Bimagrumab

Bimagrumab, also coded BYM338, is described in the inspected trial reports as a fully human monoclonal antibody that binds activin type II receptors and thereby prevents myostatin, activin A and other ligands from restraining skeletal muscle growth. The 2020 report states that dual blockade of ActRIIA and ActRIIB produced greater muscle hypertrophy than blocking one subunit or one ligand in molecular and animal studies, and that the receptor is also present on adipocytes. In every inspected human study the antibody was given by intravenous infusion and was developed by Novartis.^[1][2]

• The mechanism is taken from the introductions of two trial reports, which cite preclinical and molecular studies that were not inspected here; no structural or analytical characterisation of the antibody was inspected.
• A described mechanism does not establish the size or safety of effects in people; those are stated separately in the cited human findings.

In the 48-week trial in adults with type 2 diabetes and overweight or obesity, adverse events were reported by 31 of 37 (83.8%) bimagrumab and 31 of 38 (81.6%) placebo participants, with serious adverse events in three participants of each group (nine events in six participants) and no deaths. Diarrhoea (15 of 37, 41%, versus 4 of 38, 11%) and muscle spasms (15 of 37, 41%, versus 1 of 38, 3%) were the most frequent events with bimagrumab; diarrhoea was most frequent after the first dose and diminished afterwards. Eight adverse events led five bimagrumab participants (14%) and no placebo participants to discontinue, including one hospitalised case of pancreatitis, a Helicobacter pylori infection, muscle spasms in two participants, and raised lipase with upper abdominal pain later attributed to cholelithiasis. Early, transient rises in lipase, amylase and liver enzymes were more frequent with bimagrumab (lipase in 10.8% versus 5.3%; each liver enzyme in 2.7% versus 0%). Two bimagrumab participants developed non-neutralising anti-drug antibodies without effect on exposure. The authors state that across a development programme enrolling more than 1000 adults, two cases of acute pancreatitis had been reported, one in this trial and one unpublished.^[1]

• A 48-week trial of 75 people cannot characterise uncommon or long-term harms; people with abnormal liver tests or pancreatic enzymes, significant cardiovascular disease, malignancy or prior bariatric surgery were excluded.
• The programme-wide pancreatitis figure is an author statement that could not be checked against a published dataset in this batch.
• Laboratory shift percentages are summarised from a supplementary table described in the main text; the table itself was not inspected.
• Event frequencies describe this trial population and exposure; they are not a risk estimate for other doses, formulations or people.

In that single-dose phase 1 study all 24 participants completed, with no discontinuations or deaths; the only serious adverse event was an acetabulum fracture in a placebo recipient. Adverse events were mild or moderate and resolved without treatment. Among the 16 older adults, 10 had at least one event; upper respiratory tract infection, rash, pruritus, papule and diarrhoea each occurred in 3 of 16, and muscle-related symptoms in 3 of 12 bimagrumab recipients versus none on placebo. Among the eight obese adults, rash and muscle spasms each occurred in 5 of 6 bimagrumab recipients and in neither placebo recipient. The authors attribute muscle spasms and acne or rash, which they say recurred across the development programme, to rapid muscle accretion and to activin receptors on hair follicles and skin; they present these as explanations, not tested findings.^[2]

• Twenty-four healthy volunteers after one infusion cannot show uncommon, delayed or repeated-dose harms.
• People with cardiac disease, uncontrolled chronic conditions, cachexia-causing disease or childbearing potential were excluded.
• The mechanistic explanations for muscle spasms and rash are the authors' hypotheses.

The 48-week trial report states that participants treated with bimagrumab had decreased follicle-stimulating hormone and urate levels and increased creatine kinase relative to baseline, referring to a supplementary table; the main text gives no magnitudes and reports no other pituitary or gonadal hormone results. The same report lists low serum testosterone in men as the reason 27 people failed screening, indicating that men with low testosterone were excluded from the trial.^[1]

• The direction of the follicle-stimulating hormone change is stated in the main text only; its size, timing and clinical relevance are in an uninspected supplementary table.
• The reason for excluding men with low serum testosterone is not given in the main text; the eligibility appendix was not inspected.
• Effects on the reproductive or other endocrine axes were not primary or secondary endpoints of this trial, and no dedicated endocrine study was inspected.

In a phase 1 randomized, double-blind, placebo-controlled study, 24 healthy volunteers received a single 2-hour intravenous infusion: 16 adults aged 70 to 85 (six at 3 mg/kg, six at 30 mg/kg, four placebo) followed for 20 weeks, and eight adults with obesity (body mass index 30 to 45; six at 30 mg/kg, two placebo) followed for 12 weeks. Peak concentration was dose-proportional (mean 90.7 micrograms/mL at 3 mg/kg and 982 micrograms/mL at 30 mg/kg in older adults; 944 micrograms/mL at 30 mg/kg in obese adults), but exposure to the last measurable concentration was not (399, 7320 and 7650 microgram-days/mL), a non-linear profile the authors attribute to target-mediated drug disposition. Because of that non-linearity, clearance and half-life could not be derived by non-compartmental analysis. By the end of study, concentrations were below the detection limit of 0.643 micrograms/mL in all older adults at 20 weeks but still detectable in five of six obese participants at 12 weeks. No anti-drug antibodies were detected in either cohort.^[2]

• Six participants per active group after a single dose given in 2012; the repeated 10 mg/kg regimen used in the later type 2 diabetes trial was not studied.
• No half-life or clearance is reported, so none is published here; the persistence of detectable drug differed with the length of follow-up, not necessarily with body habitus.
• Exposure figures describe the experiment and are not a basis for any regimen.

