Apitegromab Safely Counters Muscle Growth Suppressor, Phase 1 Trial Finds

Apitegromab, Scholar Rock’s muscle-directed therapy for spinal muscular atrophy (SMA), was generally safe and showed dose-dependent accumulation and clearance of the inactive form of myostatin, a muscle growth suppressor, in healthy volunteers, according to data from a Phase 1 clinical trial.

These findings, published in the journal Advanced in Therapy, “provided an important foundation to support advancing the development of apitegromab,” Yung Chyung, MD, Scholar Rock’s chief medical officer, said in a press release.

The therapy is currently being tested in the international, proof-of-concept Phase 2 TOPAZ trial (NCT03921528), whose top-line results highlighted “apitegromab’s transformative potential to improve the persistent motor function impairments experienced by patients with Type 2 and Type 3 SMA,” Chyung said.

Based on these findings and pending discussions with regulatory authorities, the company plans to launch a pivotal Phase 3 trial by year’s end to confirm the therapy’s safety and effectiveness in a larger patient population.

The published study is titled “A Randomized Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Novel Myostatin Inhibitor Apitegromab (SRK-015): A Potential Treatment for Spinal Muscular Atrophy.”

Previously known as SRK-015, apitegromab is a fully human antibody that selectively and indirectly blocks myostatin, a growth factor mainly produced by skeletal (movement-related) muscle cells to suppress muscle growth.

Specifically, apitegromab works by preventing the conversion of myostatin’s precursor, or latent form, into its active form.

Due to this mechanism of action, the therapy is expected to cause fewer side effects than conventional suppressors of myostatin’s active form, while still improving patients’ muscle mass and strength to improve motor function.

As such, the muscle-targeted therapy could work to elevate the benefits of currently approved SMA disease-modifying therapies, which work to increase the levels of SMN, the missing protein in SMA.

Administered directly into the bloodstream, apitegromab received orphan drug designation in both the U.S. and Europe, as well as rare pediatric disease status in the U.S.; all are meant to speed its development and regulatory review.

Newly published data concerned a Phase 1 clinical trial that evaluated the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single and multiple ascending doses of apitegromab against a placebo in 66 healthy adults.

Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics measures its effects on the body. Immunogenicity is the therapy’s ability to promote immune responses against it.

Participants were assigned to single or multiple intravenous injections of either apitegromab, at doses between 1 mg/kg and 30 mg/kg, or a placebo. Multiple dosing was given every other week for a total of three doses.

Individuals were followed for up to 114 days (nearly four months), with their heart health being continuously monitored for about 12 hours after dosing. Safety data from each dose group were reviewed by a committee before the trial moving to the next dose.

Most (80%) of the enrolled participants completed the study.

Results showed that apitegromab exhibited a linear, dose-proportional pharmacokinetics profile, and a half-life of 24–31 days across all evaluated doses. Half-life is the time needed for a therapy’s initial concentration to drop to half.

Single and multiple apitegromab doses resulted in dose-dependent and sustained increases in the levels of latent myostatin in the blood, before starting to drop by day 56 (nearly two months) in the 10 and 20 mg/kg dose groups, and by day 84 (nearly three months) in the 30 mg/kg dose group.

“The latent myostatin increases in [blood] were likely due to binding of apitegromab to its target in the muscle, resulting in transport of the antibody–antigen complex into the systemic circulation, until eventual clearance,” the researchers wrote.

No significant changes in latent myostatin blood levels were observed among those given a placebo through to the study’s end.

As such, these apitegromab-induced increases in latent myostatin in the blood highlight the therapy’s “robust target engagement,” the team added.

Apitegromab was safe and well-tolerated across all doses, with no clinically meaningful changes in participants’ vital signs, electrocardiograms, or clinical laboratory parameters. No antibodies against the therapy were detected.

“The results of this study support the continued development of apitegromab for the treatment of spinal muscular atrophy,” the researchers concluded.

Based on these Phase 1 findings, the Phase 2 TOPAZ trial is testing two doses of apitegromab (2 and 20 mg/kg), given every four weeks, either alone or in combination with Spinraza — the first approved SMA disease-modifying therapy — in 58 patients, ages 2 to 21, with SMA types 2 and 3 (later-onset disease).

TOPAZ’s top-line data showed that the therapy safely and effectively improved or stabilized patients’ motor function over one year, supporting the future launch of a Phase 3 clinical trial in a larger patient population.