In generalized myasthenia gravis (gMG), activation of the complement cascade contributes to disease pathology through complement-mediated damage and C5a-driven inflammation at the neuromuscular junction. Cemdisiran is a novel N-acetylgalactosamine-conjugated small interfering RNA (siRNA) that targets C5 messenger RNA, resulting in lower circulating plasma C5 levels.
The NIMBLE trial is a phase 3, randomized, double-blind, placebo-controlled trial conducted across 86 centres in 13 countries. Eligible participants were positive for anti-AChR or anti-LRP4 antibodies and had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score greater than 6. A total of 284 adults with gMG enrolled between 2022 and 2025 were randomly assigned to one of four groups:
- Cemdisiran monotherapy, 600 mg every 12 weeks
- Pozelimab monotherapy, 200 mg every 4 weeks
- Combination therapy with cemdisiran 200 mg every 4 weeks plus pozelimab 200 mg every 4 weeks
- Placebo
The primary endpoint:
The change from baseline in MG-ADL score at week 24 in the modified intention-to-treat (mITT) population. The least-squares mean change from baseline was −4 ·5 (SE 0·4) in the cemdisiran group (n = 64), −4·0 (SE 0.4) in the combination group (n = 67), and −2.2 (SE 0.5) in the placebo group (n = 59). Compared with placebo, the least-squares mean difference was −2.3 (95% CI −3.6 to −1.0; p = 0.0005) for cemdisiran monotherapy and −1.7 (95% CI −3.0 to −0.4; p = 0.0086) for combination therapy.
Key secondary efficacy outcome:
The change in Quantitative Myasthenia Gravis (QMG) score at week 24 also favored active treatment. Least-squares mean changes from baseline were −4.2 (SE 0.6) in the cemdisiran group, −3.3 (SE 0.6) in the combination group, and −1.5 (SE 0.7) in the placebo group. The placebo-adjusted differences were −2.8 (95% CI −4.5 to −1.1; p = 0.0015) and −1.9 (95% CI −3.6 to −0.1; p = 0.035) for the cemdisiran and combination groups, respectively.
Exploratory analyses:
Showed that both the incidence of myasthenic crises and the need for rescue therapy were lower in patients receiving cemdisiran monotherapy compared with those receiving combination therapy or placebo.
An interesting aspect of these findings relates to the role of complement activation across different diseases. Cemdisiran has also been investigated in a phase 1/2 study of paroxysmal nocturnal haemoglobinuria (PNH), another complement-mediated disorder. In PNH, cemdisiran alone produced insufficient clinical benefit, whereas combining it with low-dose pozelimab, a fully human monoclonal antibody against C5, resulted in effective control. Although cemdisiran substantially reduces C5 production, it does not completely eliminate residual circulating C5. These observations suggest that PNH may require near-complete complement blockade, whereas partial inhibition may be sufficient in gMG. This biological difference could explain why cemdisiran monotherapy demonstrated a favorable safety profile in the NIMBLE trial.
Key Points:
- Cemdisiran is a novel N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) that targets C5 mRNA and is administered subcutaneously.
- In the NIMBLE trial: phase 3, randomized, double-blind, placebo-controlled trial, both cemdisiran monotherapy and cemdisiran combined with pozelimab significantly improved outcomes in patients with generalized myasthenia gravis, as demonstrated by improvements in MG-ADL scores at week 24.
- The efficacy observed with cemdisiran monotherapy, despite preservation of residual classical complement activity, suggests that complete complement blockade may not be necessary for gMG control
Reference:
Vu T, Habib AA, 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, Moore W, Meagher KA, Burczynski ME, Kokate S, Sherman S, Pawaskar D, Singh N, Souttou A, Sirulnik A, Perlee L, Yancopoulos GD, Howard JF Jr; NIMBLE Trial Investigators. Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2026 May 2;407(10540):1712-1725. doi: 10.1016/S0140-6736(26)00690-2
Publish on behalf of the Scientific Panel on Muscle and NMJ disorders