The pharmaceutical composition of claim 13, wherein the average patient annual recurrence rate is up to 0.

12.

15. A pharmaceutical composition described in claim 1, 2, 3 or 6, wherein ARR is reduced by at least 26% compared to interferon.

16. The pharmaceutical composition of claim 15, wherein the reduction in ARR is at least 63%, at least 78%, or at least 82%.

17. 10. The pharmaceutical composition of claim 1, 2, 3, or 6, wherein ofatumumab is used in patients who have been previously treated with a disease-modifying therapy other than ofatumumab, and the previous disease-modifying therapy drug is selected from ocrelizumab, rituximab, fingolimod, teriflunomide, interferon beta, and glatiramer acetate.

18. 10. The pharmaceutical composition of claim 1, 2, 3 or 6, wherein the treatment is a long-term treatment.

19. The pharmaceutical composition of claim 1, 2, 3 or 6, wherein a patient acutely or previously infected with COVID-19 is treated.

20. 20. The pharmaceutical composition of claim 19, wherein the treatment is continued during COVID-19 infection.

21. Ofatumumab is compared to fingolimod in terms of annualized T1 lesion rate, in terms of T2 lesion rate, in terms of neurofilament light chain (NfL) serum concentrations, in terms of immunogenicity and endogenous anti-drug antibodies (ADA), and / or in terms of safety and tolerability, according to the following criteria: - frequency and severity of treatment-emergent adverse events (TEAEs); -Columbia-Suicide Severity Rating Scale (C-SSRS), -12 lead ECG, - laboratory and ophthalmological data, - pulmonary function tests, - vital signs.