Primary endpoint of opicinumab for relapsing MS not met in AFFINITY trial

Opicinumab did not meet the primary or key secondary efficacy endpoints in patients with relapsing MS. Subgroup analyses demonstrated potential benefits of opicinumab for older patients, patients with longer disease duration, patients with higher Expanded Disability Status Scale (EDSS) scores, and patients who received dimethyl fumarate as a disease-modifying therapy (DMT) [1].

Opicinumab is a human monoclonal antibody, blocking LINGO-1, a leucine-rich repeat protein. The SYNERGY trial (NCT01864148) –a previous opicinumab study– did not demonstrate a significant improvement of disability following opicinumab treatment, compared with placebo in patients with relapsing MS [2]. However, further analysis showed that a subgroup of patients, defined by disease duration, magnetisation transfer ratios, and diffusion tensor imaging-radial diffusion in pre-existing T2 lesions, may benefit from opicinumab. Therefore, the current phase 2 AFFINITY trial (NCT03222973) enrolled patients with similar imaging characteristics as those who showed a promising therapy response, to assess the efficacy and safety of opicinumab. The population was expanded with patients who did not have this favourable imaging profile. Patients were randomised to opicinumab (750 mg, intravenous, every 4 weeks; n=120) as add-on therapy, or placebo (n=120), next to background DMT. The primary endpoint was the Overall Disability Response Score (ODRS) at week 72. Prof. Peter Calabresi (Johns Hopkins University, MD, USA) presented the results.

ODRS scores did not demonstrate a statistical difference between patients receiving opicinumab (adjusted mean 0.11) and placebo (adjusted mean -0.04) at week 72 (difference 0.15; P=0.148). Similarly, the key secondary endpoint –confirmed disability improvement (CDI) at week 12– was not met. Prespecified subgroup analyses showed larger efficacy signals of opicinumab in patients >40 years, patients with EDSS scores ≥3, patients with a disease duration ≥6 years, and patients from the imaging core group. However, the EDSS score ≥3 subgroup was the only subgroup that demonstrated a significant benefit of opicinumab compared with placebo (ODRS difference 0.36; P=0.025). Patients who were on dimethyl fumarate as primary DMT showed numerically higher improvements of opicinumab compared with placebo (ODRS difference 0.31; P=0.105) than interferon beta users (ODRS difference 0.02), or natalizumab users (ODRS difference 0.13). Differences between imaging subgroups and DMT subgroups on pre-defined MRI endpoints were small and non-significant. The safety analysis did not reveal new safety issues of opicinumab and the results were consistent with the known safety profile of the drug.

Prof. Calabresi argued that, despite the non-significant results of the trial, further analyses of the AFFINITY and SYNERGY datasets regarding patient population and MRI biomarkers may help in the design of future trials aiming to enhance remyelination in patients with MS.

1. Calabresi PA, et al. Efficacy and Safety of Opicinumab in Participants with Relapsing Multiple Sclerosis: A Randomized, Placebo-Controlled Phase 2 Trial (AFFINITY Part 1). OP147, ECTRIMS 2021 Virtual Congress, 13–15 October.
2. Cadavid D, et al. Lancet Neurol. 2019;18(9):845–856.

 

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Posted on 9 December 202115 February 2024