Phase 3 NIMBLE Trial Reports Topline Results for Cemdisiran in generalized myasthenia gravis
The phase 3 NIMBLE trial evaluated cemdisiran, a subcutaneous small interfering RNA therapy targeting complement factor 5, in adults with generalized myasthenia gravis (gMG). Patients were randomized to placebo or cemdisiran, either as monotherapy or in combination with pozelimab. Topline results have now been announced, highlighting its potential role in treating anti-AChR antibody-positive symptomatic gMG.
Cemdisiran is an siRNA that reduces circulating levels of complement factor 5 (C5) and, as monotherapy in this trial, was associated with an average of 74% inhibition of complement activity. The trial also assessed a combination of cemdisiran and pozelimab, a C5 antibody; this combination (“cemdi-poze”), which resulted in nearly 99% inhibition of complement activity, also met the primary and key secondary endpoints, though cemdisiran monotherapy was numerically better across these endpoints.
“Our pipeline approach to treating complement-mediated diseases allows us to tailor treatment to the underlying disease biology,” said L. Andres Sirulnik, M.D., Ph.D., Senior Vice President and Hematology Clinical Development Unit Head at Regeneron. “The results of the NIMBLE trial confirm that, in myasthenia gravis, robust efficacy can be achieved without complete complement blockade, whereas in other diseases such as paroxysmal nocturnal hemoglobinuria (PNH), complete inhibition is likely to be necessary. We have previously released data from the lead-in portion of our PNH Phase 3 trial, supporting the potential for the cemdi-poze combination to deliver best-in-class efficacy in PNH. We are also investigating systemic administration of both cemdisiran monotherapy and the cemdi-poze combination in our Phase 3 program for geographic atrophy secondary to age-related macular degeneration.”
“The NIMBLE trial results underscore the potential for cemdisiran to offer a best-in-class profile for those suffering with myasthenia gravis, providing for robust efficacy with a convenient quarterly subcutaneous administration,” said George D. Yancopoulos, M.D., Ph.D., Board co-Chair, President and Chief Scientific Officer at Regeneron. “The potential for best-in-class efficacy with less than complete complement blockade with cemdisiran monotherapy may also provide for a more favorable safety profile. These exciting results highlight the transformative potential of our siRNA and genetic medicines pipeline to deliver paradigm-changing therapies for patients.”
The NIMBLE trial evaluated adults with symptomatic gMG who have antibodies to the acetylcholine receptor (anti-AChR) and may be receiving standard of care immunosuppressants based on the investigator’s discretion. Patients were randomized to receive subcutaneous administrations of: cemdisiran (600 mg) every 12 weeks, cemdi-poze (cemdisiran 200 mg and pozelimab 200 mg) every 4 weeks, or placebo every 4 weeks. The primary endpoint assessed total score changes from baseline to week 24 in the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, a patient-reported questionnaire that measures daily functions impacted by gMG, such as talking, eating, breathing, vision and mobility. The key secondary endpoint assessed total score changes from baseline in the Quantitative Myasthenia Gravis (QMG) total score, a physician-administered assessment evaluating vision, speaking/swallowing, breathing and limb function.
Historical clinical trial data report that currently approved C5 inhibitor therapies have shown a placebo-adjusted treatment difference in MG-ADL total scores ranging from -1.6 to -2.1 at 12 to 26 weeks.
Both cemdisiran and cemdi-poze demonstrated improvements in activities of daily functioning at week 24, with cemdisiran showing numerically better results across all gMG-specific outcomes. In the MG-ADL and QMG, greater reductions in total scores indicate greater improvement in disease symptoms and better treatment effect.
There were no meningococcal infections in any patient. There were no treatment discontinuations due to adverse events through week 24 in the cemdisiran arm.
Across all arms, treatment-emergent adverse events (TEAEs) occurred in 69% of patients treated with cemdisiran, 81% with cemdi-poze, and 77% with placebo. Serious TEAEs occurred in 3% of patients treated with cemdisiran, 9% with cemdi-poze and 14% with placebo. The most common TEAEs observed in ≥5% of patients receiving cemdisiran, cemdi-poze or placebo were: worsening of MG (1%, 5%, 17%), upper respiratory tract infection (12%, 8%, 11%), urinary tract infection (5%, 6%, 3%), nasopharyngitis (5%, 3%, 4%), headache (5%, 11%, 10%), rash (5%, 3%, 1%), injection site reaction (4%, 8%, 1%), diarrhea (3%, 14%, 7%), arthralgia (1%, 6%, 1%), pain in extremity (1%, 5%, 1%), cough (1%, 5%, 1%), and pruritus (0%, 5%, 0%). There were no deaths during the 24-week placebo-controlled portion of the trial. During the extension period, one death due to pneumonia occurred in the cemdisiran arm, and one death due to septic shock occurred in the combination arm; both deaths occurred in patients who were on concomitant immuno-suppressive therapies.
Detailed results from the NIMBLE trial will be presented at an upcoming medical meeting. The U.S. regulatory application for cemdisiran is planned for the first quarter of 2026, pending discussions with the FDA.
The potential use of cemdisiran and/or pozelimab for the treatment of gMG is investigational and has not been approved by any regulatory authority. In the U.S., pozelimab monotherapy is approved as Veopoz® (pozelimab-bbfg) for adult and pediatric patients 1 year of age and older with CHAPLE disease, also known as CD55-deficient protein-losing enteropathy, which includes a Boxed Warning for life-threatening and fatal meningococcal infections.
About Myasthenia Gravis (MG)
MG is a rare and chronic autoimmune disease where abnormal antibodies activate the complement system including C5, disrupting communication between nerves and muscles that results in debilitating and potentially life-threatening muscle weakness. In the U.S., the disease impacts approximately 85,000 people. Initial manifestations are usually ocular, but approximately 85% of MG patients experience additional advancements to the disease manifestations, which is known as generalized myasthenia gravis (gMG). For these patients, the disease affects muscles throughout the body, resulting in extreme fatigue and difficulties with facial expression, speech, swallowing and mobility. Treatment-related challenges – which include frequent hospital visits, inconsistent symptom control, and lack of durable treatment effects – can further affect quality of life and long-term disease management.
