Cemdisiran siRNA Therapy Demonstrates Efficacy in Myasthenia Gravis

Cemdisiran, an investigational small interfering RNA (siRNA) therapy targeting complement component 5 (C5), met both its primary and a key secondary endpoint in the phase III NIMBLE trial of generalized myasthenia gravis, whether used alone or in combination with the C5 antibody pozelimab (Veopoz).

At 24 weeks, Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores improved from baseline by 4.5 points in the cemdisiran group, 4.0 points in the combination group, and 2.2 points in the placebo group, reported by Tuan Vu, MD, of the University of South Florida in Tampa, and colleagues.

MG-ADL placebo-adjusted improvements at week 24 were 2.3 points for cemdisiran (P<0.001) and 1.7 points for the combination therapy (P=0.009), Vu said at the American Academy of Neurology annual meeting. The findings were published simultaneously in The Lancet.

On a key secondary endpoint — the Quantitative Myasthenia Gravis (QMG) total score — mean improvement from baseline at week 24 was 4.2 points with cemdisiran, 3.3 points with combination therapy, and 1.5 points with placebo. Placebo-adjusted improvements were 2.8 points (P=0.0015) for cemdisiran and 1.9 points (P=0.035) for the combination regimen.

The MG-ADL is a patient-reported measure of disease severity and functional impairment, with scores ranging from 0 to 24. The QMG is a physician-administered evaluation of muscle function, with scores ranging from 0 to 39.

Cemdisiran is a subcutaneous siRNA therapy that reduces C5 production in the liver. Pozelimab blocks C5 and is approved to treat CD55-deficient protein-losing enteropathy (CHAPLE disease).

“In this study, we wanted to show that you can get efficacy without completely shutting down the complement cascade,” Vu told MedPage Today.

At 24 weeks, CH50 activity, a measure of classical complement pathway function, fell by 76.6% with cemdisiran monotherapy and by 99.6% with combination therapy.

Adverse events occurred in 69% of participants in the cemdisiran group, 81% in the combination group, and 77% in the placebo group. No serious or meningococcal infections were reported in the cemdisiran group,

The most common adverse event in the cemdisiran group was upper respiratory tract infection (12%), which occurred at a similar rate in the placebo group (11%). Serious adverse event rates were lower in the cemdisiran group (3%) than in the combination group (9%) or placebo group (14%).

No deaths were reported during the double-blind treatment period. Two deaths occurred afterward: one, due to pneumonia, was considered treatment-related by the investigator but not by the sponsor.

Myasthenia gravis is a rare autoimmune disease caused by antibodies that target the postsynaptic neuromuscular junction. These antibodies fall into three main categories: acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor–related protein 4 (LRP4).

Newer targeted myasthenia gravis therapies lower overall antibody concentrations or inhibit complement activity. The FDA has approved three C5 inhibitors for myasthenia gravis: eculizumab (Soliris), ravulizumab (Ultomiris), and zilucoplan (Zilbrysq). All carry boxed warnings for an elevated risk of Neisseria meningitidis infection.

These drugs — plus the neonatal Fc receptor antagonists efgartigimod (Vyvgart), rozanolixizumab (Rystiggo), and nipocalimab (Imaavy), and the anti-CD19 B-cell depleting agent inebilizumab (Uplizna) — have “fundamentally reshaped the approach to treatment in patients with generalized myasthenia gravis, who have inadequate disease control with standard therapies,” noted Raffaele Iorio, MD, PhD, of Policlinico Gemelli and Catholic University in Rome.

“However, important questions remain unanswered,” Iorio wrote in a Lancet editorial. “It is unclear which patients benefit most from which therapeutic class; how deeply, and for how long, a given pathway must be suppressed to achieve meaningful clinical improvement; and whether the infectious risks can be mitigated without sacrificing efficacy.”

The NIMBLE results suggest that meaningful clinical benefit might be achieved without complete complement blockade, Iorio noted. The drug’s safety profile deserves careful consideration: “Preservation of residual complement activity might provide a reserve of immune defense against encapsulated bacteria — a potential benefit over existing C5 inhibitors,” he observed.

One concern is the siRNA mechanism, Iorio pointed out. “Unlike protein-based C5 inhibitors, whose effects are reversible once drug levels decline after discontinuation (albeit over varying timescales across molecules), cemdisiran suppresses hepatic C5 mRNA production for approximately 3 months after each injection, a pharmacological commitment that cannot easily be titrated or rapidly reversed if intact complement activity is urgently required,” he wrote.

NIMBLE was conducted at 86 centers in 13 countries. The study randomized 284 adult generalized myasthenia gravis patients with anti-AChR or anti-LRP4 antibodies and an MG-ADL score of 6 or greater to treatment or placebo.

In total, 79 participants were randomized to 600 mg cemdisiran monotherapy every 12 weeks; 50 people to 200 mg pozelimab monotherapy every 4 weeks; 80 people to combined 200 mg cemdisiran and 200 mg pozelimab every 4 weeks; and 75 people to placebo.

Overall, 263 participants completed the 24-week double-blind treatment period. The modified intention-to-treat primary analysis group consisted of 239 participants with a mean age of 50.5 years; 57.3% were women, 56.5% were white, 33.1% were Asian, and 4.2% were Black.

Pozelimab monotherapy demonstrated limited efficacy in this study, the researchers said. Although the placebo effect was substantial in this trial, it was consistent with findings from other studies, they added.

A new drug application for cemdisiran was submitted to the FDA in the first quarter of 2026, developer Regeneron Pharmaceuticals said.