Novel anti-CD20 monoclonal approved in Canada for MS


Ofatumumab (Kesimpta), a new anti-CD20 monoclonal antibody, has received approval from Health Canada for the treatment of relapsing-remitting multiple sclerosis (RRMS) patients with active disease defined by clinical and imaging features. In clinical trials, active disease was defined as at least one relapse or one Gd-enhancing lesion in the previous year.

The recommended dose is 20 mg subcutaneously. Treatment is administered as a loading dose (20 mg in weeks 0, 1 and 2) followed by monthly 20-mg injections starting at week 4 using a pre-filled Sensoready pen. The preferred injection sites are the abdomen, thigh or upper arm. Patients should be instructed to take the medication out of the refrigerator 15-30 minutes before injecting. Prior to initiation, patients must be screened for hepatitis B and undergo quantitative serum immunoglobulin testing. Female patients should be advised to use contraception during treatment and for six months after the last dose.

Approval of ofatumumab was based on the results of the phase III ASCLEPIOS I and II trials (Hauser et al. N Engl J Med 2020;383:546-557). The studies compared ofatumumab 20 mg every four weeks versus teriflunomide 14 mg/day in 1882 relapsing MS patients. About 40% of subjects were previously untreated. The median time on treatment was 1.6 years; about 30% were on trial for more than two years.

Ofatumumab was associated with a significant reduction in the annualized relapse rate versus teriflunomide. ARR was 0.11 with ofatumumab versus 0.22 for teriflunomide in ASCLEPIOS I, and 0.10 vs. 0.25 in ASCLEPIOS II; the relative reductions in ARR were 51% and 58%, respectively. The proportion of patients with 6-month confirmed disability progression was 8.1% with ofatumumab versus 12.0% with teriflunomide (pooled), a significant 32% relative reduction. The number of Gd+ lesions per scan was 94-97% lower with ofatumumab versus teriflunomide. The number of new/enlarging T2 lesions per year was 82-85% lower with ofatumumab versus teriflunomide. There was no significant difference between the two treatments in the annual rate of brain volume loss (-0.28% vs. -0.35%). Serum neurofilament-light chain concentrations were 26-27% lower at month 12 and 23-24% lower at month 24 with ofatumumab versus teriflunomide.

The most common adverse events with ofatumumab included injection reactions, headache, upper respiratory tract infection and urinary tract infection. The rate of serious infections was 2.5% with ofatumumab and 1.8% with teriflunomide. The most common cause of discontinuation in ofatumumab-treated patients was low IgM (3.3%), defined as 10% below the lower limit of normal (LLN). The mean decrease in IgM was 4.3% at 48 weeks. The product label includes precautions for hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML).

Ofatumumab is a fully human anti-CD20 MAb, in contrast to rituximab (chimeric) and ocrelizumab (humanized). It binds specifically to a distinct CD20 epitope and induces cell lysis primarily through complement-dependent cytotoxicity (CDC). The half-life is about 15 days in men and 17 days in women. Following administration of ofatumumab, B cells are depleted to below LLN in 78% of patients at one week and 95% of patients at two weeks. The median time to B-cell repletion (>LLN in >50% of patients) is 24-36 weeks after the last dose.

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