Acceleron Halts Development of ACE-083 for CMT Based on Phase 2 Trial Data

Acceleron Pharma is discontinuing the clinical development of ACE-083, its experimental treatment candidate for Charcot-Marie-Tooth (CMT) disease, based on recent data from a Phase 2 trial.

While the trial met its primary goal of showing a significant increase in patients’ muscle volume, this increase failed to translate into significant improvements in any of the functional or quality-of-life secondary goals, compared to a placebo.

The company was planning to present the study’s final data at the American Academy of Neurology Annual Meeting, which had been scheduled to take place in Toronto, Canada, in April. However, the meeting has been cancelled because of the global COVID-19 (Coronavirus) pandemic.

Acceleron’s decision, along with its previous announcement to halt the development of ACE-083 for the treatment of another muscle-wasting disease called facioscapulohumeral muscular dystrophy, shuts down the company’s clinical program of ACE-083 entirely.

ACE-083 is a locally-acting small molecule designed to suppress the activity of ligands of the TGF-beta receptor family — such as myostatins and activins — which are responsible for limiting muscle growth.

This approach, sometimes called “myostatin-plus,” was expected to block TGF-beta signaling and promote muscle growth and regeneration, ultimately leading to functional improvements. ACE-083 is injected directly into target muscles, thereby preventing unwanted side effects in untreated muscles or other organs.

The U.S. Food and Drug Administration granted ACE-083 fast track status in December 2018, and orphan drug designation in March 2019. These designations were meant to provide regulatory support and financial benefits, accelerate ACE-083’s development and review, and to ensure seven years of marketing exclusivity in the U.S. upon regulatory approval.

“Unfortunately, over the course of multiple clinical trials, our myostatin-plus hypothesis has not resulted in the functional outcomes necessary to provide clinically meaningful benefits for patients with neuromuscular diseases,” Habib Dable, president and CEO at Acceleron, said in a press release.

“We wish to thank all of the patients, families, caregivers, and investigators for their support and participation in this research. I also want to acknowledge our team’s hard work and commitment to executing robust Phase 2 trials that have provided us the data necessary to make the difficult but informed investment decision to discontinue the program,” he added.

The two-part Phase 2 trial (NCT03124459) evaluated ACE-083’s safety, tolerability, pharmacokinetics (uptake, distribution, and elimination from the body), pharmacodynamics (effects on the body), and effectiveness in people with CMT type 1 and CMT type X.

All participants, who were enrolled at 15 U.S. states, had to show muscle weakness in the tibialis anterior, one of the major muscles of the lower leg that is responsible for raising the front of the foot when taking a step.

The trial’s first part (an open-label, dose-escalation study) involved 18 patients, divided into three groups (six patients each), who were assigned to receive injections of ACE-083 at a dose of 150, 200, or 250 mg into the tibialis anterior once every three weeks, over three months.

Preliminary data from the first part of the trial showed that ACE-083 was safe and improved patients’ total and contractile muscle volume, while lowering the proportion of fat in the muscle. These positive findings supported the advancement to the second part of the study. The dose selected to be used during the second part of the trial was not disclosed.

The second part involved 44 patients, who were randomly assigned to receive either the selected dose of ACE-083 or a placebo, once every three weeks, for a period of six months. After completion, participants had the choice to continue or switch to ACE-083 treatment for an additional six months.

The main goal of this second part of the study was to assess changes in muscle volume. Secondary goals included evaluating the proportion of fat in the muscle, muscle strength and function, balance, sensory and motor impairments, quality of life, and safety measures.

Results showed that patients treated with ACE-083 had a significant increase in mean total muscle volume, compared with those who received a placebo, meeting the trial’s primary goal. However, this benefit did not result in significant improvements in any of the functional and quality-of-life secondary goals.

In terms of safety, ACE-083 was generally well-tolerated, with most adverse events being mild to moderate in severity and associated with injection-site reactions.

The company plans to focus its resources on its experimental therapies for blood and lung diseases, as well as on pre-clinical studies to discover other potential candidates among the TGF-beta family.