Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth factor-β superfamily. Preclinical studies demonstrating the potential benefits of targeting the activities of these ligands have fueled the development of numerous biologics capable of perturbing this signaling pathway and increasing muscle mass and function. These biologics have been tested in numerous clinical trials for a wide range of indications characterized by muscle loss and excess adiposity. Here, we review the results of these trials and discuss some of the challenges and future prospects for targeting this signaling pathway to treat muscle and metabolic diseases. Myostatin inhibitors may improve metabolic outcomes by increasing muscle mass, and metabolic disorders may be attractive potential indications for these molecules.

Sarcopenia and frailty represent two burdensome conditions, contributing to a broad spectrum of adverse outcomes. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually in September 2021 to discuss the challenges in the development of drugs for sarcopenia and frailty. Lifestyle interventions are the current mainstay of treatment options in the prevention and management of both conditions. However, pharmacological agents are needed for people who do not respond to lifestyle modifications, for those who are unable to adhere, or for whom such interventions are inaccessible/unfeasible. Preliminary results of ongoing trials were presented and discussed. Several pharmacological candidates are currently under clinical evaluation with promising early results, but none have been approved for either frailty or sarcopenia. The COVID-19 pandemic has reshaped how clinical trials are conducted, in particular by enhancing the usefulness of remote technologies and assessments/interventions.

The Resilience is a construct receiving growing attention from the scientific community in geriatrics and gerontology. Older adults show extremely heterogeneous (and often unpredictable) responses to stressors. Such heterogeneity can (at least partly) be explained by differences in resilience (i.e., the capacity of the organism to cope with stressors). The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met in Boston (MA,USA) on April 20, 2022 to discuss the biological and clinical significance of resilience in older adults. The identification of persons with low resilience and the prompt intervention in this at-risk population may be critical to develop and implement preventive strategies against adverse events. Unfortunately, to date, it is still challenging to capture resilience, especially due to its dynamic nature encompassing biological, clinical, subjective, and socioeconomic factors. Opportunities to dynamically measure resilience were discussed during the ICFSR Task Force meeting, emphasizing potential biomarkers and areas of intervention. This article reports the results of the meeting and may serve to support future actions in the field.

Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults. This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18–34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1–7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study. Eighty-four of 91 (92.3

IMPORTANCE Antibody blockade of the activin type II receptor (ActRII) signaling pathway stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the human monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. OBJECTIVE This multicenter randomized study determined the efficacy and safety of bimagrumab on body composition and glycemic control in adults with overweight and obesity and who had type 2 diabetes. DESIGN This was a double-blind, placebo-controlled 48-week phase 2 study. SETTING Nine sites in the United States and United Kingdom participated in the study from February 2017 through May 2019. PARTICIPANTS Adults (n=75) with body mass index 28–40 kg/m2 64 who had type 2 diabetes and glycated hemoglobin levels 6.5%–10.0%. INTERVENTION Participants were randomized to intravenous bimagrumab or placebo every 4 weeks for 48 weeks. All patients received diet and exercise counseling. MAIN OUTCOME MEASURES The primary endpoint was least squares mean change from baseline (80% CI) to Week 48 in total body fat mass. Key secondary and exploratory endpoints included changes in lean mass, waist circumference, glycated hemoglobin, and body weight from baseline to Week 48. RESULTS At Week 48, 77.3% of patients completed the study. Total body fat mass decreased by 21% in bimagrumab-treated patients vs 0.5% in those treated with placebo (P<0.001). Secondary endpoints for bimagrumab vs placebo included a lean mass increase of 3.6% vs a decrease of 0.8% (P<0.001); waist circumference decrease of 9.00 cm vs increase of 0.45 cm (P<0.001); glycated hemoglobin reduction of 0.76 percentage points vs 0.04 percentage points (P=0.005); and weight reduction of 6.5% vs 0.8% (P<0.001). Bimagrumab was safe and well-tolerated. CONCLUSIONS AND RELEVANCE ActRII blockade with bimagrumab led to marked loss of total body fat, gain in lean mass, and metabolic improvements over 48 weeks in patients with overweight and obesity who had type 2 diabetes. ActRII pathway inhibition provides a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances. TRIAL REGISTRATION Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT03005288.

