Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis

Abstract

ObjectiveTo assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).MethodsPatients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.ResultsThe cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1–4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.ConclusionImaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.Classification of evidenceThis study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Beyond Randomized Clinical Trials: Use of External Controls

“…72 Hence, trials to test the efficacy and safety of new drugs in the pediatric MS population should make efficient use of prior knowledge about these drugs (e.g., extrapolating from existing data in the adult population) and also require innovative and efficient trial designs (e.g., adaptive designs) in order to minimize the number of participants and of procedures, consistent with good trial design. 73 The new compound under investigation, ofatumumab, is a B-cell therapy developed for patients with MS. 74 It is a potent fully human monoclonal antibody that is injected subcutaneously at doses of 20 mg. A phase III clinical program with two large double-blinded RCTs in patients with adult-relapsing MS has recently been completed. Both trials met their primary end points, and it is planned to initiate a pediatric MS trial in 2020.…”

Ofatumumab in post‐transplantation recurrence of focal segmental glomerulosclerosis in a child

“…As mentioned previously, the direct action of ofatumumab on podocytes is unknown . However, it is thought that ofatumumab may bind with more affinity to the CD 20 receptor, leading to improved complement‐dependent cytotoxicity . Compared to rituximab, ofatumumab has a slower rate of dissociation, which may make it more effective in certain patients …”

“…7 However, it is thought that ofatumumab may bind with more affinity to the CD 20 receptor, leading to improved complement-dependent cytotoxicity. [11][12][13] Compared to rituximab, ofatumumab has a slower rate of dissociation, which may make it more effective in certain patients. 18 Ofatumumab was first reported as a potential treatment for nephrotic syndrome after Basu et al noticed that a patient with CLL and SRNS treated with ofatumumab achieved remission of the SRNS.…”

“…The exact mechanism of its action is unknown. It is hypothesized that, compared to rituximab, ofatumumab's structure improves complement‐dependent cytotoxicity by avidly binding to the CD 20 receptor . Wang et al were the first to report the use of ofatumumab in post‐transplant FSGS .…”

“…It is hypothesized that, compared to rituximab, ofatumumab's structure improves complement-dependent cytotoxicity by avidly binding to the CD 20 receptor. [11][12][13][14] Wang et al were the first to report the use of ofatumumab in post-transplant FSGS. 11,12,15 Others have described their use of this medication for treatment of FSGS recurrence after transplantation.…”