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Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial

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Summary

Background

Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power.

Methods

In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408.

Findings

Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was −0·123 kg (95% CI −0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively −0·46 s (p=0·093), −1·28 s (p=0·011), −4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY.

Interpretation

Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers.

Funding

Eli Lilly and Company.

Introduction

Skeletal muscle strength and power decrease with ageing, leading to mobility disability, reduced physical activity, high risk for falls and related injuries, reduced quality of life, institutionalisation, and death.1, 2 The current standard of care for decreased lower limb muscle strength or power (risk factors for mobility impairment or falls) relies on resistance exercise,3, 4 but its efficacy is variable5 and its implementation is often limited by medical and logistical challenges commonly experienced by older adults who are mobility limited.6, 7 A drug that increases muscle strength and power in older people could prevent poor outcomes that often affect people in the last decades of life.1

Myostatin, a member of the TGFβ superfamily, binds to activin receptor IIb8 and inhibits muscle protein synthesis through the AKT–mTOR pathway.9 Postnatal inhibition of myostatin stimulates muscle protein synthesis resulting in muscle hypertrophy in mice.10 This hypertrophy translates into increased physical performance in rodent models.11, 12 Conversely, it was reported that muscle quality and specific force (force/mass) is decreased in myostatin-knockout mouse models.13 It is unknown whether these results will translate to human beings.

Research in context

Evidence before this study

Age-associated muscle weakness is responsible for several poor outcomes in older people, including mobility disability, fall-related injuries, institutionalisation, and death. The standard of care for low muscle strength or power relies on resistance exercise training, but its efficacy is variable and its implementation often challenging in older disabled people. A drug that increases muscle power could prevent these poor outcomes. We searched PubMed up to April 1, 2015, with the search terms “clinical” and “trial” and [myostatin or activin] for clinical trials testing drugs that target myostatin or its receptor (AcRIIb) with no language restrictions. Although several molecules have been reported that increase muscle mass or its surrogate, lean mass, the data available about physical performance are limited. Positive effects were reported on 6 min walking distance with bimagrumab (AcRIIb antibody) in 11 patients with sporadic inclusion body myositis versus three patients given placebo, and with follistatin (natural myostatin inhibitor) gene therapy in six patients with Becker muscular dystrophy in an open-label clinical trial. Apart from the design and size limitations of these previous trials, it was unknown whether effects recorded in a purely muscular disorder (such as sporadic inclusion body myositis or Becker muscular dystrophy) would translate into older fallers whose impaired physical performance is generally multifactorial.

Added value of this study

We did a clinical trial testing an antimyostatin antibody in 201 older fallers with low muscle strength. In addition to achieving the primary endpoint (increase in appendicular lean mass), this antibody showed efficacy on several measures of physical performance, predominantly those that are heavily dependent on muscle power (consistent with the mechanism of action) and that are functional (eg, climbing stairs). This trial provides the first robust demonstration that inhibiting myostatin increases lean mass in older weak fallers and most importantly that these changes in lean mass translate into an improved physical performance which is what matters to these patients.

Implications of all the available evidence

Although the clinical importance of these improvements and this antibody's safety remain to be formally shown in larger confirmatory trials, LY might provide significant benefits to this high-risk older population, both in terms of quality of life and prevention of adverse outcomes such as fall related injuries or mobility disability.

LY2495655 (LY) is a humanised monoclonal antibody that neutralises the activity of the myostatin protein. In a dose-escalation phase 1 trial,14 LY treatment increased thigh muscle volume of healthy volunteers. Here, we present the efficacy and safety results of a 36-week, phase 2 study of LY in older fallers with low muscle strength and power, a population at high risk for future falls.

Section snippets

Study design and patients

This phase 2 randomised, proof-of-concept, double-blind, placebo-controlled, parallel group, outpatient study was done at 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients were aged 75 years or older, had fallen once or more in the past year, had a hand grip strength of 37 kg or less for men or 21 kg or less for women, and took 12 s or longer to rise five times from a chair with arms folded on the chest or were unable to complete this

Results

Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. After application of our exclusion criteria, we randomly assigned 201 patients to receive either placebo (n=99) or LY (n=102; figure 1). Of these patients, 167 (83%) completed treatment (85 [86%] patients given placebo and 82 [80%] patients given LY), and 169 (84%) completed the study. Table 1 shows baseline characteristics: the study population had a mean age of 82 years, with 140 (70%) women. The LY group had a higher number

Discussion

This study showed that 24 weeks of LY treatment increases aLBM compared with placebo in older fallers with low muscle strength and power. We also recorded a treatment effect of LY on several performance-based measures assessed, including stair climbing, fast gait speed, and a chair rise test.

These results are consistent with the increase in thigh muscle volume (assessed by MRI) reported during LY treatment in a single dose phase 1 trial in healthy volunteers.14 Other compounds targeting

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