A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody Ly2495655 Versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty

Abstract

Background: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. Objectives: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. Design: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period. Setting: Forty-two sites in 11 countries. Participants: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization. Intervention: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. Measurements: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. Results: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. Conclusion: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.

A follistatin‐based molecule increases muscle and bone mass without affecting the red blood cell count in mice

“…Activins and growth differentiation factors (GDFs) belong to the TGF-b superfamily, and activins together with some GDFs prompt Smad2/3 signaling through activin type II receptors (ActRIIs; ActRIIA and ActRIIB) (8)(9)(10)(11)(12). Inhibitors of the activin receptor signaling pathway (IASPs) are based on various approaches, including: 1) soluble decoy receptors that trap ligands extracellularly and consist of ActRIIA or ActRIIB ectodomains fused with the Fc portion of human IgG1 (13,14); 2) neutralizing antibodies, peptibodies, or adnectins against ligands (15)(16)(17)(18)(19)(20)(21); 3) antibodies against ActRIIA or ActRIIB (or both) that prevent ligand-receptor interaction (22,23); and 4) endogenous TGF-b superfamily antagonists, such as GDFassociated serum protein (24) or follistatin (FST) (25,26).…”

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs

“…Safety was also an issue for Landogrozumab because of a high frequency of serious adverse events and survival concerns in subjects with pancreatic cancer ( 359 ). Similar concerns were not evident in trials with older fallers ( 358 ) or subjects with hip arthroplasty ( 360 ), and deaths in subjects with pancreatic cancer were mostly disease-related ( 359 ).…”

Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial

“…An expected low level of function was the main reason for selecting patients with a recent hip fracture, rather than those who had undergone elective total hip arthroplasty. 34 Of note, these improvements were observed independently of the rehabilitation programme, which was not standardised or managed in this study.…”