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Cited by 111Muscle Physiology and DisordersChronic Obstructive Pulmonary Disease (COPD) ResearchNutrition and Health in Aging

Activin Type II Receptor Blockade for Treatment of Muscle Depletion in Chronic Obstructive Pulmonary Disease. A Randomized Trial

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Polkey, Michael I., Praestgaard, Jens, Berwick, Amy, Franssen, Frits M. E., Singh, Dave, Steiner, Michael C., Casaburi, Richard, Tillmann, Hanns-Christian +3 more·2019·American Journal of Respiratory and Critical Care Medicine
DOI 10.1164/rccm.201802-0286ocPMC PMC6363975
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Abstract

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).

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  • A recent clinical trial using a monoclonal antibody blocking the myostatin receptor has not shown potent results in treating skeletal muscle wasting for COPD patients, despite promising results previously obtained in cancer models.

    “However, a recent clinical trial using a monoclonal antibody blocking its receptor has not shown potent results in treating skeletal muscle wasting for COPD patients [177], despite promising results previously obtained in cancer models [178].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [177]

    The Abstract identifies bimagrumab as a monoclonal antibody blocking activin type II receptors, and the Results report no significant improvement in walking distance or most measures of muscle strength and mobility. But the Abstract and Discussion report substantial gains in thigh muscle volume and lean body mass, so the trial did show a benefit for muscle wasting, though not for functional performance. The cancer-model claim carries a separate citation and is not assessed here. (LLM, conf=0.88)

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  • Strategies aiming to block protein degradation have not been proven effective yet.

    “Finally, it seems that less attention has been paid to protein synthesis pathways in COPD muscle, although they represent an interesting therapeutic pool, as strategies aiming to block protein degradation have not been proven effective yet [177].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [177]

    The Discussion (p. 313–320; specific page unavailable in our copy) reports that ActRII blockade increased muscle volume in patients with COPD but did not improve most measures of muscle or physical performance. This supports a lack of demonstrated functional benefit for the treatment studied, but the paper does not identify it as a protein-degradation blocker or establish that strategies blocking protein degradation generally have not proved effective. (LLM, conf=0.78)

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Research works printed but not linked: 43

