On 26 August, Regeneron announced exciting results from Phase III clinical trial NIMBLE (NCT05070858) evaluating the efficacy and safety of pozelimab + cemdisiran combination therapy and cemdisiran monotherapy for adult patients living with generalised myasthenia gravis (gMG). The results showed that both cemdisiran monotherapy and pozelimab + cemdisiran combination therapy met their primary endpoints, displaying a significant improvement over 24 weeks, as measured through reductions in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale score. This means that the pozelimab + cemdisiran combination and cemdisiran alone have the potential to challenge currently marketed disease-modifying therapies (DMTs) for MG. With that being said, the existing DMTs are highly effective, and pozelimab and cemdisiran will have to differentiate themselves in a crowded MG market to gain traction.
Regeneron’s pozelimab and Alnylam Pharmaceuticals’ cemdisiran work through mediating C5 complement inhibition. C5 is a protein that is thought to be involved in the damage of acetylcholine receptors and is a frequent target of DMTs within the MG treatment landscape. The Phase III trial randomised 190 adults with symptomatic gMG, who tested positive for anti-AChR antibodies (AChR+) or anti-LRP4 antibodies (LRP4+), to receive one of three regimens. Around one-third of patients received single-agent cemdisiran, an siRNA designed to silence the gene that makes C5 in the liver, every 12 weeks. Another third of patients received cemdisiran in combination with pozelimab, a C5 antibody, every four weeks. The remaining patients received a placebo. At Week 24, scores on the MG-ADL measure of gMG symptoms fell 2.3 points on cemdisiran compared to placebo. The figure for the combination arm was a decline of 1.74 points. The results were statistically significant, achieving the trial’s primary endpoint. This indicates that pozelimab + cemdisiran has the potential to rival existing complement inhibitors in the MG market.
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As a DMT, pozelimab + cemdisiran would be entering a highly competitive space in the market, as they are treatments targeting the AChR+ MG patient population, the most common form of MG. Furthermore, they are complement inhibitors, which are a well-established treatment pathway in the MG treatment paradigm. According to GlobalData’s drugs database, there are six DMTs currently marketed across the seven major pharmaceutical markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan) for AChR+ patients. Of these six DMTs, three are complement inhibitors: Soliris (eculizumab), Ultomiris (ravulizumab), and Zilbrysq (zilucoplan). Key opinion leaders (KOLs) previously interviewed by GlobalData have stated that there may not be much additional room in the MG market for another anti-complement agent, and that the combination of pozelimab + cemdisiran would have to display efficacy over existing anti-complement treatments in order to prompt clinicians to switch to this new combination therapy.
Regeneron and Alnylam have already made a strategic move to display pozelimab + cemdisiran’s efficacy over existing complement inhibitors. In announcing the results of the NIMBLE trial, Regeneron compared the results to clinical trials that linked currently approved C5 inhibitor therapies to placebo-adjusted differences in MG-ADL of -1.6 to -2.1 at 12 to 26 weeks, thus displaying pozelimab + cemdisiran’s superior efficacy to other complement inhibition treatments. Pozelimab + cemdisiran may also have an added advantage over existing treatments, in that the NIMBLE trial sought to recruit patients who were LRP4+. KOLs interviewed by GlobalData have noted that there is a significant unmet need for effective treatments targeting the LRP4+ patient population.
There currently is not an effective DMT on the market that targets the LRP4+ MG population, meaning that Regeneron can position pozelimab + cemdisiran to meet this unmet need. Another advantage that Regeneron and Alnylam possess is that cemdisiran’s promising results versus placebo could also open the door for it to be used as a monotherapy. This is a testament to cemdisiran’s diversity and potential to be applied in different use cases. A common issue that DMTs for MG encounter is that they are very expensive, an issue that 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 both Regeneron and Alnylam, who are co-developing the pozelimab + cemdisiran combination therapy. Developing cemdisiran as a monotherapy may bring potential complications from a co-marketing perspective and could jeopardise their strategic alliance. GlobalData forecasts that pozelimab + cemdisiran combination therapy could drive sales of approximately $1.9bn by 2034 in the 7MM as one of the promising pipeline products, given its superior comparative efficacy and targeting of the overlooked LRP4+ MG patient segment.
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By GlobalDataThe Phase III clinical trial results for pozelimab + cemdisiran mark a significant milestone in the treatment of gMG. With clinically meaningful improvements in the MG-ADL score, pozelimab + cemdisiran offers hope for both AChR+ and LRP4+ patients. However, Regeneron and Alnylam face challenges as they are entering a highly competitive market filled with established DMTs, and must ensure that their marketing strategies are aligned in order to facilitate a successful launch. The pozelimab + cemdisiran combination therapy 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.
