Overviewing Phase 3 NIMBLE Trial Design and Patient Population

The role of complement activation in generalized myasthenia gravis (gMG) varies according to antibody subtype, making patient selection an important consideration when evaluating complement-targeted therapies. In acetylcholine receptor antibody-positive disease, complement-mediated injury at the neuromuscular junction is a well-established component of disease pathology. By contrast, muscle-specific kinase (MuSK) antibody-positive myasthenia gravis is predominantly associated with IgG4 antibodies, which do not effectively activate the classical complement pathway. These distinctions have helped shape the development and clinical evaluation of complement inhibitors in gMG.

In this NeurologyLive^® Special Report, Ali Habib, MD, a neuromuscular specialist at UCI Health, discusses the phase 3 NIMBLE trial (NCT05070858), which investigated the small interfering RNA therapeutic cemdisiran, the monoclonal antibody pozelimab, and their combination in adults with gMG. The conversation was recorded during the 2026 AANEM Annual Meeting, held September 29 to October 2 in Orlando, Florida, where additional exploratory analyses examined hospitalization outcomes associated with cemdisiran treatment. The randomized, double-blind trial included a 24-week treatment period, with change from baseline in MG-ADL score serving as the primary efficacy endpoint.

In this episode, Habib provides an overview of NIMBLE's design and the clinical rationale behind its patient population. He discusses the importance of antibody status in understanding complement activation, explains the differences between the investigational treatment approaches, and outlines the study's four randomized groups. The conversation also touches on the enrolled population's similarities to patients evaluated in other recent gMG trials, providing context for interpreting the study's findings.

Transcript edited for clarity.

Ali Habib, MD: In myasthenia gravis, we have always known the distinction between AChR and MuSK antibody myasthenia since the discovery of these antibodies.

We also, in the last several years, have known that MuSK myasthenia involves a different type of IgG that does not activate complement, so complement activation is not a major part of MuSK myasthenia.

In acetylcholine receptor antibody disease, complement activation has been well documented, and that's the main target here. So, what's different from some of the other trials, but very characteristic of complement inhibition therapy trials in myasthenia gravis, is that this trial was looking at the acetylcholine receptor antibody population for the most part.

In the trial, there are 2 approaches being tested for complement inhibition. Cemdisiran is one of those therapies. The other investigational product was pozelimab.

Pozelimab is more along the lines of your other complement inhibitors, where it's a monoclonal antibody inhibiting complement C5 activation in the periphery, not impacting anything in the liver.

So, in the trial, what you have is a 4-arm study where patients are randomized 1:1:1:1 to receive either cemdisiran monotherapy, pozelimab monotherapy, cemdisiran and pozelimab combination therapy, or placebo.

That's the overall design. The randomized, double-blind period was a 24-week period, and the primary outcome measure is a change from baseline in the Myasthenia Gravis Activities of Daily Living scale, the MG-ADL, which is very familiar to folks in the field. So, it's a change from baseline to week 24 in those different arms.

The primary population being assessed in NIMBLE was patients with generalized myasthenia gravis. The majority of the patients enrolled, which is the primary intention-to-treat population, were AChR antibody-positive. There were also some patients included in the study who were LRP4 antibody-positive with generalized myasthenia gravis.

In general, the population of patients enrolled in the study was reflective of our general myasthenia gravis population and similar to the populations enrolled in some of the other trials that have taken place recently in myasthenia gravis.