Cemdisiran Shows Efficacy for Generalized Myasthenia Gravis in Phase III Trial
USA: The investigational siRNA therapy cemdisiran met both its primary and a key secondary endpoint in the phase III NIMBLE trial for generalized myasthenia gravis. The treatment was effective whether used alone or in combination with the C5 antibody pozelimab, supporting its potential as a promising therapeutic option.
A multinational research team led by Tuan Vu conducted the NIMBLE trial to assess the clinical value of targeting complement component 5 (C5), a key driver of disease pathology in antibody-positive generalized myasthenia gravis (gMG). In this autoimmune condition, antibodies—particularly against acetylcholine receptors—trigger complement activation, leading to neuromuscular junction damage and muscle weakness. The study, published in The Lancet, explored whether silencing C5 production through small interfering RNA (siRNA) could improve patient outcomes, either as a standalone therapy or alongside complement inhibition with pozelimab.
The phase 3, randomized, double-blind, placebo-controlled trial was carried out across 86 centres in 13 countries. It enrolled adults with confirmed generalized myasthenia gravis who tested positive for anti-acetylcholine receptor or anti-LRP4 antibodies and had clinically meaningful symptom burden, defined by a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least six. Participants were randomly assigned to receive cemdisiran alone every 12 weeks, pozelimab alone every four weeks, a combination of both agents, or placebo, all administered subcutaneously over 24 weeks.
The findings of the trial were as follows:
- Cemdisiran treatment led to a significant improvement in disease symptoms in patients with generalized myasthenia gravis.
- At 24 weeks, the reduction in MG-ADL scores was greater with cemdisiran compared to placebo.
- The combination of cemdisiran with pozelimab also resulted in meaningful symptom improvement.
- The degree of benefit was slightly higher with cemdisiran monotherapy than with combination therapy.
- Findings support that siRNA-mediated inhibition of complement activity can produce clinically meaningful symptom relief.
- Cemdisiran showed a generally favorable safety profile.
- The overall rate of adverse events was similar across cemdisiran, combination therapy, and placebo groups.
- Upper respiratory tract infection was the most commonly reported adverse event with cemdisiran, with an incidence comparable to placebo.
- No serious infections, including meningococcal infections, were observed in patients receiving cemdisiran.
- Discontinuation due to adverse events was infrequent.
- No deaths occurred during the double-blind treatment phase.
- Two deaths were reported after the treatment phase, with only one considered potentially treatment-related by investigators.
Overall, the findings suggest that cemdisiran, administered as a subcutaneous injection every 3 months, could offer a convenient and effective treatment option for patients with generalized myasthenia gravis. Its ability to improve symptoms both as monotherapy and in combination with pozelimab positions it as a promising addition to the evolving landscape of targeted therapies for this chronic autoimmune disorder.
Reference:
Vu, T., Habib, A. A., Jacob, S., Mantegazza, R., Murai, H., Vissing, J., Shaibani, A., Levine, T., Hussain, Y., Meisel, A., Adamczak-Ratajczak, A., Ilkowski, J., Sgobbi, P., Guerreiro, A., Luo, S., Pavani, R., Chaudhari, U., Jalali, N., DeVeaux, M., . . . Tharmarajah, S. (2026). Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): A double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet. https://doi.org/10.1016/S0140-6736(26)00690-2
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