IMPORTANCE Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. OBJECTIVE To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity. DESIGN, SETTING, AND PARTICIPANTS This double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA(1c)) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis. INTERVENTIONS Patients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. MAIN OUTCOMES AND MEASURES The primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA(1c) level, and body weight (BW) changes from baseline to week 48. RESULTS A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA(1c) level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, -20.5% (-7.5 kg [80% CI, -8.3 to -6.6 kg]) vs -0.5% (-0.18 kg [80% CI, -0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs -0.8% (-0.4 kg [80% CI, -1.0 to 0.1 kg]) (P < .001); WC, -9.0 cm (80% CI, -10.3 to -7.7 cm) vs 0.5 cm (80% CI, -0.8 to 1.7 cm) (P < .001); HbA(1c) level, -0.76 percentage points (80% CI, -1.05 to -0.48 percentage points) vs -0.04 percentage points (80% CI, -0.23 to 0.31 percentage points) (P = .005); and BW, -6.5% (-5.9 kg [80% CI, -7.1 to -4.7 kg]) vs -0.8% (-0.8 kg [80% CI, -1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies. CONCLUSIONS AND RELEVANCE In this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes. ActRII pathway inhibition may provide a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances.

Background Older adult patients (ie, those aged >= 60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. Methods This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15-35 kg/m(2) who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. Findings Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0.2 kg [SD 2.0]) in the bimagrumab 210 mg group (1.9 kg [1.7]; p<0.0001) and in the bimagrumab 700 mg group 2.8 kg [2.2]; p<0.0001) but not in the bimagrumab 70 mg group (0.6 kg [SD 2.2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. Interpretation Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. Copyright (C) 2021 The Authors. Published by Elsevier Ltd.

Background: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. Methods: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. Results: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. Conclusions: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

OBJECTIVES To develop an evidence-based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self-reported mobility limitation, falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literature review and SDOC's analyses of eight epidemiologic studies, six randomized clinical trials, four cohort studies of special populations, and two nationally representative population-based studies. METHODS Thirteen position statements related to the putative components of a sarcopenia definition, informed by the SDOC analyses and literature synthesis, were reviewed by an independent international expert panel (panel) iteratively and voted on by the panel during the Sarcopenia Position Statement Conference. Four position statements related to grip strength, three to lean mass derived from dual-energy x-ray absorptiometry (DXA), and four to gait speed; two were summary statements. RESULTS The SDOC analyses identified grip strength, either absolute or scaled to measures of body size, as an important discriminator of slowness. Both low grip strength and low usual gait speed independently predicted falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults. Lean mass measured by DXA was not associated with incident adverse health-related outcomes in community-dwelling older adults with or without adjustment for body size. CONCLUSION The panel agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia. These position statements offer a rational basis for an evidence-based definition of sarcopenia. The analyses that informed these position statements are summarized in this article and discussed in accompanying articles in this issue of the journal. J Am Geriatr Soc 68:1410-1418, 2020.

Key Points Question What is the effect on physical function of adding bimagrumab treatment to optimized standard of care in community-dwelling older adults with sarcopenia? Findings In this randomized clinical trial in 180 adults aged 70 years and older meeting the criteria for sarcopenia, there was no statistically significant difference in improvement in physical function between bimagrumab vs placebo. Participants who received bimagrumab had increased lean body mass and reduced fat mass vs placebo. Meaning These findings suggest that the addition of bimagrumab does not substantially enhance the effect of adequate diet and habitual light exercise, which can improve physical function and reduce the impact of sarcopenia in older adults.

Bimagrumab prevents activity of myostatin and other negative regulators of skeletal muscle mass. This randomized double‐blind, placebo‐controlled study investigated safety, pharmacokinetics (PK), and pharmacodynamics of bimagrumab in healthy older and obese adults.

