Regeneron’s Phase III generalised myasthenia gravis (gMG) trial shows high disease control potential of cemdisiran.
The Phase III NIMBLE study (NCT05070858) evaluated cemdisiran and pozelimab in patients with gMG.
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The trial sought to evaluate subcutaneously administered cemdisiran and pozelimab as monotherapies or in combination in participants with generalized MG (Myasthenia Gravis Foundation of America [MGFA] Class II–V) who are acetylcholine receptor antibody-positive (AChR+) and/or low-density lipoprotein receptor-related protein 4-positive (LRP4+).
The trial met its primary endpoint, which was a change from baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL), at week 24, as well as key secondary endpoints, including a change in baseline in the Quantitative Myasthenia Gravis (QMG) score at week 24 and the cumulative rate of treatment-emergent adverse events (TEAEs).
Cemdisiran is an investigational RNA interference (RNAi) therapeutic designed to lower the production of the complement component 5 (C5) protein in the liver. Cemdisiran is a disease-modifying treatment (DMT) that is thought to lower the levels of the C5 protein by targeting C5 messenger RNA (mRNA) in the liver, which helps prevent complement-mediated tissue damage.
NIMBLE is a Phase III, randomized, double-blinded, placebo-controlled, four-arm trial (cemdisiran 600mg every 12 weeks, pozelimab 200mg every four weeks, cemdisiran 200mg + pozelimab 200mg, and placebo), and the data highlighted the effectiveness of cemdisiran as a monotherapy. The data showed that the cemdisiran arm of the trial saw a change in baseline at week 24 in MG-ADL total score of -4.5 and achieved terminal complement inhibition of 76.6%. Likewise, cemdisiran elicited a change in baseline at week 24 in QMG total score of -4.2.
Clinically meaningful improvements occurred within two weeks of treatment initiation, and were sustained throughout the 24-week double-blinded treatment period. Cemdisiran monotherapy achieved robust efficacy while preserving residual complement activity, with no waning of efficacy throughout the dosing interval. Cemdisiran monotherapy was generally well-tolerated, and no serious infections were reported. The cemdisiran + pozelimab combination therapy was also found to have no additional benefit over cemdisiran monotherapy.
The NIMBLE trial sought to recruit patients who were LRP4+. Key opinion leaders (KOLs) previously interviewed by GlobalData noted that there is a significant unmet need for effective treatments targeting the LRP4+ patient population. Currently, there is no effective DMT on the market that targets the LRP4+ MG population, Cemdisiran’s promising results open the door for it to be used as a monotherapy, which means that Regeneron can position cemdisiran to meet this unmet need. Regeneron is also co-developing and investigating cemdisiran as a combination therapy with Alnylam Pharmaceuticals’ pozelimab, a C5 antibody, but GlobalData expects this combination therapy to be very expensive. A common issue that DMTs for MG encounter is that they are very expensive. This issue is not likely to be resolved if they are used in combination.
If cemdisiran were to be approved as a monotherapy, this could alleviate some of the financial constraints surrounding the use of this DMT. However, the approval of cemdisiran as a monotherapy would have to be carefully considered by Regeneron, as this could potentially mark the end of its strategic alliance with Alnylam, developing the potentially lucrative combination therapy of pozelimab + cemdisiran. GlobalData forecasts that the pozelimab + cemdisiran combination therapy could drive sales of approximately $1.9 billion by 2034 in the seven major pharmaceutical markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan), driven by its targeting of multiple MG subtypes, including AChR+ patients and the overlooked LRP4+ MG patient segment. Cemdisiran would also present a novel mechanism of action, targeting c5 messenger RNA in the liver, which sets it apart from other c5 attenuating therapies.
The Phase III clinical trial results for cemdisiran mark a significant milestone in the treatment of gMG. With clinically meaningful improvements in the MG-ADL score and QMG, as well as meaningful safety data, cemdisiran offers hope for both AChR+ and LRP4+ patients. However, Regeneron will face challenges as it is entering a highly competitive market filled with established DMTs and must ensure that it opts for a lucrative marketing strategy to facilitate a successful launch, given that launching cemdisiran in combination with pozelimab may not garner the best results both therapeutically and commercially for patients and clinicians, based on this most recent trial data. Cemdisiran monotherapy has the potential to become a valuable addition to the gMG treatment paradigm, offering new possibilities for disease management, should Regeneron be able to successfully navigate the complexities of market competition and opt for a congruent marketing strategy.
