Daniel Rooks

Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia

Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death.

DESIGNING PHARMACEUTICAL TRIALS FOR SARCOPENIA IN FRAIL OLDER ADULTS: EU/US TASK FORCE RECOMMENDATIONS

An international task force of academic and industry leaders in sarcopenia research met on December 5, 2012 in Orlando, Florida to develop guidelines for designing and executing randomized clinical trials of sarcopenia treatments. The Task Force reviewed results from previous trials in related disease areas to extract lessons relevant to future sarcopenia trials, including practical issues regarding the design and conduct of trials in elderly populations, the definition of appropriate target populations, and the selection of screening tools, outcome measures, and biomarkers. They discussed regulatory issues, the challenges posed by trials of different types of interventions, and the need for standardization and harmonization. The Task Force concluded with recommendations for advancing the field toward better clinical trials.

Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof‐of‐Concept Study

To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations.

Bimagrumab improves body composition and insulin sensitivity in insulin‐resistant individuals

To test the hypothesis that an improving body composition in insulin‐resistant individuals could enhance insulin sensitivity.

Effect of bimagrumab on thigh muscle volume and composition in men with casting‐induced atrophy

Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization.

Developing and Implementing Performance Outcome Assessments: Evidentiary, Methodologic, and Operational Considerations

The use of performance outcome (PerfO) assessments to measure cognitive or physical function in drug trials presents several challenges for both sponsors and regulators, owing in part to a relative lack of scientific guidance on their development, implementation, and interpretation. In December 2016, the Duke-Margolis Center for Health Policy convened a 2-day workshop to explore the evidentiary, methodologic, and operational challenges associated with PerfO measures, and to identify potential paths to addressing these challenges. This paper presents both a summary of the discussion as well as additional input from a working group of experts from FDA, industry, academia, and public-private consortia. It is intended to advance the discussion around the development and use of PerfO measures to assess patient functioning in clinical trials intended to support registration of new treatments, and to highlight the key gaps in knowledge where additional research, collaboration, and discussion are needed.

Reply to:: New Hope for Sarcopenia

only 9 received a second dose at Day 57. In contrast to the early effect (from Week 2) of bimagrumab on the increase in thigh muscle volume, there was no additional effect with the second dose at Week 16, although there was an increase in thigh muscle volume at the end of study (Week 24). The early effect of bimagrumab on thigh muscle volume was a remarkable result. In contrast to bimagrumab, other myostatin antibody showed no significant effect on the increase in appendicular lean body mass at Week 12 but the effect was observed at Week 24. To understand the difference of onset of action among the myostatin inhibitor, plausible explanations such as pharmacokinetic data of bimagrumab should be supported. Second, it is not clear why the sample size was calculated to show the difference in gait speed (one of the secondary endpoints of the study) instead of the primary endpoint (thigh muscle volume change). Because there was no significant difference in gait speed between bimagrumab and placebo, this study failed to show any significant effect of bimagrumab with this sample size. Third, protein intake and exercise are important factors associated with skeletal muscle mass and function. Accordingly, data regarding protein intake and exercise should be presented and adjusted for the independent effect of bimagrumab on skeletal muscle mass and function. Finally, the authors found greater improvement in gait speed and 6-minute walk distance in slow walkers. It would be interesting to see whether the improvement in gait speed or walking distance was greater in participants with greater muscle mass increase with bimagrumab. I believe that addressing these points would increase the transparency of this study.

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes

Bimagrumab is a human monoclonal antibody inhibitor of activin type II receptors (ActRII), with anabolic action on skeletal muscle mass by blocking binding of myostatin and other negative regulators of muscle growth. Bimagrumab is under evaluation for muscle wasting and associated functional loss in hip fracture and sarcopenia, and in obesity. Bimagrumab also blocks other endogenous ActRII ligands, such as activins, which act on the neurohormonal axes, pituitary, gonads and adrenal glands.