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

Garito, Tania; Roubenoff, Ronenn; Hompesch, Marcus; Morrow, Linda; Gómez, Katherine; Rooks, Daniel; Meyers, Charles D.; Buchsbaum, Monte S.; Neelakantham, Srikanth; Swan, Therese; Filosa, Lee Anne; Laurent, Didier; Pétricoul, Olivier; Zakaria, Marjorie

doi:10.1111/dom.13042

Cited by 61 publications

(57 citation statements)

References 40 publications

(83 reference statements)

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Section: Discussionsupporting

confidence: 87%

“…Mild acne was noted in subjects treated with bimagrumab regardless of sex, and in no subjects on placebo, consistent with the observations in other clinical trials with bimagrumab. 3,26,27 All cases were responsive to local treatment of good skin hygiene and resolved within the EOS. Analysing the pathogenesis of acne and the putative effects of activin on the skin, we focused on the increased sebum production mediated by androgens: the absence of changes in androgen levels, whether basal or stimulated, whether from adrenal or gonadal origin, indicates that acne, in bimagrumab-treated subjects, is not due to hyperandrogenism that is detectable in the circulation.…”

Section: Results Of Gnrh Stimulation Test Atmentioning

confidence: 93%

“…Clearance of bimagrumab over time was nonlinear, consistent with its reported profile in other trials. 3,4,26 The PK variability for men and women was relatively low, with a coefficient of variation for maximum concentration and area under the curve of approximately 15%-20%. .099…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Bimagrumab is a human monoclonal antibody that blocks ActRIIs from binding endogenous ligands: activins A and B, myostatin (growth and differentiation factor‐8, GDF‐8) and GDF‐11 . The blockade of myostatin binding to ActRII in the skeletal muscle is the target that bimagrumab tackles for further development for conditions of muscle atrophy/weakness and for obesity in type II diabetes . Indeed, the use of a soluble ActRIIB/Fc fusion protein in mice resulted in skeletal muscle growth, prevention of obesity and increased insulin sensitivity; but ActRIIs are also widely expressed in humans pituitary, gonadal and adrenal glands.…”

Section: Introductionmentioning

confidence: 99%

“…To date, bimagrumab has been safe and well tolerated in clinical trials in healthy volunteers and patients. Muscle cramps, diarrhoea and acneiform rash being the most common adverse events . This study was designed to evaluate whether blockade of ActRII by bimagrumab affects androgen production by the gonads and adrenal glands as a potential mechanism for the acneiform rash.…”

Section: Introductionmentioning

confidence: 99%

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

Garito

Zakaria

Papanicolaou

et al. 2018

Clinical Endocrinology

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Section: Discussionsupporting

confidence: 87%

Section: Results Of Gnrh Stimulation Test Atmentioning

confidence: 93%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Garito

Zakaria

Papanicolaou

et al. 2018

Clinical Endocrinology

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Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Heymsfield

Coleman²,

Miller³

et al. 2021

JAMA Netw Open

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140

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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 PARTICIPANTSThis 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. INTERVENTIONSPatients 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 MEASURESThe 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 RELEVANCEIn 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 (continued) Key Points Question What are the effects of bimagrumab, an antibody that blocks activin type II receptors and stimulates skeletal muscle growth, on total body fat mass and glycemic control in patients with type 2 diabetes and excess adiposity? Findings In this phase 2 randomized clinical trial of 75 patients with type 2 diabetes and body mass index between 28 and 40 who received bimagrumab or placebo du...

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Metabolic regulation of activins in healthy individuals and in obese patients undergoing bariatric surgery

Perakakis

Kokkinos

Peradze

et al. 2020

Diabetes Metabolism Res

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ObjectiveFollistatin binds and inactivates activins, which are potent inhibitors of muscle growth and metabolism and are currently being developed for the treatment of obesity and type 2 diabetes (T2D). We have recently reported that follistatin is regulated by glucose (and not lipids) and can prospectively predict the metabolic improvements observed after bariatric surgery. We utilized novel assays herein to investigate whether activins are regulated by glucose or lipids, whether their circulating levels change after bariatric surgery and whether these changes are predictors of metabolic outcomes up to 12 months later.Design and MethodsActivin A, B, AB and their ratios to follistatin were measured in (a) healthy humans (n = 32) undergoing oral or intravenous lipid or glucose intake over 6 h, (b) morbidly obese individuals with or without type 2 diabetes undergoing three different types of bariatric surgery (gastric banding, Roux‐en‐Y bypass or sleeve gastrectomy) in two clinical studies (n = 14 for the first and n = 27 for the second study).ResultsGlucose intake downregulates circulating activin A, B and AB, indicating the presence of a feedback loop. Activin A decreases (~30%), activin AB increases (~25%) and activin B does not change after bariatric surgery. The changes in activin AB and its ratio to follistatin 3 months after bariatric surgery can predict the BMI reduction and the improvement in insulin and HOMA‐IR observed 6 months postoperatively.ConclusionActivins are implicated in glucose regulation in humans as part of a feedback loop with glucose or insulin and predict metabolic outcomes prospectively after bariatric surgery.

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

Cited by 61 publications

References 40 publications

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

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

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Metabolic regulation of activins in healthy individuals and in obese patients undergoing bariatric surgery

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