Phase 3 NIMBLE Trial to Test Effects of Pozelimab and Cemdisiran in Myasthenia Gravis

Author(s):

Key Takeaways

The NIMBLE trial assesses pozelimab and cemdisiran for generalized myasthenia gravis, involving 235 patients in a multinational, randomized, double-blind study.
Primary endpoint is the change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) score over 24 weeks, with secondary outcomes including other MG-related scores and safety measures.
Prior phase 2 studies in paroxysmal nocturnal hemoglobinuria showed the combination was well-tolerated, with no severe treatment-emergent adverse events.

Pozelimab and cemdisiran work together to block the complement pathway, which plays a key role in gMG, using two different approaches—one suppresses liver production of a key protein, while the other targets it directly with antibodies.

Saiju Jacob, MD, DPhil, MBBS, FRCP

Investigators will assess the therapeutic potential of a combination of pozelimab (Regeneron), a monoclonal antibody inhibitor to C5, and cemdisiran, an N-acetylgalactosamine-conjugated small interfering RNA, in an ongoing phase 3 trial of patients with myasthenia gravis (MG), dubbed NIMBLE (NCT05070858). The study, which began enrolling patients in 2021, is expected to include approximately 235 patients with symptomatic generalized MG.¹

Presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, the multinational, randomized, double-blind trial includes patients with clinically confirmed generalized MG who are seropositive for anti-acetylcholine receptor (AChR) or anti-lipoprotein receptor-related protein 4 (LRP4) antibodies. NIMBLE is comprised of a 24-week double-blind treatment period, 28-week extension treatment period (ETP), 68-week open-lable treatment period, and 52-week off-treatment follow up period.

Led by Saiju Jacob, MD, DPhil, MBBS, FRCP, a consultant neurologist at the University of Birmingham, patients will be randomly assigned to one of 4 treatment groups. These include a combination regimen of pozelimab and cemdisiran for the entirety of the study, cemdisiran monotherapy, pozelimab monotherapy in the double-blind period followed by combination in the ETP, and placebo in the double-blind period followed by combination or cemdisiran in the ETP and open-label extension. The study will use change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, an assessment of functional impairment and disability, as the primary end point, over a 24-week period.

The study also has several notable secondary outcomes, including change in Quantitative Myasthenia Gravis score, proportion of patients responding to either MG-ADL or QMG, and change in the Myasthenia Gravis Composite total score. Investigators will also observed concentrations of total complement C5 in plasma, safety, incidence of anti-drug antibodies, and changes in total complement hemolysis activity assay over time. Above all, the study looks to see whether pozelimab and cemdisiran are effective when used in combination as well as when used as a monotherapy for patients with generalized MG.

To be included in the study, patients must have MG-ADL scores of at least 6 at screening, with ocular items not contributing more than 50% of MG-ADL total score. Patients may also be on immunosuppressive therapy (IST); however, these patients are not anticipated to have IST dosage changed before randomization or during the double-blind period. Those with an antibody profile that is only positive for muscle specific tyrosine kinase (MuSK), as well as those with a history of thymectomy or malignant thymoma, are excluded from the study.

Prior to NIMBLE, the combination of pozelimab and cemdisiran was previously tested in a phase 2 study (NCT04811716) of paroxysmal nocturnal hemoglobinuria (PNH), a rare autoimmune condition that can sometimes occur together with MG. In the study, patients (n = 24) were randomly assigned 1:1 to either sucbtuaneous cemdisiran 200 mg every 4 weeks plus pozelimab 400 mg at a frequency of either Q4W (arm 1) or every 2 weeks (Q2Q; arm 2). Published in 2023, the trial featured a screening period, a 28-week open-label treatment period, an optional open-label extension (52 weeks), and a safety follow-up period (52 weeks).²

Overall, the combination of pozelimab and cemdisiran was generally well tolerated in patients with PNH, regardless of treatment arm. Overall, 83.3% of treated patients maintained adequate control of hemolysis, most maintaining normalization of lactate dehydrogenase with 75% achieving hemoglobin stabilization during the open-label treatment period. In the study, there were no serious/severe treatment-emergent adverse events considered related to the study treatment, as well as no meningococcal infections, thrombotic events, or deaths.

Click here for more coverage of AANEM 2024.

REFERENCES
1. Jacob S, Chaudhari U, Perlee L, et al. Pozelimab and cemdisiran combination therapy in patients with myasthenia gravis: phase 3 NIMBLE trial design. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA. ABSTRACT 216
2. Jang JJ, Wong R, Pavani R, et al. A PHASE 2, RANDOMIZED TRIAL EVALUATING THE SAFETY AND EFFICACY OF POZELIMAB AND CEMDISIRAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA. Hemasphere. 2023;7:e0181707. doi: 10.1097/01.HS9.0000970032.01817.07