Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

Hanna, Michael G.; Badrising, Umesh A.; Benveniste, Olivier; Lloyd, Thomas E.; Needham, Merrilee; Chinoy, Hector; Akiyama, Masashi; Machado, Pedro; Liang, Christina; Reardon, Katrina; Visser, Marjolein; Ascherman, Dana P.; Barohn, Richard J.; Dimachkie, Mazen M.; Miller, James; Kissel, John T.; Oskarsson, Björn; Joyce, Nanette C.; Bergh, Peter Van den; Baets, Jonathan; Bleecker, Jan De; Karam, Chafic; David, William S.; Mirabella, Massimiliano; Nations, Sharon P.; Jung, Hans H.; Pegoraro, Elena; Maggi, Lorenzo; Rodolico, Carmelo; Filosto, Massimiliano; Shaibani, Aziz; Sivakumar, Kumaraswamy; Goyal, Namita; Mori‐Yoshimura, Madoka; Yamashita, Satoshi; Suzuki, Naoki; Katsuno, Masahisa; Murata, Kenya; Nodera, Hiroyuki; Nishino, Ichizo; Romano, Carla; Williams, Valerie; Vissing, John; Auberson, Lixin Zhang; Wu, Min; Vera, Ana de; Papanicolaou, Dimitris A.; Amato, Anthony A.

doi:10.1016/s1474-4422(19)30200-5

Cited by 106 publications

(85 citation statements)

References 26 publications

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“…The favorable safety profile seen in this trial was consistent with prior studies with bimagrumab in adults receiving the same dose level with a similar or longer duration. 43,44 To our knowledge, this is the largest study evaluating a drug targeting the myostatin-ActRII pathway in an international population of community-dwelling older adults with confirmed sarcopenia. Our results are consistent with prior studies in older adults of drugs acting on the myostatin-ActRII pathway.…”

Section: Discussionmentioning

confidence: 99%

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

Rooks¹,

Swan²,

Goswami

et al. 2020

JAMA Netw Open

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IMPORTANCE 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 plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was

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Section: Discussionmentioning

confidence: 99%

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

Rooks¹,

Swan²,

Goswami

et al. 2020

JAMA Netw Open

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“…Responsive and clinically meaningful outcome measures are crucial to the success of clinical trials. The RESILIENT Study, a recent trial of bimagrumab, an activin type 2 receptor antibody, in 251 participants with IBM did not meet the primary end point of significant change from baseline in the 6‐Minute Walk Distance (6‐MWD) test . The authors highlighted concerns over suitability of the 6‐MWD test for future trials.…”

Section: Discussionmentioning

confidence: 99%

Long‐term strength and functional status in inclusion body myositis and identification of trajectory subgroups

et al. 2020

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Introduction Objective information on longitudinal disease progression in inclusion body myositis (IBM) is lacking. Methods Longitudinal dynamometry and functional status data were collated from a cohort of IBM patients. Annual change was calculated by means of linear modeling. Trajectories of change in grip, knee extension, IBM Functional Rating Scale (IBM‐FRS) and Neuromuscular Symptom Score (NSS) were identified by means of latent growth mixture modeling. Results Data were collated from 75 IBM patients (348 person‐years follow‐up). Annual strength loss was greatest for pinch (−10%) and knee extension (−4%). Functional deterioration was greatest for males. Three distinct trajectory groups were identified. Rapid deterioration trajectory for grip strength was associated with younger diagnosis age. Rapid deterioration for knee extension strength was associated with older age of diagnosis. Discussion This study has quantified strength change in IBM and identified distinct trajectory groups, which will aid prognostication and stratification for inclusion into future clinical trials.

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“…[74] In 2013, the Food and Drug Administration (FDA) granted the breakthrough therapy designation to bimagrumab for sIBM. However, while the phase 2 clinical trial in 14 sIBM patients demonstrated increases in thigh muscle volume and 6-min walking distance after a single injection (30 mg/kg), [74] subsequent phase 2/3 clinical trial completed in 2016 failed to show improvement in 6-mintue walking distance, muscle strength, or grip and pinch strength, [75] resulting in discontinuation of further development of bimagrumab for sIBM. In a phase 2 clinical trial conducted in subjects older than 65 years with sarcopenia, treatment with bimagrumab (30 mg/kg) for 16 weeks significantly improved thigh muscle volume, gait speed, and 6-min walking distance.…”

Section: ) Muscle-wasting Diseasesmentioning

confidence: 99%

Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

Suh

Lee

2020

J Bone Metab

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Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.

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Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

Cited by 106 publications

References 26 publications

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

Long‐term strength and functional status in inclusion body myositis and identification of trajectory subgroups

Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

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