In a phase 2, quadruple-masked, placebo-controlled trial at nine United States and United Kingdom sites, 75 adults with type 2 diabetes and a body mass index of 28 to 40 were randomized to intravenous bimagrumab 10 mg/kg (capped at 1200 mg) or placebo every 4 weeks for 48 weeks, with dietary and physical-activity counselling in both groups. The primary endpoint, total body fat mass by dual-energy X-ray absorptiometry, fell by 7.49 kg (20.5%) with bimagrumab and by 0.18 kg (0.5%) with placebo at week 48, a difference of 7.31 kg (80% CI 6.14 to 8.48 kg; P < .001). Lean mass rose 1.70 kg (3.6%) with bimagrumab and fell 0.44 kg (0.8%) with placebo, and body weight fell 5.90 kg (6.5%) versus 0.79 kg (0.8%), a placebo-corrected weight difference of 5.10 kg. Of the 75 participants, 58 (77.3%) completed the study, and the week 48 estimates rest on 26 bimagrumab and 29 or 30 placebo participants.^[1][3]

• A sponsor-funded proof-of-concept trial analysed with two-sided 80% confidence intervals and one-sided P values at the 10% level, a standard the authors state the sponsor chose; eight authors were Novartis employees.
• The groups were unbalanced by sex (62% women on bimagrumab versus 32% on placebo) and baseline weight; missing data were assumed missing at random without imputation.
• Lean mass by absorptiometry can include water; total body water was not measured.
• The placebo weight figure is the value corrected by the February 2021 erratum; the first-published Discussion described a 0.8% weight gain.
• A trial exposure is described; it is not a recommendation, and the drug has no described approved indication in these sources.

In the same 48-week trial, glycated haemoglobin changed by -0.76 percentage points with bimagrumab and by +0.04 with placebo (difference -0.80; 80% CI -1.20 to -0.41; P = .005); the placebo value was corrected by a March 2021 erratum from the -0.04 first printed in the abstract. Waist circumference fell 9.0 cm with bimagrumab against a 0.45 cm rise with placebo. Between-group differences in the 36-week HOMA2 index (P = .08) and the 48-week Matsuda index (P value corrected to .10) were not significant, while the QUICKI index at week 36 differed (P = .03). Hepatic fat fraction and abdominal visceral fat by magnetic resonance imaging were exploratory endpoints measured in a minority of participants; at week 48 they rest on five bimagrumab participants and on five (hepatic fat) or four (visceral fat) placebo participants. Serum lipids and high-sensitivity C-reactive protein did not change significantly, and hand-grip strength showed no treatment effect.^[1][4]

• Participants remained on background metformin and/or DPP-4 inhibitor therapy and received diet and activity counselling; the trial does not describe effects in people without diabetes.
• Insulin-sensitivity indices are surrogate measures reported at different weeks; the imaging endpoints have very small week 48 denominators.
• The same liberal statistical standard and sponsor role apply as for the primary endpoint.
• Lipid, inflammatory and grip-strength results are summarised from supplementary tables the main text describes but which were not inspected.

In the 16 older adults of that phase 1 study, thigh muscle volume by magnetic resonance imaging rose 5.3 ± 1.8% after 3 mg/kg and 6.1 ± 2.2% after 30 mg/kg versus 0.5 ± 2.1% with placebo at week 4 (both P ≤ 0.02); at week 16 the 30 mg/kg group remained 4.5 ± 3.3% above baseline while the 3 mg/kg group had returned to baseline. Total lean body mass increased at week 4 (6.0 ± 3.2% at 3 mg/kg, P = 0.03 versus placebo; 2.4 ± 2.2% at 30 mg/kg) and returned to near baseline by the end of follow-up. Fat mass differed significantly from placebo only for 30 mg/kg at week 16 (-9.3 ± 8.1% versus -1.1 ± 1.5%; P = 0.02). No change in leg-press strength was detected in either bimagrumab group.^[2]

• The study was not powered for these endpoints; the authors present the P values as exploratory and applied no multiplicity correction.
• Groups were small and imbalanced: the 3 mg/kg group was six women and three of the four placebo recipients were men.
• Body composition was not measured in the obese cohort, so these results describe healthy older volunteers only.
• An increase in measured muscle volume or lean mass without a strength change is what the authors report; it is not evidence of functional benefit.

A 2024 systematic review searched PubMed, Ovid/Medline, Web of Science and the Cochrane Library to June 2024 and pooled seven placebo-controlled randomized trials of bimagrumab with 660 participants and 12 to 48 weeks of follow-up. Bimagrumab increased thigh muscle volume (mean difference 5.29%; 95% CI 4.08 to 6.50; four trials; I-squared 38%) and fat-free mass (1.90 kg; 95% CI 1.57 to 2.23; five trials; I-squared 30%) and reduced fat mass (-4.55 kg; 95% CI -5.08 to -4.01; five trials; I-squared 89%). Leave-one-out analysis attributed most of the fat-mass heterogeneity to the 48-week type 2 diabetes trial. No significant effect was found on knee-extension strength, gait speed or six-minute walk distance, and hand-grip results were mixed; only a subgroup analysis within one trial, of participants with slower baseline gait or shorter walk distance, favoured bimagrumab.^[5]

• The review describes its population as sarcopenia, but the pooled trials include healthy young men with cast-induced atrophy, people with chronic obstructive pulmonary disease, older adults after hip fracture and adults with type 2 diabetes and obesity; its own Table 1 gives a sarcopenia definition for only two of the seven trials.
• Doses ranged from single 3 mg/kg or 30 mg/kg infusions to repeated fixed or weight-based regimens; the review does not state the administration route of every pooled trial, and the pooled estimates do not describe any one regimen.
• Adverse events were not pooled; the review's statement that bimagrumab is safe is narrative.
• All pooled trials were Novartis-funded, and two of them are the trials cited elsewhere on this page, so this is not independent corroboration of those two.