Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study

Abstract

Objective: To 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).

Methods: Patients (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.

Results: The 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.

Conclusion: Imaging 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 evidence: This 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.

Trial registration: ClinicalTrials.gov NCT01457924.

Figure 1. Study design

Screening was performed up to 6 weeks before randomization. After completion (or premature discontinuation) of the 24-week treatment phase, patients entered the 24-week follow-up, which assessed patient safety and B-cell repletion. Thereafter (week 48 onwards), individual patients whose CD19+ B-lymphocyte counts remained below the LLN and who did not start a DMT, entered the IFU period. CD = conditioning dose; PBO = placebo; q4w = every 4 weeks; q12w = every 12 weeks.

Figure 2. Efficacy and pharmacodynamics

(A) Primary efficacy outcome measure: mean (95% confidence interval) cumulative number of GdE T1 lesions over time (all evaluable scans dataset). (B) New lesion evolution (post hoc): mean number of new GdE T1 lesions at different MRI time points. From week 8 through 24, the appearance of new GdE T1 lesions was very low at doses of ≥30 mg every 12 weeks. (C) Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups. (A) Faster repletion time (of ≈6 months) was noted for the placebo group, who received a single ofatumumab 3 mg dose at week 12 (and in whom 32% did not deplete). Of those patients whose B cells had repleted by the end of the study, the time to repletion appeared to generally be longer in the 60-mg ofatumumab dose groups compared with the other ofatumumab dose groups. There were no signs of B-cell repletion during the 4-week interdosing interval with the every 4 weeks regimen. Some B-cell repletion was seem. GdE = gadolinium-enhancing; LLN = lower limit of normal; q4w = every 4 weeks; q12w = every 12 weeks.