Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof-of-Concept Study
01 Sep 2017-Journal of the American Geriatrics Society (John Wiley & Sons, Ltd)-Vol. 65, Iss: 9, pp 1988-1995
TL;DR: To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations, a large number of patients with these conditions are referred to a single hospital for evaluation.
Abstract: Objectives
To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations.
Design
A 24-week, randomized, double-blind, placebo-controlled, parallel-arm, proof-of-concept study.
Setting
Five centers in the United States.
Participants
Community-dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women.
Intervention
Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21).
Measurements
Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6-minute walk distance (6MWD).
Results
Thirty-two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab-treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 ± 2.19% vs −0.34 ± 2.59%, P < .001; Week 4: 6.12 ± 2.56% vs 0.16 ± 3.42%, P < .001; Week 8: 8.01 ± 3.70% vs 0.35 ± 3.32%, P < .001; Week 16: 7.72 ± 5.31% vs 0.42 ± 5.14%, P < .001; Week 24: 4.80 ± 5.81% vs −1.01 ± 4.43%, P = .002). Participants with slower walking speed at baseline receiving bimagrumab had clinically meaningful and statistically significantly greater improvements in gait speed (mean 0.15 m/s, P = .009) and 6MWD (mean 82 m, P = .022) than those receiving placebo at Week 16. Adverse events in the bimagrumab group included muscle-related symptoms, acne, and diarrhea, most of which were mild in severity and resolved by the end of study.
Conclusion
Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed.
Citations
More filters
TL;DR: Differences in conceptual definition of sarcopenia in the elderly and in CKD are discussed, as well as etiology of sarc Openia, prevalence, outcome, and interventions that attempted to reverse the loss of muscle mass, strength and mobility in CKd and ESKD patients are described.
Abstract: The term sarcopenia was first introduced in 1988 by Irwin Rosenberg to define a condition of muscle loss that occurs in the elderly. Since then, a broader definition comprising not only loss of muscle mass, but also loss of muscle strength and low physical performance due to ageing or other conditions, was developed and published in consensus papers from geriatric societies. Sarcopenia was proposed to be diagnosed based on operational criteria using two components of muscle abnormalities, low muscle mass and low muscle function. This brought awareness of an important nutritional derangement with adverse outcomes for the overall health. In parallel, many studies in patients with chronic kidney disease (CKD) have shown that sarcopenia is a prevalent condition, mainly among patients with end stage kidney disease (ESKD) on hemodialysis (HD). In CKD, sarcopenia is not necessarily age-related as it occurs as a result of the accelerated protein catabolism from the disease and from the dialysis procedure per se combined with low energy and protein intakes. Observational studies showed that sarcopenia and especially low muscle strength is associated with worse clinical outcomes, including worse quality of life (QoL) and higher hospitalization and mortality rates. This review aims to discuss the differences in conceptual definition of sarcopenia in the elderly and in CKD, as well as to describe etiology of sarcopenia, prevalence, outcome, and interventions that attempted to reverse the loss of muscle mass, strength and mobility in CKD and ESKD patients.
168 citations
TL;DR: A systematic review of the CT literature found considerable variation in the CT approaches used for the assessment of muscle mass and myosteatosis, and there is a need to develop consensus for CT-based evaluation of sarcopenia and mysteatosis.
Abstract: Background/objective There is increasing use of computed tomography (CT) in sarcopenia research using a wide variety of techniques. We performed a systematic review of the CT literature to identify the differences between approaches used. Methods A comprehensive search of PubMed from 1983 to 2017 was performed to identify studies that used CT muscle measurements to assess muscle mass and myosteatosis. The CT protocols were evaluated based on anatomic landmark(s), thresholding, muscle(s) segmented, key measurement (ie, muscle attenuation, cross-sectional area, volume), derived variables, and analysis software. From the described search, 657 articles were identified and 388 studies met inclusion criteria for this systematic review. Results Muscle mass was more commonly assessed than myosteatosis (330 vs. 125). The most commonly assessed muscle or muscle groups were total abdominal wall musculature (142/330 and 49/125 for muscle mass and myosteatosis, respectively) and total thigh musculature (90/330 and 48/125). The most commonly used landmark in the abdomen was the L3 vertebra (123/142 and 45/49 for muscle mass and myosteatosis, respectively). Skeletal muscle index and intermuscular adipose tissue were the most commonly used measures of abdominal wall muscle mass (114/142) and myosteatosis (27/49), respectively. Cut points varied across studies. A significant majority of studies failed to report important CT technical parameters, such as use of intravenous contrast and slice thickness (94% and 63%, respectively). Conclusions There is considerable variation in the CT approaches used for the assessment of muscle mass and myosteatosis. There is a need to develop consensus for CT-based evaluation of sarcopenia and myosteatosis.