Background: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab on skeletal muscle mass, strength, and physical function in community-dwelling older adults with sarcopenia. Design: Randomized, double-blind, placebo-controlled. Setting: 38 sites in 13 countries. Participants: 180 community-dwelling, men and women aged ≥70 years meeting gait speed and skeletal muscle criteria for sarcopenia. Intervention: Bimagrumab 700 mg (n=113) or placebo (n=67) monthly for 6-months with appropriate diet and home-based exercise. Measurements: Short Physical Performance Battery (SPPB), 6-minute walk distance (6MWD), gait speed, handgrip strength, total lean body mass (LBM), and standard safety parameters. Results: 159/180 (88.3%) participants (mean age: 79.1 years; 60.6% women) completed the study. Bimagrumab was safe, well-tolerated and increased LBM by 6.0% over placebo (P<0.001). The mean SPPB score increased by 1.34 (0.90–1.77, mean, 95%CI) with bimagrumab versus 1.03 (0.53–1.52) with placebo (P=0.134); 6MWD increased by 24.60 m (7.65–41.56 m) versus 14.30 m (−4.64–33.23 m; P=0.163); and gait speed increased by 0.14 m/s (0.09–0.18 m/s) versus 0.11 m/s (0.05–0.16 m/s; P=0.161). Handgrip strength did not change. Limitation: Powered only for key functional endpoints. Conclusion: Bimagrumab treatment over 6-months was safe, well-tolerated and increased LBM in community-dwelling older adults with sarcopenia. Appropriate nutrition and exercise improved physical performance in this vulnerable population; bimagrumab did not significantly enhance this effect. At the completion of the study, a majority of participants in both treatment groups no longer met sarcopenia criteria. Sarcopenia, an increasing cause of disability in the elderly, is reversible with proper diet and exercise. ClinicalTrials.gov identifier: NCT02333331 Keywords: bimagrumab; sarcopenia; muscle; lean body mass; SPPB; gait speed; 6-minute walk test

RATIONALE:Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators. OBJECTIVES:To assess the effects of bimagrumab on skeletal muscle mass and function in patients with chronic obstructive pulmonary disease (COPD) and reduced skeletal muscle mass. METHODS:Sixty-seven patients with COPD (mean FEV1, 1.05 L [41.6% predicted]; aged 40-80 yr; body mass index < 20 kg/m2 or appendicular skeletal muscle mass index ≤ 7.25 [men] and ≤ 5.67 [women] kg/m2), received two doses of either bimagrumab 30 mg/kg intravenously (n = 33) or placebo (n = 34) (Weeks 0 and 8) over 24 weeks. MEASUREMENTS AND MAIN RESULTS:We assessed changes in thigh muscle volume (cubic centimeters) as the primary endpoint along with 6-minute-walk distance (meters), safety, and tolerability. Fifty-five (82.1%) patients completed the study. Thigh muscle volume increased by Week 4 and remained increased at Week 24 in bimagrumab-treated patients, whereas no changes were observed with placebo (Week 4: +5.9% [SD, 3.4%] vs. 0.0% [3.3%], P < 0.001; Week 8: +7.0% [3.7%] vs. -0.7% [2.8%], P < 0.001; Week 16: +7.8% [5.1%] vs. -0.9% [4.5%], P < 0.001; Week 24: +5.0% [4.9%] vs. -1.3% [4.3%], P < 0.001). Over 24 weeks, 6-minute-walk distance did not increase significantly in either group. Adverse events in the bimagrumab group included muscle-related symptoms, diarrhea, and acne, most of which were mild in severity. CONCLUSIONS:Blocking the action of negative muscle regulators through the activin type II receptors with bimagrumab treatment safely increased skeletal muscle mass but did not improve functional capacity in patients with COPD and low muscle mass. Clinical trial registered with www.clinicaltrials.gov (NCT01669174).

