Drugs for Treating Obesity.

Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3 mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4 mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4 mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.

Therapeutic potential of muscle growth promoters in a stress urinary incontinence model.

Weakness of urinary sphincter and pelvic floor muscles can cause insufficient urethral closure and lead to stress urinary incontinence. Bimagrumab is a novel myostatin inhibitor that blocks activin type II receptors, inducing skeletal muscle hypertrophy and attenuating muscle weakness. ß2-Adrenergic agonists, such as 5-hydroxybenzothiazolone derivative (5-HOB) and clenbuterol, can enhance muscle growth. We hypothesized that promoting muscle growth would increase leak point pressure (LPP) by facilitating muscle recovery in a dual-injury (DI) stress urinary incontinence model. Rats underwent pudendal nerve crush (PNC) followed by vaginal distension (VD). One week after injury, each rat began subcutaneous (0.3 mL/rat) treatment daily in a blinded fashion with either bimagrumab (DI + Bim), clenbuterol (DI + Clen), 5-HOB (DI + 5-HOB), or PBS (DI + PBS). Sham-injured rats underwent sham PNC + VD and received PBS (sham + PBS). After 2 wk of treatment, rats were anesthetized for LPP and external urethral sphincter electromyography recordings. Hindlimb skeletal muscles and pelvic floor muscles were dissected and stained. At the end of 2 wk of treatment, all three treatment groups had a significant increase in body weight and individual muscle weight compared with both sham-treated and sham-injured rats. LPP in DI + Bim rats was significantly higher than LPP of DI + PBS and DI + Clen rats. There were more consistent urethral striated muscle fibers, elastin fibers in the urethra, and pelvic muscle recovery in DI + Bim rats compared with DI + PBS rats. In conclusion, bimagrumab was the most effective for increasing urethral pressure and continence by promoting injured external urethral sphincter and pelvic floor muscle recovery.

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).

A review on the treatment of sporadic inclusion body myositis with Bimagrumab and Alemtuzumab.

BACKGROUND: Sporadic inclusion body myositis is the most common inflammatory myopathy over the age of 50. The aetiopathogenesis of the disease remains unclear and to the day there is no effective treatment. OBJECTIVES: The aim of the present review is to present the latest data on the new insights and developments in the treatment of sporadic inclusion body myositis, focusing on Bimagrumab and Alemtuzumab. METHODS: For the purpose of the review we searched multiple internet databases in order to find the most recent studies and clinical trials on the safety, tolerability and efficacy of Bimagrumab and Alemtuzumab in sporadic inclusion body myositis. RESULTS: We found four trials on Bimagrumab, with one of them being an extension phase III study, and one small series trial on Alemtuzumab. The first clincopathological trial on Bimagrumab showed promising evidence, which were partially confirmed by the double-blinded controlled multicentre trial, however the primary endpoint of improving 6-m walking distance or improving the muscle strength has not been reached. The evidence from the Alemtuzumab trial was also promising, but the risk of bias of the study was relatively high, because it was open labelled, the number of patient was low and the yearly disease progression was much higher than in other recent studies. CONCLUSIONS: Although both Bimagrumab and Alemtuzumab were well tolerated and showed promising results, the Bimagrumab trial did not reach the primary endpoint, and the Alemtuzumab trial has a relatively high risk of bias and the results need to be interpreted with caution.

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

BACKGROUND: 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. AIM: To evaluate the effect of bimagrumab on the pituitary-gonadal and pituitary-adrenal axes in humans. METHODS: Healthy 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. RESULTS: At 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. CONCLUSION: Bimagrumab 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.

Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals.

AIM: To test the hypothesis that an improving body composition in insulin-resistant individuals could enhance insulin sensitivity. METHODS: A 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. RESULTS: Bimagrumab 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). CONCLUSION: Taking 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.

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?

There is a new generation of antiobesity drugs in development or just arriving on the scene. First, setmelanotide has been approved for three of the ultrarare genetic conditions that cause obesity-pro-opiomelanocortin deficiency, proprotein convertase subtilisin and kexin type 1 (an important enzyme in the melanocortin pathway) and leptin receptor deficiency. Setmelanotide marks the first in a personalized medicine approach to obesity. Second, semaglutide 2.4 mg once weekly has been submitted to regulators in the United States and the European Union for approval for patients with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one weight related comorbidity. This drug has been studied in five phase 3 clinical trials, four discussed herein: semaglutide produces roughly twice as much weight loss as we have seen in older antiobesity medications. Semaglutide is already in use for treatment of diabetes and, as a glucagon-like peptide 1 (GLP-1) receptor analog, is part of a class of drugs used widely in diabetes. Tirzepatide, a glucose-insulin peptide and GLP-1 dual agonist is in phase 3 study for obesity management, and bimagrumab is a new agent in phase 2 with a unique mechanism of action; they are generating much interest. The purpose of this narrative review is lay the groundwork for a discussion of the clinical impact of these new medications on the clinical practice of obesity. Further, these developments shall be used to launch a speculation of what is likely to be their impact on the future of obesity pharmacotherapy.

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.

[Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT): Japanese cohort data].

A global, randomized, double-blind placebo-controlled study was conducted to confirm that BYM338 (bimagrumab), an anti-activin type II receptor antibody, improves motor function in patients with sporadic inclusion body myositis after 52 weeks' treatment consisting of intravenous administration every 4 weeks at doses of 10, 3, and 1 mg/kg. In a Japanese sub-population (20 patients in total, 5 per dose group), no significant differences in the change from baseline of the 6-minute walking distance at Week 52 (primary endpoint) were observed between the placebo group and each BYM338 dose group. Furthermore, the lean body mass as an indicator of skeletal muscle mass increased in all BYM338 groups compared with the placebo group and the effects were dose-dependent. Overall, the Japanese sub-population showed similar trends as observed in the entire population (251 patients in total).

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

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.

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.