  1. [2]Swallow EB, Reyes D, Hopkinson NS, Man WD, Porcher R, Cetti EJ, et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax. 2007;62:115–120. doi: 10.1136/thx.2006.062026. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  2. [3]Marquis K, Debigaré R, Lacasse Y, LeBlanc P, Jobin J, Carrier G, et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166:809–813. doi: 10.1164/rccm.2107031. [DOI] [PubMed] [Google Scholar] · DOI
  3. [4]Greening NJ, Harvey-Dunstan TC, Chaplin EJ, Vincent EE, Morgan MD, Singh SJ, et al. Bedside assessment of quadriceps muscle by ultrasound after admission for acute exacerbations of chronic respiratory disease. Am J Respir Crit Care Med. 2015;192:810–816. doi: 10.1164/rccm.201503-0535OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [5]Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350:2682–2688. doi: 10.1056/NEJMoa040933. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  5. [6]Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 1997;7:910–916. doi: 10.1101/gr.7.9.910. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  6. [7]Man WD, Natanek SA, Riddoch-Contreras J, Lewis A, Marsh GS, Kemp PR, et al. Quadriceps myostatin expression in COPD. Eur Respir J. 2010;36:686–688. doi: 10.1183/09031936.00032510. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  7. [8]Pomiès P, Rodriguez J, Blaquière M, Sedraoui S, Gouzi F, Carnac G, et al. Reduced myotube diameter, atrophic signalling and elevated oxidative stress in cultured satellite cells from COPD patients. J Cell Mol Med. 2015;19:175–186. doi: 10.1111/jcmm.12390. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  8. [9]Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med. 2000;109:207–212. doi: 10.1016/s0002-9343(00)00472-1. [DOI] [PubMed] [Google Scholar] · DOI
  9. [10]Troosters T, Probst VS, Crul T, Pitta F, Gayan-Ramirez G, Decramer M, et al. Resistance training prevents deterioration in quadriceps muscle function during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:1072–1077. doi: 10.1164/rccm.200908-1203OC. [DOI] [PubMed] [Google Scholar] · DOI
  10. [11]Vogiatzis I, Simoes DC, Stratakos G, Kourepini E, Terzis G, Manta P, et al. Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J. 2010;36:301–310. doi: 10.1183/09031936.00112909. [DOI] [PubMed] [Google Scholar] · DOI
  11. [12]Moore E, Palmer T, Newson R, Majeed A, Quint JK, Soljak MA. Pulmonary rehabilitation as a mechanism to reduce hospitalizations for acute exacerbations of COPD: a systematic review and meta-analysis. Chest. 2016;150:837–859. doi: 10.1016/j.chest.2016.05.038. [DOI] [PubMed] [Google Scholar] · DOI
  12. [13]Puhan MA, Gimeno-Santos E, Cates CJ, Troosters T. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016;12:CD005305. doi: 10.1002/14651858.CD005305.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  13. [14]Steiner M, McMillan V, Lowe D, Saleem Khan M, Holzhauer-Barrie J, Van Loo V, et al. National Chronic Obstructive Pulmonary Disease (COPD) Audit Programme: outcomes from the clinical audit of pulmonary rehabilitation services in England 2015. London: Royal College of Physicians; 2017. Pulmonary rehabilitation: beyond breathing better. [Google Scholar]
  14. [15]Becker C, Lord SR, Studenski SA, Warden SJ, Fielding RA, Recknor CP, et al. STEADY Group. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2015;3:948–957. doi: 10.1016/S2213-8587(15)00298-3. [DOI] [PubMed] [Google Scholar] · DOI
  15. [16]Attie KM, Borgstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013;47:416–423. doi: 10.1002/mus.23539. [DOI] [PubMed] [Google Scholar] · DOI
  16. [20]Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–799. doi: 10.1016/j.clnu.2008.06.013. [DOI] [PubMed] [Google Scholar] · DOI
  17. [21]Baum JI, Kim IY, Wolfe RR. Protein consumption and the elderly: what is the optimal level of intake? Nutrients. 2016;8:359. doi: 10.3390/nu8060359. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. [22]Positano V, Christiansen T, Santarelli MF, Ringgaard S, Landini L, Gastaldelli A. Accurate segmentation of subcutaneous and intermuscular adipose tissue from MR images of the thigh. J Magn Reson Imaging. 2009;29:677–684. doi: 10.1002/jmri.21699. [DOI] [PubMed] [Google Scholar] · DOI
  19. [23]Steiner MC, Barton RL, Singh SJ, Morgan MD. Bedside methods versus dual energy X-ray absorptiometry for body composition measurement in COPD. Eur Respir J. 2002;19:626–631. doi: 10.1183/09031936.02.00279602. [DOI] [PubMed] [Google Scholar] · DOI
  20. [24]ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–117. doi: 10.1164/ajrccm.166.1.at1102. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  21. [25]LeBrasseur NK, Bhasin S, Miciek R, Storer TW. Tests of muscle strength and physical function: reliability and discrimination of performance in younger and older men and older men with mobility limitations. J Am Geriatr Soc. 2008;56:2118–2123. doi: 10.1111/j.1532-5415.2008.01953.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [26]Bean JF, Kiely DK, LaRose S, Alian J, Frontera WR. Is stair climb power a clinically relevant measure of leg power impairments in at-risk older adults? Arch Phys Med Rehabil. 2007;88:604–609. doi: 10.1016/j.apmr.2007.02.004. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  23. [28]American Thoracic Society/European Respiratory Society. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166:518–624. doi: 10.1164/rccm.166.4.518. [DOI] [PubMed] [Google Scholar] · DOI