Purpose of ReviewThis paper aims to provide an overview of sarcopenia, an enigmatic skeletal muscle disease where age, disuse, injury, and chronic disease can all contribute to the accelerated loss of mass and strength beyond normal variation, and that can negatively affect a person's physical function and quality of life.Recent FindingsA rapid and pervasive "graying" of societies worldwide is expected to continue in the coming decades. Due to this projected increase in the number of older adults, sarcopenia and its associated costs will be a significant public health concern. New international guidelines address the need for clinic-based approaches to identify vulnerable patients through quick and simple screening, while lifestyle-based interventions including resistance exercise training, general physical activity, and adequate nutrition remain the mainstays of treatment. The development of new, viable treatment options, including nutrition products and pharmacotherapy, are progressing with results expected in the near future.SummaryThe refinement of diagnostic criteria, recent designation as an internationally recognized medical condition, and the introduction of evidence-based treatment, is advancing sarcopenia as a treatable disease for a rapidly growing population of patients.

Background Digital technologies and advanced analytics have drastically improved our ability to capture and interpret health-relevant data from patients. However, only limited data and results have been published that demonstrate accuracy in target indications, real-world feasibility, or the validity and value of these novel approaches. Objective This study aimed to establish accuracy, feasibility, and validity of continuous digital monitoring of walking speed in frail, elderly patients with sarcopenia and to create an open source repository of raw, derived, and reference data as a resource for the community. Methods Data described here were collected as a part of 2 clinical studies: an independent, noninterventional validation study and a phase 2b interventional clinical trial in older adults with sarcopenia. In both studies, participants were monitored by using a waist-worn inertial sensor. The cross-sectional, independent validation study collected data at a single site from 26 naturally slow-walking elderly subjects during a parcours course through the clinic, designed to simulate a real-world environment. In the phase 2b interventional clinical trial, 217 patients with sarcopenia were recruited across 32 sites globally, where patients were monitored over 25 weeks, both during and between visits. Results We have demonstrated that our approach can capture in-clinic gait speed in frail slow-walking adults with a residual standard error of 0.08 m per second in the independent validation study and 0.08, 0.09, and 0.07 m per second for the 4 m walk test (4mWT), 6-min walk test (6MWT), and 400 m walk test (400mWT) standard gait speed assessments, respectively, in the interventional clinical trial. We demonstrated the feasibility of our approach by capturing 9668 patient-days of real-world data from 192 patients and 32 sites, as part of the interventional clinical trial. We derived inferred contextual information describing the length of a given walking bout and uncovered positive associations between the short 4mWT gait speed assessment and gait speed in bouts between 5 and 20 steps (correlation of 0.23) and longer 6MWT and 400mWT assessments with bouts of 80 to 640 steps (correlations of 0.48 and 0.59, respectively). Conclusions This study showed, for the first time, accurate capture of real-world gait speed in slow-walking older adults with sarcopenia. We demonstrated the feasibility of long-term digital monitoring of mobility in geriatric populations, establishing that sufficient data can be collected to allow robust monitoring of gait behaviors outside the clinic, even in the absence of feedback or incentives. Using inferred context, we demonstrated the ecological validity of in-clinic gait assessments, describing positive associations between in-clinic performance and real-world walking behavior. We make all data available as an open source resource for the community, providing a basis for further study of the relationship between standardized physical performance assessment and real-world behavior and independence.

Sarcopenia, the associated loss of skeletal muscle mass and strength and impaired physical function seen with aging, is a growing, global public health challenge in need of accepted, proven treatments that address the needs of a broad range of older adults. While exercise, primarily resistance training, and increased dietary protein have been shown to delay and even reverse losses in muscle mass, strength and physical function seen with aging, proven treatments that are accessible globally, cost effective and sustainable by patients are needed. While no drug has yet demonstrated the substantial safety and clinical value needed to be the first pharmacological therapy registered for muscle wasting or sarcopenia, the field is active. Several approaches to treating the muscle loss and subsequent functional decline are being studied in a variety of patient populations across every continent. We provide a review of the leading programs and approaches and available findings from recent studies. In addition, we briefly discuss several related issues needed to facilitate the development of a safe and efficacious pharmacotherapeutic that could be used as part of a treatment plan for older men and women with sarcopenia.