153 citations
TL;DR: The utility of phage display as a powerful platform for therapeutic antibodies discovery is illustrated and all the approved mAbs derived fromphage display are described.
Abstract: Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage–derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display.
116 citations
TL;DR: The purpose of this umbrella review was to assess the associations between sarcopenia and adverse health‐related outcomes.
Abstract: Objective The purpose of this umbrella review was to assess the associations between sarcopenia and adverse health-related outcomes. Design An umbrella review of meta-analyses of observational studies. Setting and participants Patients with sarcopenia and controls without sarcopenia were included. Measures The PubMed, Web of Science and Embase were searched for relevant systematic review and meta-analysis. AMSTAR and GRADE system were used for methodological quality and evidence quality assessments, respectively. Results Totally 54 outcomes extracted from 30 meta-analyses were analyzed. Twenty out of 21 prognostic outcomes indicated that sarcopenia was significantly associated with poorer prognosis of gastric cancer, hepatocellular cancer, urothelial cancer, head and neck cancer, hematological malignancy, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, esophageal cancer, and ovarian cancer. Besides, 10 out of 16 postoperative outcomes suggested that sarcopenia significantly increased the risk of multiple postoperative complications and prolonged the length of hospitalization of patients with digestive cancer. In age-related outcomes, sarcopenia significantly increased the risk of dysphagia, cognitive impairment, fractures, falls, hospitalization, and all-cause mortality of elderly populations. Moreover, sarcopenia was also associated with higher level of albuminuria, risk of depression, and several metabolic diseases. Conclusions and implications Sarcopenia significantly affected a wide range of adverse health-related outcomes, particularly in patients of tumor and elderly populations. Because evidences of most outcomes were rated as "low" and "very low," more prospective cohort studies are required in the future.
103 citations
TL;DR: Sarcopenia is a risk factor for pneumonia in older people, and aspiration pneumonia inpatients with low muscle mass show high mortality rates.
Abstract: Pneumonia is a major cause of death in older people, and the number of such deaths is increasing. Present guidelines for pneumonia management are based on a pathogen-oriented strategy that relies on the optimal application of antibiotics. Older pneumonia inpatients show the high incidence of aspiration pneumonia. The main cause of aspiration pneumonia is an impairment in the swallowing and cough reflexes. These facts suggest a limitation of present management strategies and a requirement for new strategies for aspiration pneumonia. Sarcopenia is the loss of muscle strength and mass, and declining physical function with aging. Recently, a decrease in the mass or strength of the swallowing muscles was suggested to be associated with reduced swallowing function. Accordingly, dysphagia caused by sarcopenia of the systemic and swallowing-related muscles was named sarcopenic dysphagia. Presently, few studies have shown associations between aspiration pneumonia and sarcopenic dysphagia. As for the cough reflex, strong cough prevents aspiration pneumonia, and its strength is regulated by respiratory muscles. A few studies have reported a relationship between muscles and pneumonia in older people. Sarcopenia is a risk factor for pneumonia in older people, and aspiration pneumonia inpatients with low muscle mass show high mortality rates. Aspiration pneumonia induced muscle atrophy in respiratory, swallowing, and skeletal muscles in an animal model and humans. Associations between respiratory muscle strength and pneumonia are currently under investigation. Evaluation and management of sarcopenia could potentially become a new strategy to prevent and treat pneumonia in older patients, and research has only recently been launched. Geriatr Gerontol Int 2020; 20: 7-13.
91 citations
References
More filters
TL;DR: The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia as discussed by the authors.
Abstract: The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics-European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as 'presarcopenia', 'sarcopenia' and 'severe sarcopenia'. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.
8,440 citations
TL;DR: In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults and predicted survival was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function.
Abstract: Context Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates. Objective To evaluate the relationship between gait speed and survival. Design, Setting, and Participants Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34 485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s. Main Outcome Measures Survival rates and life expectancy. Results There were 17 528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P Conclusion In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.
3,393 citations
"Treatment of Sarcopenia with Bimagr..." refers background in this paper
...1 m/s and 25–50 m, respectively).(11,16) Bimagrumab was safe and well tolerated in older adults with low muscle mass and slower walking speed meeting the criteria for sarcopenia....
