Efficacy and Safety of Vemircopan in Generalized Myasthenia Gravis: A Randomized Clinical Trial.

IMPORTANCE

Inhibition of terminal complement component 5 has proven effective in acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG) but requires intravenous or daily subcutaneous administration and is associated with an increased meningococcal infection risk. Targeting the complement alternative pathway (AP) may offer similar benefits while sparing the classical and lectin pathways, preserving some immune responses against infection.

OBJECTIVE

To evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan, an oral, selective factor D inhibitor that blocks AP-mediated complement activation and amplification, in adults with AChR-Ab+ gMG.

DESIGN, SETTING, AND

PARTICIPANTS

This double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial was conducted between April 14, 2022, and April 3, 2024, at 60 sites across 8 countries. Adults with AChR-Ab+ gMG, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 5 or greater, and Myasthenia Gravis Foundation of America classes II through IV classification were eligible for inclusion. Data were unblinded in June 2024; final analysis was completed October 2024.

INTERVENTION: Randomization 2:1:2 to twice-daily oral vemircopan, 180 mg or 120 mg, or placebo.

MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of participants achieving a 2-point or greater reduction in MG-ADL total score from baseline for 4 consecutive weeks, without rescue therapy, during the 8-week, double-blind primary evaluation period. Secondary end points were change from baseline to week 8 in MG-ADL total score, Quantitative Myasthenia Gravis total score, and Neurological Disorders Fatigue questionnaire score.

RESULTS

Of 99 individuals screened, 70 met eligibility criteria, and 29 were excluded. Of 70 participants randomized (vemircopan, 180 mg: n = 28; vemircopan, 120 mg: n = 14; placebo: n = 28), 38 participants (54%) were female; mean (SD) age at diagnosis was 45.4 (18.5) years. The proportion of participants achieving the primary end point did not differ significantly between placebo (18 of 28 [64%]; 90% CI, 47%-79%) and either vemircopan group (180 mg: 16 of 28 [57%]; 90% CI, 40%-73%; 120 mg: 8 of 14 [57%]; 90% CI, 33%-79%). No significant differences were observed for the secondary end points. No cases of meningococcal infection were reported; 1 participant died due to hepatic failure and 1 discontinued study treatment due to herpes simplex meningitis.

CONCLUSIONS AND RELEVANCE: In this double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial, vemircopan did not meet the prespecified threshold for efficacy, and consequently, the study was terminated.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05218096.