Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338).

Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults.This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18-34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1-7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study.Eighty-four of 91 (92.3%) randomized participants (mean age 74.5 years; BMI 28.0 kg/m2) completed the study. Demographic characteristics were generally balanced across the groups. A target-mediated drug disposition profile was observed following both intravenous and subcutaneous administration. The absolute subcutaneous bioavailability was estimated at approximately 40%. LBM increased by 4-6% (1.5-2 kg) from baseline throughout the treatment period for intravenous and subcutaneous regimens, except for the 52.5 mg subcutaneous dose, which did not differ from placebo. Concurrently, there was a decrease in FBM (approximately 2-3 kg) for all intravenous and subcutaneous regimens. Bimagrumab was generally safe and well tolerated; adverse events were mostly mild to moderate in severity.Dose levels of bimagrumab administered weekly subcutaneously resulted in PK profiles and PD effects comparable with monthly intravenous dosing, which supports the feasibility of the subcutaneous route of administration for bimagrumab for future clinical development

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

Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) Targeting B cells by BAFF receptor-blockade coupled with enhanced, antibody-dependent cellular cytotoxicity

Objectives To evaluate the efficacy and safety of VAY736 (ianalumab), a B-cell-depleting, BAFF-receptor blocking, monoclonal antibody, in patients with active primary Sjögren’s syndrome in a double blind, placebo-controlled, phase II, single center study. Methods Patients with primary Sjögren’s syndrome (pSS), disease activity ESSDAI 6, were randomized to VAY736 single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12), or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B-cells numbers had recovered. Clinical outcomes included ESSDAI, ESSPRI, salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity. Results A similar trend showing positive therapeutic effect by VAY736 was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, MFI, SF3-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B-cell depletion of long lasting duration occurred after a single infusion of VAY736 at either dose. Serum Ig light chains decreased with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild-to-moderate infusion reactions within 24 hours of VAY736 administration. Conclusions Overall results in this single dose study suggest potent and sustained B-cell depletion by VAY736 could provide therapeutic benefits in pSS patients without major side effects

Bimagrumab, an Activin Type II Receptor Antagonist, for the Treatment of Obesity and Type 2 Diabetes: A Randomized ClinicalTrial

IMPORTANCE Antibody blockade of the activin type II receptor (ActRII) signaling pathway stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the human monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. OBJECTIVE This multicenter randomized study determined the efficacy and safety of bimagrumab on body composition and glycemic control in adults with overweight and obesity and who had type 2 diabetes. DESIGN This was a double-blind, placebo-controlled 48-week phase 2 study. SETTING Nine sites in the United States and United Kingdom participated in the study from February 2017 through May 2019. PARTICIPANTS Adults (n=75) with body mass index 28–40 kg/m2 64 who had type 2 diabetes and glycated hemoglobin levels 6.5%–10.0%. INTERVENTION Participants were randomized to intravenous bimagrumab or placebo every 4 weeks for 48 weeks. All patients received diet and exercise counseling. MAIN OUTCOME MEASURES The primary endpoint was least squares mean change from baseline (80% CI) to Week 48 in total body fat mass. Key secondary and exploratory endpoints included changes in lean mass, waist circumference, glycated hemoglobin, and body weight from baseline to Week 48. RESULTS At Week 48, 77.3% of patients completed the study. Total body fat mass decreased by 21% in bimagrumab-treated patients vs 0.5% in those treated with placebo (P<0.001). Secondary endpoints for bimagrumab vs placebo included a lean mass increase of 3.6% vs a decrease of 0.8% (P<0.001); waist circumference decrease of 9.00 cm vs increase of 0.45 cm (P<0.001); glycated hemoglobin reduction of 0.76 percentage points vs 0.04 percentage points (P=0.005); and weight reduction of 6.5% vs 0.8% (P<0.001). Bimagrumab was safe and well-tolerated. CONCLUSIONS AND RELEVANCE ActRII blockade with bimagrumab led to marked loss of total body fat, gain in lean mass, and metabolic improvements over 48 weeks in patients with overweight and obesity who had type 2 diabetes. ActRII pathway inhibition provides a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances. TRIAL REGISTRATION Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT03005288

Bimagrumab for treatment of sarcopenia in community-dwelling older adults: a phase II, randomized, controlled trial