[...]
TL;DR: High-intensity resistance exercise training is a feasible and effective means of counteracting muscle weakness and physical frailty in very elderly people, in contrast to multi-nutrient supplementation without concomitant exercise, which does not reduce muscle weakness orPhysical frailty.
Abstract: Background Although disuse of skeletal muscle and undernutrition are often cited as potentially reversible causes of frailty in elderly people, the efficacy of interventions targeted specifically at these deficits has not been carefully studied. Methods We conducted a randomized, placebo-controlled trial comparing progressive resistance exercise training, multinutrient supplementation, both interventions, and neither in 100 frail nursing home residents over a 10-week period. Results The mean (±SE) age of the 63 women and 37 men enrolled in the study was 87.1 ±0.6 years (range, 72 to 98); 94 percent of the subjects completed the study. Muscle strength increased by 113 ±8 percent in the subjects who underwent exercise training, as compared with 3 ±9 percent in the nonexercising subjects (P<0.001). Gait velocity increased by 11.8 ±3.8 percent in the exercisers but declined by 1.0 ±3.8 percent in the nonexercisers (P = 0.02). Stair-climbing power also improved in the exercisers as compared with the nonexercis...
2,722 citations
United States Department of Agriculture1, French Institute of Health and Medical Research2, Research Triangle Park3, Boston University4, Saint Louis University5, University of Pittsburgh6, University of Erlangen-Nuremberg7, Nestlé8, Uppsala University9, Merck & Co.10, Sapienza University of Rome11, National Institutes of Health12, Novartis13, University of Verona14
TL;DR: Sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health, and 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.
2,378 citations
TL;DR: The magnitude of small meaningful and substantial individual change in physical performance measures is estimated and their responsiveness is evaluated to evaluate their responsiveness.
Abstract: OBJECTIVES: To estimate the magnitude of small meaningful and substantial individual change in physical performance measures and evaluate their responsiveness.
DESIGN: Secondary data analyses using distribution- and anchor-based methods to determine meaningful change.
SETTING: Secondary analysis of data from an observational study and clinical trials of community-dwelling older people and subacute stroke survivors.
PARTICIPANTS: Older adults with mobility disabilities in a strength training trial (n=100), subacute stroke survivors in an intervention trial (n=100), and a prospective cohort of community-dwelling older people (n=492).
MEASUREMENTS: Gait speed, Short Physical Performance Battery (SPPB), 6-minute-walk distance (6MWD), and self-reported mobility.
RESULTS: Most small meaningful change estimates ranged from 0.04 to 0.06 m/s for gait speed, 0.27 to 0.55 points for SPPB, and 19 to 22 m for 6MWD. Most substantial change estimates ranged from 0.08 to 0.14 m/s for gait speed, 0.99 to 1.34 points for SPPB, and 47 to 49 m for 6MWD. Based on responsiveness indices, per-group sample sizes for clinical trials ranged from 13 to 42 for substantial change and 71 to 161 for small meaningful change.
CONCLUSION: Best initial estimates of small meaningful change are near 0.05 m/s for gait speed, 0.5 points for SPPB, and 20 m for 6MWD and of substantial change are near 0.10 m/s for gait speed, 1.0 point for SPPB, and 50 m for 6MWD. For clinical use, substantial change in these measures and small change in gait speed and 6MWD, but not SPPB, are detectable. For research use, these measures yield feasible sample sizes for detecting meaningful change.
1,833 citations
"Treatment of Sarcopenia with Bimagr..." refers background or methods or result in this paper
...Gait speed was assessed over 6 m, with the first meter to allow for acceleration to a consistent speed of usual walking before measurement over 4 m and the final meter beyond the end of 4 m to avoid deceleration during the measured distance.(11) The fastest of two recorded trials following one practice trial was used for analysis....
[...]
...1 m/s more over baseline at Week 16 in the intervention group than in the placebo group.(11) An initial comparison of changes in gait speed according to treatment group showed similar increases in both treatment arms (Figure 2E), but when changes from baseline were plotted against baseline gait speed, visual inspection suggested that the increase from baseline was greater for participants with slower baseline speed....
[...]
...1 m/s and 25–50 m, respectively).(11,16) Bimagrumab was safe and well tolerated in older adults with low muscle mass and slower walking speed meeting the criteria for sarcopenia....
[...]
...The cut-off of 300 m was based on a distance of less than the fifth percentile for healthy older adults.(11,13) The group of slower walkers (6MWD <300 m) that received Table 1....
[...]