Cemdisiran Monotherapy Improves Activities of Daily Living in Myasthenia Gravis

Author(s):

Luke Halpern, Assistant Editor

Key Takeaways

Cemdisiran monotherapy improved quality of life in gMG patients, surpassing the cemdisiran-pozelimab combination in specific outcomes.
Cemdisiran achieved 74% inhibition of complement activity, while the combination reached nearly 99%, both showing broad effectiveness.
No meningococcal infections were reported, and no treatment discontinuations due to adverse events occurred in the cemdisiran group.
Cemdisiran's clinical profile is bolstered by the NIMBLE trial, making it an attractive option for gMG symptom relief compared to standard treatments.

Both cemdisiran alone and combined with pozelimab improved the Myasthenia Gravis Activities of Daily Living score in patients with generalized myasthenia gravis.

In the phase 3 NIMBLE trial (NCT05070858), cemdisiran monotherapy met key primary and secondary end points in adults with generalized myasthenia gravis (gMG), improving quality of life compared with baseline as measured by the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score at week 24, according to a news release from Regeneron. Furthermore, the combination of cemdisiran and pozelimab (Veopoz; Regeneron) also resulted in improvements in MG-ADL scores at week 24, but cemdisiran monotherapy was superior across all gMG-specific outcomes.¹

Neuromuscular disorders neon glow nervous system visualizing diseases like ALS myasthenia gravis being treated advanced therapies under Neurology

Myasthenia gravis can impact muscle function. | Image Credit: © Robin - stock.adobe.com

Both cemdisiran monotherapy and the combination of cemdisiran and pozelimab—coined “cemdi-poze” by the investigators—resulted in the inhibition of complement activity. Cemdisiran monotherapy, a small interfering RNA (siRNA) that reduces circulating levels of complement factor 5 (C5), was linked to an average of 74% inhibition of complement activity. Accordingly, the cemdi-poze combination resulted in nearly 99% inhibition of complement activity. In MG, activation of the C5 factor can disrupt communication between muscles and nerves, resulting in the hallmark symptom of muscle weakness; each investigated regimen showed broad effectiveness at C5 inhibition, a critical measure of success.¹

“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,” George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron, said in the news release. “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.”¹

NIMBLE Trial: Methods and Key Results

Investigators of the NIMBLE trial enrolled adults with symptomatic gMG who harbored antibodies to the acetylcholine receptor (anti-AChR) and may have been receiving standard of care immunosuppressants. Enrolled patients were randomized to receive either 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.¹

Primarily, the investigators assessed total score changes from baseline to week 24 in the MG-ADL score, which measures daily functions impacted by gMG through a patient-reported questionnaire assessing talking, eating, vision, breathing, and mobility. A key secondary end point assessed changes from baseline in the Quantitative Myasthenia Gravis (QMG) total score, which is a physician-administered assessment that measures vision, speaking/swallowing, breathing, and limb function.¹

Cemdisiran induced a greater change from baseline MG-ADL total score compared with cemdi-poze, according to placebo-adjusted treatment difference (–2.30 vs –1.74) and mean change from baseline (–4.52 vs –3.96). For change in baseline in QMG total score, the placebo-adjusted treatment difference with cemdisiran was greater compared with cemdi-poze (–2.77 vs –1.86), as well as the mean change from baseline (–4.24 vs –3.32).¹

Cemdisiran and Cemdi-Poze Combination Proven Safe

Regarding safety, indications were positive across the cohort. According to the package insert for pozelimab, the drug can heighten the chance of acquiring a serious, life-threatening meningococcal infection that could cause death if not recognized early. Importantly, no meningococcal infections were reported in the study population for NIMBLE, and there were no treatment discontinuations due to adverse events (AEs) through 24 weeks in patients receiving cemdisiran.¹

Across all study arms, treatment-emergent AEs (TEAEs) occurred in about 69% of patients who received cemdisiran, 81% with cemdi-poze, and 77% with placebo. Regarding serious TEAEs, only 3% of patients in the cemdisiran arm and 9% in the cemdi-poze arm reported any such occurrences. Commonly reported TEAEs observed in patients across the trial were worsening of MG, upper respiratory tract infection, urinary tract infection, nasopharyngitis, and headache. During the 24-week placebo-controlled trial portion, there were no deaths reported to the investigators.¹

Although the results of NIMBLE are investigational, they bolster the clinical profile of cemdisiran and the combination of the drug with pozelimab. The combination has already been investigated in a phase 3 head-to-head exploratory cohort from the ACCESS-1 trial (NCT05133531), in which it helped patients with paroxysmal nocturnal hemoglobinuria achieve and maintain stronger disease control as compared with standard of care. Cemdisiran is also being further investigated in Regeneron’s phase 3 program for geographic atrophy secondary to age-related macular degeneration. These clinical developments make cemdisiran an attractive option for symptom relief in gMG compared with standard treatment options.^1,2