  24. [30]Rooks D, Bartlett M, Petricoul O, Laurent D, Roubenoff R. Safety, pharmacokinetics and pharmacodynamics of bimagrumab: a phase I, randomised, double-blind study in elderly and obese healthy human participants. J Frailty Aging. 2017;6(S1):13. [Google Scholar]
  25. [31]Spruit MA, Polkey MI, Celli B, Edwards LD, Watkins ML, Pinto-Plata V, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study investigators. Predicting outcomes from 6-minute walk distance in chronic obstructive pulmonary disease. J Am Med Dir Assoc. 2012;13:291–297. doi: 10.1016/j.jamda.2011.06.009. [DOI] [PubMed] [Google Scholar] · DOI
  26. [32]Kon SS, Jones SE, Schofield SJ, Banya W, Dickson MJ, Canavan JL, et al. Gait speed and readmission following hospitalisation for acute exacerbations of COPD: a prospective study. Thorax. 2015;70:1131–1137. doi: 10.1136/thoraxjnl-2015-207046. [DOI] [PubMed] [Google Scholar] · DOI
  27. [33]Schols AMW, Soeters PB, Mostert R, Pluymers RJ, Wouters EFM. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease: a placebo-controlled randomized trial. Am J Respir Crit Care Med. 1995;152:1268–1274. doi: 10.1164/ajrccm.152.4.7551381. [DOI] [PubMed] [Google Scholar] · DOI
  28. [34]Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, et al. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:870–878. doi: 10.1164/rccm.200305-617OC. [DOI] [PubMed] [Google Scholar] · DOI
  29. [35]Yeh SS, DeGuzman B, Kramer T M012 Study Group. Reversal of COPD-associated weight loss using the anabolic agent oxandrolone. Chest. 2002;122:421–428. doi: 10.1378/chest.122.2.421. [DOI] [PubMed] [Google Scholar] · DOI
  30. [36]Ferreira IM, Verreschi IT, Nery LE, Goldstein RS, Zamel N, Brooks D, et al. The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients. Chest. 1998;114:19–28. doi: 10.1378/chest.114.1.19. [DOI] [PubMed] [Google Scholar] · DOI
  31. [37]Burdet L, de Muralt B, Schutz Y, Pichard C, Fitting JW. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 1997;156:1800–1806. doi: 10.1164/ajrccm.156.6.9704142. [DOI] [PubMed] [Google Scholar] · DOI
  32. [38]Miki K, Maekura R, Nagaya N, Nakazato M, Kimura H, Murakami S, et al. Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial. PLoS One. 2012;7:e35708. doi: 10.1371/journal.pone.0035708. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  33. [40]Deschênes D, Pepin V, Saey D, LeBlanc P, Maltais F. Locus of symptom limitation and exercise response to bronchodilation in chronic obstructive pulmonary disease. J Cardiopulm Rehabil Prev. 2008;28:208–214. doi: 10.1097/01.HCR.0000320074.73846.3b. [DOI] [PubMed] [Google Scholar] · DOI
  34. [41]Man WD, Soliman MG, Gearing J, Radford SG, Rafferty GF, Gray BJ, et al. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;168:562–567. doi: 10.1164/rccm.200302-162OC. [DOI] [PubMed] [Google Scholar] · DOI
  35. [42]Celli B, Tetzlaff K, Criner G, Polkey MI, Sciurba F, Casaburi R, et al. COPD Biomarker Qualification Consortium; Insights from the COPD Biomarker Qualification Consortium. The 6-minute-walk distance test as a chronic obstructive pulmonary disease stratification tool. Am J Respir Crit Care Med. 2016;194:1483–1493. doi: 10.1164/rccm.201508-1653OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [43]Borel B, Provencher S, Saey D, Maltais F. Responsiveness of various exercise-testing protocols to therapeutic interventions in COPD. Pulm Med. 2013;2013:410748. doi: 10.1155/2013/410748. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. [44]Brønstad E, Rognmo O, Tjonna AE, Dedichen HH, Kirkeby-Garstad I, Håberg AK, et al. High-intensity knee extensor training restores skeletal muscle function in COPD patients. Eur Respir J. 2012;40:1130–1136. doi: 10.1183/09031936.00193411. [DOI] [PubMed] [Google Scholar] · DOI
  38. [45]Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Diaphragm strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154:1310–1317. doi: 10.1164/ajrccm.154.5.8912741. [DOI] [PubMed] [Google Scholar] · DOI
  39. [46]Polkey MI, Luo Y, Guleria R, Hamnegård CH, Green M, Moxham J. Functional magnetic stimulation of the abdominal muscles in humans. Am J Respir Crit Care Med. 1999;160:513–522. doi: 10.1164/ajrccm.160.2.9808067. [DOI] [PubMed] [Google Scholar] · DOI
  40. [47]Polkey MI, Lyall RA, Green M, Nigel Leigh P, Moxham J. Expiratory muscle function in amyotrophic lateral sclerosis. Am J Respir Crit Care Med. 1998;158:734–741. doi: 10.1164/ajrccm.158.3.9710072. [DOI] [PubMed] [Google Scholar] · DOI
  41. [48]Epstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med. 1998;158:489–493. doi: 10.1164/ajrccm.158.2.9711045. [DOI] [PubMed] [Google Scholar] · DOI
  42. [49]Shields GS, Coissi GS, Jimenez-Royo P, Gambarota G, Dimber R, Hopkinson NS, et al. Bioenergetics and intermuscular fat in chronic obstructive pulmonary disease-associated quadriceps weakness. Muscle Nerve. 2015;51:214–221. doi: 10.1002/mus.24289. [DOI] [PubMed] [Google Scholar] · DOI
  43. [50]Wells CE, Polkey MI, Baker EH. Insulin resistance is associated with skeletal muscle weakness in COPD. Respirology. 2016;21:689–696. doi: 10.1111/resp.12716. [DOI] [PubMed] [Google Scholar] · DOI

