NIMBLE Trial Reveals New Insights on Complement Inhibition in gMG

In a recent video interview with Applied Clinical Trials, Umesh Chaudhari, executive medical director, global program head of the C5 programs, Regeneron, discussed recently released data from the Phase III NIMBLE clinical trial (NCT05070858), which evaluated the efficacy of cemdisiran monotherapy and a combination of cemdisiran and pozelimab in generalized myasthenia gravis (gMG). The study showed a 2.3-point reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, indicating improved daily functioning. The combination therapy had a 17% worsening rate, compared to 1% in the cemdisiran monotherapy group. Chaudhari highlighted the trial's robust design, including double-blind, double-dummy protocols, and standardized assessments, which ensured high data quality. The findings suggest that lower complement inhibition levels may be optimal for efficacy, with implications for future research in autoimmune diseases.

ACT: Could you provide an overview of the latest results from the NIMBLE study? What do they mean in regard to the future of gMG research?

Chaudhari: In summary, the NIMBLE study showed a reduction, a placebo adjusted reduction of -2.3 in the MG-ADL. If you look at historical trials and complement inhibitors, this is on the high end of that, it was one of the largest Phase III studies, and it gave us a remarkable insight into the role that different levels of complement inhibition play in the efficacy, and we could say the safety. The last thing I want to mention that was, for us, really exciting, and we think hasn't really been observed in other trials, is the impact that it had on what we call the adverse event of worsening of myasthenia gravis. When you look at that, there was a reporting of 1% of worsening of myasthenia gravis in the cemdisiran arm versus 17% in the combination arm. That degree of separation, if you will, has really not been observed with other FcRn inhibitor trials or complement inhibitor trials.

One point that I mentioned was the role of complement, I think that provides a very important understanding. I'll start with the context of myasthenia gravis, and what it means maybe for autoimmune and antibody-mediated diseases. In terms of what this means for myasthenia gravis, we were able to show that cemdisiran lowered what we call a complement assay, it inhibited complement by about 75-76%. The combination inhibited complement by 100%. These were as predicted. Actually, we thought this would be the outcome, and lo and behold, that was the case, but what was very intriguing were the outcomes of the results that lesser complement inhibition was associated with cemdisiran had actually optimal efficacy, and whereas the combination, it wasn't associated with even greater efficacy than cemdisiran, so that’s an important insight, and there are multiple questions around that, we're working through that and the biology about that in particular, and the implications that has to other autoimmune diseases, so this is a fascinating piece in terms of the scientific understanding.