A Randomized Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Novel Myostatin Inhibitor Apitegromab (SRK-015): A Potential Treatment for Spinal Muscular Atrophy

Abstract

Introduction: Apitegromab (SRK-015) is an anti-promyostatin monoclonal antibody under development to improve motor function in patients with spinal muscular atrophy, a rare neuromuscular disease. This phase 1 double-blind, placebo-controlled study assessed safety, pharmacokinetic parameters, pharmacodynamics (serum latent myostatin), and immunogenicity of single and multiple ascending doses of apitegromab in healthy adult subjects.

Methods: Subjects were administered single intravenous ascending doses of apitegromab of 1, 3, 10, 20, 30 mg/kg or placebo, and multiple intravenous ascending doses of apitegromab of 10, 20, 30 mg/kg or placebo.

Results: Following single ascending doses, the pharmacokinetic parameters of apitegromab appeared to be similar across all dose groups, following a biphasic pattern of decline in the concentration-time curve. The mean apparent terminal t_1/2 after single intravenous doses of apitegromab ranged from 24 to 31 days across dose groups. Dose-related increases were observed in C_max following multiple ascending doses. Single and multiple apitegromab doses resulted in dose-dependent and sustained increases in serum latent myostatin, indicating robust target engagement. Apitegromab was safe and well tolerated, on the basis of the adverse event (AE) profile with no clinically meaningful changes in baseline vital signs, electrocardiograms, or clinical laboratory parameters and no anti-drug antibody formation.

Conclusion: These results support continued investigation of apitegromab for the treatment of patients with milder forms (type 2 and 3) of spinal muscular atrophy.

Keywords: Apitegromab; Human monoclonal antibody; Myostatin; Pharmacodynamics; Pharmacokinetics; Phase 1 study; SRK-015; Safety; Spinal muscular atrophy; Tolerability.

Fig. 1

Study design. In part A (single ascending dose, SAD), an initial sentinel group of subjects in each cohort (one active, one placebo) were administered apitegromab to allow for initial safety assessments. A minimum of 24 h elapsed after the start of infusion of the last sentinel subject before the remainder of the cohort was treated. Dosing of subjects 3–8 proceeded if no safety issues were identified by the Dose Escalation Committee (DEC) for the first two subjects in each cohort. In part B (multiple ascending dose, MAD), subjects received apitegromab or placebo every 2 weeks on days 0, 14, and 28. Initiation of part B did not occur until the planned cumulative apitegromab dose for part B (30 mg/kg) had been administered as a single dose to the full cohort in part A and the DEC had determined that it was safe to proceed

Fig. 2

Pharmacokinetic and pharmacodynamic results. a Following single ascending doses, the C_max for apitegromab occurred soon after completion of the IV infusion. Mean serum concentrations, C_max, and AUC values increased proportionally with increasing dose. b Multiple ascending doses resulted in dose-related increases in C_max. An accumulation of apitegromab from the first dose to the last resulted in increasing AUC values. Pre-dose time points for all subjects and all time points for placebo subjects were measured for apitegromab exposure and were reported below the limit of quantitation (BLQ). c Single ascending doses of apitegromab resulted in dose-related increases in serum latent myostatin reaching a plateau between days 14 and 28 for doses ≤ 10 mg/kg and days 42 and 56 for 20 mg/kg and 30 mg/kg doses which then declined in all dose groups. d Following multiple ascending doses of apitegromab, mean latent myostatin concentrations increased after the first dose and remained elevated after the administration of the third dose. Latent myostatin concentrations began to decline by day 56 in the 10 and 20 mg/kg dose cohorts and day 84 in the 30 mg/kg dose cohorts