Background: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab on skeletal muscle mass, strength, and physical function in community-dwelling older adults with sarcopenia. Design: Randomized, double-blind, placebo-controlled. Setting: 38 sites in 13 countries. Participants: 180 community-dwelling, men and women aged ≥70 years meeting gait speed and skeletal muscle criteria for sarcopenia. Intervention: Bimagrumab 700 mg (n=113) or placebo (n=67) monthly for 6-months with appropriate diet and home-based exercise. Measurements: Short Physical Performance Battery (SPPB), 6-minute walk distance (6MWD), gait speed, handgrip strength, total lean body mass (LBM), and standard safety parameters. Results: 159/180 (88.3%) participants (mean age: 79.1 years; 60.6% women) completed the study. Bimagrumab was safe, well-tolerated and increased LBM by 6.0% over placebo (P<0.001). The mean SPPB score increased by 1.34 (0.90–1.77, mean, 95%CI) with bimagrumab versus 1.03 (0.53–1.52) with placebo (P=0.134); 6MWD increased by 24.60 m (7.65–41.56 m) versus 14.30 m (−4.64–33.23 m; P=0.163); and gait speed increased by 0.14 m/s (0.09–0.18 m/s) versus 0.11 m/s (0.05–0.16 m/s; P=0.161). Handgrip strength did not change. Limitation: Powered only for key functional endpoints. Conclusion: Bimagrumab treatment over 6-months was safe, well-tolerated and increased LBM in community-dwelling older adults with sarcopenia. Appropriate nutrition and exercise improved physical performance in this vulnerable population; bimagrumab did not significantly enhance this effect. At the completion of the study, a majority of participants in both treatment groups no longer met sarcopenia criteria. Sarcopenia, an increasing cause of disability in the elderly, is reversible with proper diet and exercise. ClinicalTrials.gov identifier: NCT02333331 Keywords: bimagrumab; sarcopenia; muscle; lean body mass; SPPB; gait speed; 6-minute walk tes

Bimagrumab improves body composition and insulin sensitivity in insulin-resistant subjects

Background: Skeletal muscle is a key mediator of insulin resistance. Bimagrumab, an antibody against activin receptor type II (ActRII), prevents binding of negative muscle regulators, like myostatin, and increases lean mass and decreases fat mass in animal models. Objective: We hypothesized that an improving body composition in insulin resistant individuals could enhance insulin sensitivity. Methods: Sixteen individuals with mean body mass index (BMI)=29.3 kg/m2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at Week 10 for insulin sensitivity, with hyperinsulinemic euglycemic (H-E) clamp and intravenous glucose tolerance test (IVGTT), and for body composition, with dual energy X-ray absorptiometry (DXA) and Positron emission tomography (PET) scan. Results: Bimagrumab increased lean mass by 2.7% (p<0.05) and reduced fat mass by 7.9% (p=0.011) at Week 10 compared to placebo, with a neutral effect on body weight. Bimagrumab reduced HbA1c by 0.21% at Week 18 (p<0.001) and improved insulin sensitivity by ~20% (using the clamp) to ~40% (using the IVGTT). Conclusion: Taken the observed changes together and in consideration that these occurred without accompanying dietary intervention and without any prescribed regular physical exercise, bimagrumab may offer a novel approach for the treatment of metabolic complications of obesity

A placebo-controlled study to evaluate the safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy

Background Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor (AR) gene. We assessed safety, tolerability, and preliminary efficacy of BVS857, an insulin like growth factor-1 (IGF-1) mimetic, in SBMA patients. SBMA patients have low IGF-1 levels, and studies of IGF-1 showed benefit in a transgenic model of SBMA. A study of BVS857 in healthy volunteers showed it to be well tolerated. Methods This study was double-blind, and placebo-controlled. Following a safety and tolerability evaluation with 8 SBMA patients, BVS857 was administered weekly for 12 weeks to 27 patients, with 2:1 drug to placebo randomization. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. Secondary and exploratory outcome measurements included pharmacokinetics, muscle strength and function, lean body mass by dual-energy x-ray absorptiometry scan, and pharmacodynamic biomarkers in blood and muscle biopsy samples. Findings BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo, with a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients. There was no difference in study measures of muscle strength or function. Immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to endogenous IGF-1 in 5 patients. Interpretation TMV remained stable in BVS857 treated SBMA patients after 12 weeks of dosing. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Treatment with BVS857 for 12 weeks did not demonstrate benefit in SBMA. Additional studies may be needed to evaluate the efficacy of activating the IGF-1 pathway

Safety, tolerability, and preliminary e cacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Background Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed bene t in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary e cacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a con rmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0\ub706 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the e ects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary e cacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No signi cant di erences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in ve patients. TMV decreased from baseline to day 85 in the placebo group (\u20133\ub74% [\u2013110 cm3]) but not in the BVS857 group (0% [2 cm3]). A signi cant di erence in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1\ub704 [90% CI 1\ub701\u20131\ub707]; p=0\ub702). There were no di erences between groups in measures of muscle strength and function. Interpretation TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the e cacy of activating the IGF-1 pathway in this disease. Funding Novartis Pharmaceuticals and the US National Institutes of Health

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy:a randomised, placebo-controlled trial

BackgroundSpinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932.Findings31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function.InterpretationTMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease.FundingNovartis Pharmaceuticals and the US National Institutes of Health