New drug cemdisiran may offer gMG symptom relief with 4 doses a year

Cemdisiran, an experimental therapy given by injection under the skin every three months, was shown to significantly and sustainably ease symptoms of generalized myasthenia gravis (gMG) in a global, late-stage clinical trial called NIMBLE.

In addition to suggesting that cemdisiran is an effective gMG treatment, the trial results provided valuable insight into the underlying biology of the disease, according to investigators and Regeneron Pharmaceuticals, the therapy’s developer.

“While current therapies have managed disease activity, there remains an unmet need for options that achieve rapid and sustained efficacy with reduced treatment burden,” Tuan Vu, MD, a global principal investigator of NIMBLE at the University of South Florida Morsani College of Medicine, said in a press release from Regeneron. Vu noted that gMG is marked by “unpredictable symptoms that impact [the] daily life” of patients.

“These impressive results suggest cemdisiran can represent a transformative advance in care for people living with gMG, offering compelling efficacy coupled with convenient four-times-a-year subcutaneous [under-the-skin] administration,” Vu said.

Based on these positive data, Regeneron has already submitted an application asking the U.S. Food and Drug Administration to approve cemdisiran for treating gMG.

The company is planning to submit similar applications in other markets, including the European Union, this year, according to Umesh Chaudhari, MD, Regeneron’s executive medical director and global program head of C5 programs. C5 is an immune complement protein involved in the abnormal immune attacks that drive gMG and whose levels cemdisiran works to reduce.

“These results are a testament to our relentless pursuit of understanding disease biology and combining that with the latest technology to deliver medicines with transformative potential,” Chaudhari said in a written Q&A with Myasthenia Gravis News. “By following the science and investigating multiple therapeutic modalities, we aim to develop innovative solutions that have the potential to redefine treatment paradigms in gMG and beyond.”

Full results from the Phase 3 NIMBLE trial (NCT05070858) were presented at the annual meeting of the American Academy of Neurology (AAN), in a plenary oral presentation titled “Rapid and Sustained Efficacy of Cemdisiran Without Complete Complement Blockade in Patients with Generalized Myasthenia Gravis (gMG): Primary Efficacy and Safety Results from the Phase Three NIMBLE Trial.”

The findings were simultaneously published in The Lancet, in a study titled “Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial.”

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In gMG, the immune system mistakenly makes antibodies against proteins that are key for nerve-muscle communication, resulting in symptoms such as muscle weakness. These autoimmune attacks lead to the activation of a group of immune proteins called the complement cascade, including C5, which contribute to gMG-related damage.

Cemdisiran was designed to ease symptoms of gMG

Cemdisiran uses a molecular technology called small interfering RNA to specifically reduce C5 production. The therapy, given through subcutaneous injections, aims to lessen antibody-mediated damage, thereby easing gMG symptoms.

Regeneron sponsored NIMBLE to test cemdisiran, alone or in combination with pozelimab — the developer’s antibody-based therapy designed to block C5 — in adults with gMG. Pozelimab, also given via subcutaneous injections, is already approved under the brand name Veopoz for an ultra-rare immune disease.

The study enrolled 288 participants, making it “the largest global interventional gMG trial conducted to-date,” Chaudhari said.

A central focus of our trial was measuring outcomes that matter to patients from their perspective, including assessments of symptoms and day-to-day functioning.

To be eligible, patients had to be positive for MG-causing antibodies targeting one of two proteins, acetylcholine receptor or lipoprotein receptor-related protein 4. Participants were randomly assigned to receive either cemdisiran alone, once every three months, cemdisiran plus pozelimab once a month, pozelimab alone once a month, or a placebo once a month, for six months.

The study was double-blind, meaning that neither participants nor researchers knew who was given which medication. The goal was the same for all groups:

“A central focus of our trial was measuring outcomes that matter to patients from their perspective, including assessments of symptoms and day-to-day functioning,” Chaudhari said. “We also evaluated additional exploratory measures such as patient-reported outcomes, including fatigue and overall health status, which we plan to share at future medical meetings.”

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The trial’s main goal was to assess changes in the MG-ADL, or Myasthenia Gravis-Activities of Daily Living, a standard assessment of how much MG interferes with day-to-day life. In this assessment, higher scores indicate a more severe impact.

At six months, MG-ADL scores dropped — indicating improvement — by a mean of 4.5 points in participants given cemdisiran, by four points in the combo group, and by 2.2 points for those given the placebo. Clinically meaningful score reductions were seen within two weeks of starting treatment with cemdisiran, alone or in combination with pozelimab, and these improvements deepened over time.

Another measure of MG severity, the Quantitative MG score (QMG), showed a similar trend, with scores dropping by a mean of 4.2 points with cemdisiran, 3.3 points with the combo, and 1.3 points with the placebo.

Exploratory analyses showed that the cemdisiran group also had the lowest rate of hospitalizations and the shortest hospitalization duration.

“While [cemdisiran plus pozelimab] also met the primary and key secondary [goals], cemdisiran was numerically better,” Chaudhari said.

Cemdisiran’s superiority was seen despite suppressing complement activity to a lesser extent than the combo (by a mean of 76.6% vs. 99.6%), the researchers noted.

“In the trial, patients treated with subcutaneous cemdisiran … experienced clinically meaningful improvements over placebo within two weeks,” Chaudhari said, noting improvements in “daily functions impacted by gMG (such as talking, eating, breathing, vision and mobility) and muscle function (such as vision, speaking/swallowing, breathing and limb mobility).”

According to Chaudhari, the new data also “have advanced our understanding of the disease.”

“These investigational findings suggest that, in gMG, robust efficacy can be achieved without complete complement blockade,” Chaudhari said, adding that this contrasts with other complement-mediated disorders where full complement suppression is often required for disease control.