MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. — VialBase Research

Summary

Most elderly patients admitted for hip fracture suffer functional decline, and earlier studies with MK-0677 in hip fracture patients had suggested possible benefits to functional recovery. This randomized, double-blind, multicenter phase IIb study tested that: 123 elderly hip fracture patients were assigned to receive either 25 mg/day of MK-0677 (n = 62) or placebo (n = 61). The primary outcomes were a rank analysis of change during the study in objective functional performance measurements and in blood insulin-like growth factor-1 (IGF-1) levels. At 24 weeks, mean stair climbing power increased by 12.5 W in the MK-0677 group relative to placebo, a non-significant difference (95% CI = -10.95-35.88; p = 0.292). Gait speed did improve, by a 0.7-score difference in the means (95% CI = 0.17-1.28; p = 0.011). Several other functional performance measures showed no improvement in MK-0677-treated patients. The MK-0677 group experienced fewer falls during the study than placebo and a smaller number of patients had any falls, but this did not reach conventional significance (p = 0.096). IGF-1 levels in treated patients increased by 51.4 ng/ml versus placebo (95% CI = 34.42-68.44; p < 0.001). The trial was terminated early due to a safety signal of congestive heart failure in a limited number of patients. The authors’ conclusion is direct: in hip fracture patients treated with 25 mg/day MK-0677, the increase in plasma IGF-1 levels was not paralleled by improvement in most functional performance measures, and MK-0677 has an unfavorable safety profile in this patient population.

Key Findings

• The study was terminated early because of a safety signal of congestive heart failure in a limited number of patients
• The authors state that MK-0677 has an unfavorable safety profile in this patient population — their words, in the abstract’s conclusion
• 123 elderly hip fracture patients randomized double-blind to MK-0677 25 mg/day (n = 62) or placebo (n = 61), across multiple centres
• IGF-1 rose by 51.4 ng/ml versus placebo (95% CI = 34.42-68.44; p < 0.001), confirming the drug engaged its intended biological target
• That IGF-1 increase was not paralleled by improvement in most functional performance measures: stair climbing power was non-significant (12.5 W; 95% CI = -10.95-35.88; p = 0.292), gait speed did improve (0.7-score difference; 95% CI = 0.17-1.28; p = 0.011), and several other measures showed no improvement
• Falls were numerically fewer on MK-0677, both in total and in number of patients with any fall, but the difference did not reach significance (p = 0.096)

Relevance to MK-677

This is the most rigorous human evidence in the MK-677 set — multicenter, randomized, double-blind, placebo-controlled, 123 patients — and it is a negative trial on both axes that matter. On efficacy, the drug did what it is supposed to do biochemically, raising IGF-1 by 51.4 ng/ml, and that biochemical success did not convert into functional recovery: one secondary-looking measure (gait speed) improved, the pre-specified stair climbing power measure did not, and several other functional measures showed nothing. That dissociation is the important lesson, because MK-677 is marketed on exactly the biomarker this trial moved. Raising IGF-1 is not the same as producing a clinical benefit, and here it demonstrably was not. On safety, the trial was stopped early for congestive heart failure occurring in treated patients, and the investigators concluded the safety profile was unfavorable in this population. The population was elderly hip fracture patients, so the cardiac signal cannot be transferred directly to a healthy 30-year-old buying MK-677 online — but a development programme halted for heart failure is a serious datum about an unapproved compound now sold as a supplement, and it is one reason MK-677 never became an approved medicine.

Citation

Adunsky A, Chandler J, Heyden N, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Archives of gerontology and geriatrics. 2011;53(2):183-9. doi:10.1016/j.archger.2010.10.004.

See Also

• Parent compound: MK-677