Loading ...

Positive topline results from two phase 3 trials reported this week may expand the treatment landscape for generalized myasthenia gravis (gMG), a rare autoimmune disease marked by debilitating muscle weakness.

Monotherapy with the investigational drug cemdisiran for acetylcholine receptor (AChR)-antibody-positive gMGmet the primary and key secondary endpoints in the phase 3 NIMBLE study, including a 2.3-point placebo-adjusted improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, manufacturer Regeneron announced.

Meanwhile, argenx reported positive topline results from its phase 3 ADAPT SERON study of efgartigimod (Vyvgart) in patients with AChR-antibody-negative gMG, a group that represents about 20% of the population and has historically lacked effective treatments. The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in MG-ADL total scores compared to placebo. 

On the basis of the results, both companies said they plan to move forward with drug applications to the FDA. 

Cemdisiran Monotherapy

Cemdisiran, a small interfering RNA (siRNA) that reduces circulating levels of complement factor 5 (C5), was evaluated in adults with symptomatic AChR-antibody-positive gMG, the most common form of gMG. 

In the NIMBLE trial, 190 patients were randomly assigned to receive subcutaneous administrations of cemdisiran (600 mg) every 12 weeks; cemdisiran (200 mg) with the C5 antibody pozelimab (200 mg) every 4 weeks; or placebo every 4 weeks. Standard-of-care immunosuppressants were allowed, based on the investigator’s discretion. 

Use of cemdisiran monotherapy was associated with an average of 74% inhibition of complement activity, as well as a level of improvement on the MG-ADL that surpassed historical benchmarks for currently approved C5 therapies, the company said. 

Combination treatment with cemdisiran and pozelimab led to nearly 99% inhibition of complement activity and also met the primary and key secondary endpoints, although cemdisiran monotherapy was numerically better across these endpoints.

The percentage of patients achieving 3-point or greater improvement on the MG-ADL was 77% for cemdisiran monotherapy, 66% for cemdisiran plus pozelimab, and 44% for placebo.

The corresponding percentage of patients achieving at least a 5-point improvement on the Quantitative Myasthenia Gravis (QMG) total score — a physician-administered assessment evaluating vision, speaking/swallowing, breathing, and limb function — was 48%, 36%, and 19%, respectively. 

Treatment-emergent adverse events (TEAEs) occurred in 69% of patients treated with cemdisiran monotherapy, 81% with cemdisiran-pozelimab, and 77% with placebo. Serious TEAEs occurred in 3%, 9%, and 14%, respectively. 

The most common TEAEs (≥ 5% of patients) were worsening of MG, upper respiratory tract infection, urinary tract infection, nasopharyngitis, headache, rash, injection-site reaction, diarrhea, arthralgia, extremity pain, cough, and pruritus. 

There were no deaths during the 24-week placebo-controlled portion of the trial. During an extension period, one death due to pneumonia occurred in the cemdisiran group, and one death due to septic shock occurred in the combination group; both deaths occurred in patients who were on concomitant immunosuppressive therapies.

There were no meningococcal infections in any patient and no treatment discontinuations due to adverse events through 24 weeks in the cemdisiran monotherapy group.

Detailed results from the NIMBLE trial will be reported at an upcoming medical meeting. 

Pending discussions with the FDA, Regeneron plans to submit a US regulatory application for cemdisiran in the first quarter of 2026.

Label Extension for Efgartigimod?

Topline results from the phase 3 ADAPT SERON study of efgartigimod (Vyvgart) offered similarly promising results. The trial included 119 patients with AChR-antibody-negative gMG and had two parts. 

In the first part, patients received four once-weekly infusions of efgartigimod IV or placebo, followed by a 5-week follow-up and primary analysis. The second part of the study was an open-label extension in which patients received two fixed cycles of four once-weekly efgartigimod infusions (4-week interval between cycles). Additional cycles could be started ≥ 1 week after the last administration of the previous cycle, based on clinical status.

The study met its primary endpoint (P =.0068), with patients treated with efgartigimod achieving a statistically significant and clinically meaningful improvement in MG-ADL total score compared to placebo.

The benefits of efgartigimod were observed across all AChR-antibody seronegative gMG subtypes (MuSK-positive, LRP4-positive, and triple seronegative).

Safety findings were consistent with the established profile of the drug, argenx reported, including increased risk for infection, most commonly urinary tract and respiratory tract infections. Hypersensitivity reactions and infusion-related reactions have also been reported. 

“The results of the ADAPT SERON study, the largest study to date of AChR-Ab seronegative gMG, confirm that Vyvgart now has the potential to be a targeted, effective, safe, and necessary treatment for patients living with gMG, regardless of autoantibody status,” James F. Howard Jr., MD, Department of Neurology, University of North Carolina at Chapel Hill School of Medicine and principal investigator for the ADAPT SERON trial, said in a statement. 

Detailed results from the ADAPT SERON study will be presented at an upcoming medical meeting.

On the basis of the results, argenx plans to submit a supplemental biologics license application to the FDA, seeking expansion of the efgartigimod label to include adult AChR-Ab seronegative gMG patients across all three subtypes. 

The FDA first approved efgartigimod for adults with anti-AChR antibody positive gMG in 2021.