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Authors
Polkey, M. I., Praestgaard, J., Berwick, A., Franssen, F. M. E., Singh, D., Steiner, M. C., Casaburi, R., Tillmann, H.-C., Lach-Trifilieff, E., Roubenoff, R., & Rooks, D. S.
Affiliations
  • National Health Service (GB)
  • Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
  • Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
  • Ciro (NL)
  • University of Manchester (GB)
  • Glenfield Hospital (GB)
  • University of California, Los Angeles (US)
  • Novartis Institutes for BioMedical Research (CH)
  • Novartis Institutes for BioMedical Research, Basel, Switzerland
Corresponding author
Polkey, Michael I.
ORCID
Venue
American Journal of Respiratory and Critical Care Medicine
Publisher
Oxford University Press (OUP)
Published
2019-02-01
Volume
199
Issue
3
Pages
313-320
ISSN
  • 1073-449X (ISSN-L)
  • 1535-4970
DOI
10.1164/rccm.201802-0286oc
PMC
PMC6363975
OpenAlex
W2886434005
Cited by
111
References
6
Citations by year
2026: 18 · 2025: 9 · 2024: 8 · 2023: 18 · 2022: 14 · 2021: 16 · 2020: 17 · 2019: 8 · 2018: 3
FWCI
3.91
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory and Critical Care Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • Novartis Institutes for BioMedical Research
  • National Institute for Health Research
  • Respiratory Biomedical Research Unit
  • Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College
  • National Health Service
  • The National Institute for Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
Keywords
bimagrumab, chronic obstructive pulmonary disease, muscle atrophy, skeletal muscle mass, thigh muscle volume, myostatin, 6-minute walk distance, functional capacity, adverse events
MeSH terms
Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Body Composition, Double-Blind Method, Female, Humans, Male, Middle Aged, Muscular Atrophy, Thigh, Muscle, Skeletal, Antibodies, Blocking, Activin Receptors, Pulmonary Disease, Chronic Obstructive, Antibodies, Monoclonal, Humanized

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