Digital technologies and advanced analytics have drastically improved our ability to capture and interpret health relevant data from patients. However, to date, limited data and results have been published detailing real-world patient compliance, demonstrating accuracy in target indications or examining what novel insights and clinical value can be derived. Here we present novel, digital mobility data from two studies: an independent, non-interventional validation study with elderly, naturally slow walking subjects, and a global, multi-site phase IIb clinical trial involving patients with age-related muscle loss and slow walking speed (sarcopenia). Based on these data, we validate the accuracy of a novel algorithm for capturing in-clinic and real-world gait speed in frail, slow-walking adults. We demonstrate the feasibility of continuous monitoring with a wearable inertial sensor in elderly adults in real-world settings, and propose minimum thresholds for compliance required for robust capture of gait behaviors in this population. We also show how simple, inferred contextual information, describing the length of a given walking bout, can explain some of the variation in real-world gait speed, and use this information to demonstrate for the first time a relationship between in-clinic performance and real-world gait speed behavior. This work lays a foundation for exploration of the clinical relevance and value of such measures and is a first step in building a more complete chain of evidence between standardized physical performance assessment, real-world behavior, and subjective perceptions of mobility, independence and health. This dataset contains data collected during the independent validation study: derived data from raw accelerometry data, and summary performance data. The full dataset, including raw accelerometry data, is available here: https://s3.console.aws.amazon.com/s3/buckets/mueller-et-al-2019

AimTo test the hypothesis that an improving body composition in insulin‐resistant individuals could enhance insulin sensitivity.MethodsA total of 16 people with a mean body mass index of 29.3 kg/m2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at week 10 for insulin sensitivity, using a hyperinsulinaemic‐euglycaemic clamp and an intravenous glucose tolerance test (IVGTT), and for body composition using dual energy X‐ray absorptiometry and positron‐emission tomography.ResultsBimagrumab increased lean mass by 2.7% (P < .05) and reduced fat mass by 7.9% (P = .011) at week 10 compared with placebo, and had a neutral effect on body weight. Bimagrumab reduced glycated haemoglobin by 0.21% at week 18 (P < .001) and improved insulin sensitivity by ~20% (according to the clamp) to ~40% (according to the IVGTT).ConclusionTaking the observed changes together, and given that these occurred without accompanying dietary intervention and without any prescribed regular physical exercise, bimagrumab may offer a novel approach for the treatment of the metabolic complications of obesity.

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.

SummaryBackgroundBimagrumab 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.AimTo evaluate the effect of bimagrumab on the pituitary‐gonadal and pituitary‐adrenal axes in humans.MethodsHealthy men and women, aged 55 to 75 years, received bimagrumab intravenously 10 mg/kg or placebo on Day 1 and Day 29. Pituitary‐gonadal and pituitary‐adrenal functions were evaluated with basal hormone measurement and standard gonadotropin‐releasing hormone (GnRH) and adrenocorticotropic hormone (ACTH) stimulation tests at baseline, Week 8 and at the end of study (EOS)—Week 20.ResultsAt Week 8, follicle‐stimulating hormone (FSH) levels were reduced by 42.16 IU/L (P < .001) and luteinizing hormone (LH) levels were increased by 2.5 IU/L (P = .08) over placebo in response to bimagrumab in women but not in men. Effects that were reversible after bimagrumab was cleared. Gonadal and adrenal androgen levels were not affected by exposure to bimagrumab.ConclusionBimagrumab alters the function of pituitary gonadotroph cells, consistent with blockade of activin on local ActRII. This effect is reversible with clearance of bimagrumab. Bimagrumab did not impact gonadal and adrenal androgen secretion.