Acceleron Pharma’s ACE-083 might meet its primary efficacy endpoint of muscle growth in its Phase II Charcot-Marie-Tooth (CMT) disease trial, but without addressing the underlying nerve degeneration, the functional benefit may be limited, most experts said.

One of the experts, however, said the drug is not attempting to provide a permanent cure anyway and has a clear mechanism of action that targets muscle weakness caused by CMT.

Given doubts on functional benefit, some experts noted they would like to see the functional efficacy outcomes ranked higher as key secondary endpoints for greater confidence in the drug’s benefit. An expert also noted that having certain subset baseline data could help enhance understanding.

While analyst sentiments raised caution for ACE-083’s CMT programme on the back of a failed Phase II trial in facioscapulohumeral muscular dystrophy (FSHD), experts said it does not necessitate a failure in CMT. The two diseases have different pathophysiologies, and ACE-083’s activin and myostatin inhibition might fare differently in CMT, they explained. CMT is characterised by progressive loss of
muscle tissue and touch sensation across various parts of the body.

ACE-083 is in a 63-patient Phase II trial (NCT03124459), with results expected in 1Q20, according to a 16 September company press release. Acceleron has a market cap of $2.52b. A company spokesperson said it could not comment on ACE-083’s potential clinical effects.

Nerve disease could still progress despite muscle growth

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By GlobalData

Some experts noted that the muscle growth primary endpoint might be met in the trial, but had questions about its long-term durability. A US-based Phase II investigator, however, was not as concerned about durability as he said this drug is not intended to be a cure. The Phase II trial is measuring adverse events and change in muscle volume growth from baseline as coprimary endpoints.

The mechanism of action has shown promising trends in muscle growth in animal models and a Phase I trial, but it is too early to say whether physiological gains will translate into functional gains, said Dr Peter Dyck, neurologist, Mayo Clinic, Rochester, Minnesota. Preclinical mouse models of CMT showed treatment with ACE-083 resulted in substantial increases in muscle mass as well as improvements in muscle twitch and measures of muscle contraction, the spokesperson said.

ACE-083’s inhibition of transforming growth factor-beta (TGF-B) proteins—namely myostatin and activin—could very well help patients regrow muscle, but without tackling the underlying nerve degeneration, it is doubtful that a monotherapy approach could have a lasting impact on function, said Dr Alexander Fay, assistant professor in neurology, UCSF Weil Institute for Neurosciences, San Francisco, California.

Xiang-Lei Yang, PhD, professor, Department of Molecular Medicine, Scripps Research Institute, California Campus, California, said she was uncertain of the long-term benefit of targeting a secondary phenomenon of the disease. Even if ACE-083 were to succeed in the Phase II trial, it is not clear whether patients will continue to respond to treatment as the disease progresses, Fay said. As patients continue to lose nerve function, it will be likely they will respond less to ACE-083 as any grown muscle will ultimately deteriorate in the absence of healthy nerve signalling, he said.

The Phase II appears to select for patients who have some preserved level of function already — literature suggests that earlier intervention yields better results—but the relatively short 20-week trial period cannot predict that patients will continue to benefit from myostatin inhibition unless some nerve intervention occurs, he explained. The investigator, however, said worries about the durability of muscle impact are not entirely relevant since the drug is not aimed at permanently curing the disease. ACE-083 targets a secondary effect in muscle weakness and any improvement in muscle strength it can bring about will be beneficial until a permanent cure is found, he said. In that sense, there is long-term value to focusing on muscle regrowth, he explained. Besides, there is no guarantee that treatments that directly target the nerve will produce a permanent cure, he said.

Nebulous expert perspectives on functional endpoints While some experts were doubtful of the effect of ACE-083 on muscle functionality, which comprise the majority of the secondary endpoints, the investigator said he was confident about the MOA. ACE-083 is a ligand trap and works by trapping a compound produced by the body that limits muscle contractile protein production, the investigator explained. This allows the muscles to produce more contractile protein which should make them stronger and hence improve functionality, he said. But it is not clear whether the functional endpoints in the Phase II trial will be met, even with adequate muscle growth, Fay said.

Functional endpoints include the six-minute walk test and balance tests. Without understanding what the patients’ baseline function is, it is difficult to tell how much function can be gained simply by regenerating more muscle, Dyck said. Measuring nerve conduction velocity could enlighten that aspect, he added. Fay agreed, though noting that nerve conduction velocity data would be helpful for a broader understanding of response potential, rather than as an endpoint since ACE-083 does not affect nerve function. Other than just muscle gain, baseline nerve function and patient subset information would allow for better confidence of proof-of-concept, Dyck said.

The spokesperson commented that as the Phase II trial is exploratory in nature to establish proof of concept, it does not need to mirror the primary and secondary endpoints of a pivotal trial. Failure in FSHD irrelevant for ACE-083 in CMT Three analyst reports stated that ACE-083’s failure in an FSHD Phase II trial (NCT02927080) warrants pessimism in the ongoing CMT disease trial, but experts disagreed. The aforementioned press release states ACE-083 did not attain functional secondary endpoints in that study. FSHD is a genetic muscle disorder in which the face, shoulder blades and upper arms muscles are predominantly affected.

In FSHD, the genetic defect primarily affects the muscle, whereas in CMT the defect affects the nerve, said the investigator. It appears that muscle fibre growth as a result of myostatin inhibition could be more fragile as the genetic defects affect the muscle, Fay said. Muscle growth would likely be normal in a CMT model, leading to a possibility of meeting the muscle growth endpoint in Phase II, he added. Yang added that FSHD also appears to have an immune component that makes it a distinct disease from CMT. The spokesperson said it is not possible to predict whether the CMT trial will mimic the FSHD trial.

by Shaun Sim in New York and Ayisha Sharma in London

Shaun Sim is a Senior Reporter and Ayisha Sharma is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.