Rapid and Sustained Efficacy of Subcutaneously Administered Cemdisiran Without Complete Complement Blockade in Patients with Generalized Myasthenia Gravis (gMG): Primary Efficacy and Safety Results from the Phase Three NIMBLE Trial
Tuan Vu1, Ali Habib2, Saiju Jacob3, Renato Mantegazza4, Hiroyuki Murai5, John Vissing6, Aziz Shaibani7, Todd Levine8, Yessar Hussain9, Andreas Meisel10, Rodrigo Pavani11, Umesh Chaudhari11, Neda Jalali11, Michelle DeVeaux11, Karoline A. Meagher11, Steven Sherman11, Dipti Pawaskar11, Amal Souttou11, Lorah Perlee11, James Howard12
1University of South Florida, 2University of California, Irvine, 3University Hospitals Birmingham NHS Foundation Trust, 4Fondazione IRCCS Istituto Neurologico Carlo Besta, 5International University of Health and Welfare, 6University of Copenhagen, 7Nerve and Muscle Center of Texas, 8Bob Bové Neuroscience Institute, 9Austin Neuromuscular Center, 10Charité Universitätsmedizin Berlin, 11Regeneron Pharmaceuticals, Inc., 12University of North Carolina, Chapel Hill
Objective:
Report on phase 3 NIMBLE trial (NCT05070858) comparing subcutaneous cemdisiran or pozelimab plus cemdisiran with placebo in patients with gMG.
Background:
gMG is characterized by complement activation at the neuromuscular junction. Cemdisiran (a siRNA which reduces hepatic-C5 expression) and pozelimab (an anti-C5 monoclonal antibody) were evaluated as monotherapies and in combination to determine the level of terminal complement inhibition required for maximal efficacy.
Design/Methods:
NIMBLE is a randomized, double-blind, placebo-controlled, 4 arm trial (cemdisiran 600mg Q12W, pozelimab 200mg Q4W [to test contribution of components of combination], combination both 200mg Q4W, and placebo) in 284 AChR+ and/or LRP4+ adults with gMG. Efficacy (modified intention-to-treat population, n=239) was assessed by change in Myasthenia Gravis Activities of Daily Living (MG-ADL) at week 24 (primary) and by Quantitative Myasthenia Gravis (QMG) change and ≥3-/≥5-point MG-ADL/QMG reductions (secondary). Safety was evaluated in 277 patients.
Results:
NIMBLE met its primary and key secondary endpoints. In cemdisiran (n=64) and combination arms (n=67), least squares (LS) mean (SD) change in MG-ADL from baseline to Week 24 was -4.5 (0.4) and -4.0 (0.4), with placebo-adjusted differences of -2.3 (P=0.0005) and -1.7 (P=0.0086); placebo adjusted difference in QMG was –2.8 (0.9) for cemdisiran, -1.9 (0.9) combination. Patients achieved MG-ADL ≥3-point reductions in 76.6% (cemdisiran), 65.7% (combination), 44.1% (placebo) while QMG ≥5-point reductions occurred in 48.4% (cemdisiran), 35.8% (combination), and 19% (placebo). Cemdisiran monotherapy achieved 76.6% and combination 99.6% terminal complement inhibition. Pozelimab monotherapy was not significant vs placebo, as expected. TEAEs occurred in 69.2% (cemdisiran), 81.3% (combination), and 77.1% (placebo). No serious infections, meningococcal infections, or deaths occurred during double-blind treatment period (DBTP). Two deaths (pneumonia [cemdisiran], septic shock [combination]) occurred post-DBTP.
Conclusions:
Although both arms demonstrated rapid and sustained improvements versus placebo and were generally well‑tolerated in patients with gMG, quarterly SC dosing of cemdisiran achieved efficacious outcomes without complete complement blockage.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.