Effect of Bimagrumab on body composition: a systematic review and meta-analysis.

BACKGROUND: Sarcopenia, a condition marked by progressive muscle mass and function decline, presents significant challenges in aging populations and those with chronic illnesses. Current standard treatments such as dietary interventions and exercise programs are often unsustainable. There is increasing interest in pharmacological interventions like bimagrumab, a monoclonal antibody that promotes muscle hypertrophy by inhibiting muscle atrophy ligands. Bimagrumab has shown effectiveness in various conditions, including sarcopenia. AIM: The primary objective of this meta-analysis is to evaluate the impact of bimagrumab treatment on both physical performance and body composition among patients diagnosed with sarcopenia. MATERIALS AND METHODS: This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched PubMed, Ovid/Medline, Web of Science, and the Cochrane Library databases up to June 2024 using appropriate Medical Subject Headings (MeSH) terms and keywords related to bimagrumab and sarcopenia. Eligible studies were randomized controlled trials (RCTs) that assessed the effects of bimagrumab on physical performance (e.g., muscle strength, gait speed, six-minute walk distance) and body composition (e.g., muscle volume, fat-free body mass, fat body mass) in patients with sarcopenia. Data extraction was independently performed by two reviewers using a standardized form, with discrepancies resolved through discussion or consultation with a third reviewer. RESULTS: From an initial search yielding 46 records, we screened titles, abstracts, and full texts to include seven RCTs in our meta-analysis. Bimagrumab treatment significantly increased thigh muscle volume (mean difference [MD] 5.29%, 95% confidence interval [CI] 4.08% to 6.50%, P < 0.001; moderate heterogeneity χ2 = 6.41, I2 = 38%, P = 0.17) and fat-free body mass (MD 1.90 kg, 95% CI 1.57 kg to 2.23 kg, P < 0.001; moderate heterogeneity χ2 = 8.60, I2 = 30%, P = 0.20), while decreasing fat body mass compared to placebo (MD - 4.55 kg, 95% CI - 5.08 kg to - 4.01 kg, P < 0.001; substantial heterogeneity χ2 = 27.44, I2 = 89%, P < 0.001). However, no significant improvement was observed in muscle strength or physical performance measures such as gait speed and six-minute walk distance with bimagrumab treatment, except among participants with slower baseline walking speeds or distances. DISCUSSION AND CONCLUSION: This meta-analysis provides valuable insights into the effects of bimagrumab on sarcopenic patients, highlighting its significant improvements in body composition parameters but limited impact on functional outcomes. The observed heterogeneity in outcomes across studies underscores the need for cautious interpretation, considering variations in study populations, treatment durations, and outcome assessments. While bimagrumab shows promise as a safe pharmacological intervention for enhancing muscle mass and reducing fat mass in sarcopenia, its minimal effects on muscle strength and broader physical performance suggest potential limitations in translating body composition improvements into functional gains. Further research is needed to clarify its long-term efficacy, optimal dosing regimens, and potential benefits for specific subgroups of sarcopenic patients.

A preliminary pilot study investigating the impact of endovascular treatment on leg muscle volume in peripheral artery disease and its relation to baseline glycemic control.

BACKGROUND AND AIMS: Peripheral artery disease (PAD), intermittent claudication, and impaired mobility contribute to the loss of skeletal muscle. This study investigated the impact of endovascular treatment (EVT) in patients suffering from PAD above the knee and its relation to baseline glycemic control. METHODS AND RESULTS: Mid-thigh muscle volume was measured before EVT, 3 months after EVT and 6 months after EVT. Mid-thigh muscle volumes of ipsilateral PAD patients with ischemic and non-ischemic legs were compared. Correlations between total thigh muscle volume and clinical characteristics were analyzed using univariable and multivariable analysis. Overall, thigh muscle volume increased after EVT. The mid-thigh muscle volume was significantly lower in patients with ipsilateral lesions and in those with ischemic lower limbs. The thigh muscle volume of those with ischemic lower limbs increased after EVT. Baseline glycated hemoglobin was the only factor that was negatively correlated with changes in the muscle volume after EVT. Muscle volume significantly increased in normoglycemic HbA1c<6.5% (47 mmol/mol) patients. There was no significant alteration in the muscle volume of hyperglycemic HbA1c ≥ 6.5% patients. CONCLUSION: Ischemic muscle atrophy was ameliorated after EVT in normoglycemic patients. There is a need for a large-scale trial to investigate whether EVT can protect or delay skeletal muscle loss.

Activin Type II Receptor Blockade for Treatment of Muscle Depletion in Chronic Obstructive Pulmonary Disease. A Randomized Trial.

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).

Safety and pharmacokinetics of bimagrumab in healthy older and obese adults with body composition changes in the older cohort.

BACKGROUND: 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. METHODS: A cohort of older adults (aged 70-85 years) received single intravenous infusions of bimagrumab 30 mg/kg (n = 6) or 3 mg/kg (n = 6) or placebo (n = 4) and was followed for 20 weeks. A second cohort of obese participants [body mass index (BMI) 30-45 kg/m2 , aged 18-65 years] received a single intravenous infusion of bimagrumab 30 mg/kg (n = 6) or placebo (n = 2) and was followed for 12 weeks. Outcomes included the safety, tolerability, and PK of bimagrumab, in both cohorts. Measures of pharmacodynamics were performed in the older adult cohort to evaluate the effects of bimagrumab on thigh muscle volume (TMV), total lean body mass (LBM), total fat body mass, and muscle strength. RESULTS: All 24 randomized participants completed the study. The older adults had a mean (±SD) age of 74.5 ± 3.4 years and BMI of 26.5 ± 3.5 kg/m2 . The obese participants had a mean (±SD) age of 40.4 ± 11.8 years, weight of 98.0 ± 11.3 kg, and BMI of 34.3 ± 3.9 kg/m2 . Adverse events in both cohorts were mostly mild. In older adults, most commonly reported adverse events were upper respiratory tract infection, rash, and diarrhoea (each 3/16, 19%). Obese participants reported muscle spasms and rash (both 5/8, 63%) most often. Non-linearity was observed in the PK concentration profiles of both cohorts due to target-mediated drug disposition. Bimagrumab 3 and 30 mg/kg increased mean (±SD) TMV (Week 4: 5.3 ± 1.8% and 6.1 ± 2.2%, vs. placebo: 0.5 ± 2.1%, both P ≤ 0.02) and LBM (Week 4: 6.0 ± 3.2%, P = 0.03 and 2.4 ± 2.2%, vs. placebo: 0.1 ± 2.4%), which were maintained longer with higher dose level, while total fat body mass (Week 4: -2.7 ± 2.9% and -1.6 ± 3.0%, vs. placebo: -2.3 ± 3.2%) decreased from baseline in older adults, with no change in muscle strength. CONCLUSIONS: Bimagrumab was safe and well tolerated and demonstrated similar PK in older and obese adults. A single dose of bimagrumab rapidly increased TMV and LBM and decreased body adiposity in older adults. Muscle hypertrophy and fat loss were sustained with extended drug exposure.

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

BACKGROUND: 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. METHODS: In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. RESULTS: Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. CONCLUSIONS: A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.