The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial

James T Dalton, Kester G Barnette, Casey E Bohl, Michael L Hancock, Domingo Rodriguez, Shontelle T Dodson, Ronald A Morton, Mitchell S Steiner, James T Dalton, Kester G Barnette, Casey E Bohl, Michael L Hancock, Domingo Rodriguez, Shontelle T Dodson, Ronald A Morton, Mitchell S Steiner

Abstract

BACKGROUND: Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation. METHODS: A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety. RESULTS: GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups. CONCLUSION: GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

Figures

Fig. 1
Fig. 1
Percentage change from baseline to day 86/EOS in total lean body mass: evaluable population. EOS end of study, *P < 0.001 3 mg vs. placebo (T test)
Fig. 2
Fig. 2
Percentage change from baseline to day 86/EOS in stair climb power: evaluable population. EOS end of study, *P = 0.013 3 mg vs. placebo (T test)

References

    1. Argiles JM, Busquets S, Felipe A, Lopez-Soriano FJ. Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia. Int J Biochem Cell Biol. 2005;37(5):1084–1104. doi: 10.1016/j.biocel.2004.10.003.
    1. Baracos VE. Management of muscle wasting in cancer-associated cachexia. Cancer. 2001;92(6 Suppl):1669–1677. doi: 10.1002/1097-0142(20010915)92:6+<1669::AID-CNCR1495>;2-S.
    1. Roubenoff R. Sarcopenia and its implications for the elderly. Eur J Clin Nutr. 2000;54(Suppl 3):S40–S47.
    1. Tan BHL, Fearon KC. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care. 2008;11(4):400–407. doi: 10.1097/MCO.0b013e328300ecc1.
    1. Guralnick JM. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med. 1995;332:556–561. doi: 10.1056/NEJM199503023320902.
    1. 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.
    1. Hughes VA, Frontera WR, Roubenoff R, Evans WJ, Singh MA. Longitudinal changes in body composition in older men and women: role of body weight change and physical activity. Am J Clin Nutr. 2002;76(2):473–481.
    1. Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147(8):755–763.
    1. Mitch WE, Price SR. Mechanisms activated by kidney disease and the loss of muscle mass. Am J Kidney Dis. 2001;38(6):1337–1342. doi: 10.1053/ajkd.2001.29249.
    1. Kamel HK. Sarcopenia and aging. Nutr Rev. 2003;61(5 Pt 1):157–167. doi: 10.1301/nr.2003.may.157-167.
    1. von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachex Sarcopenia Muscle. 2010;1(1):1–5. doi: 10.1007/s13539-010-0002-6.
    1. Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr. 2010;91:1S–5S. doi: 10.3945/ajcn.2010.28608A.
    1. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69(4):491–497. doi: 10.1016/S0149-2918(05)80001-3.
    1. Prado CMM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9(7):629–635. doi: 10.1016/S1470-2045(08)70153-0.
    1. Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition. BMJ. 1997;315(7117):1219–1222.
    1. National Cancer Institute. Nutrition in cancer care (PDQ). National Cancer Institute 2010 contract no.: 04/06/2011.
    1. Borst SE. Interventions for sarcopenia and muscle weakness in older people. Age Ageing. 2004;33(6):548–555. doi: 10.1093/ageing/afh201.
    1. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, et al. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab. 2006;2(3):146–159. doi: 10.1038/ncpendmet0120.
    1. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109–122. doi: 10.1056/NEJMoa1000485.
    1. Srinivas-Shankar U, Wu FC. Drug insight: testosterone preparations. Nat Clin Pract Urol. 2006;3(12):653–665. doi: 10.1038/ncpuro0650.
    1. Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J Clin Endocrinol Metab. 1999;84(10):3459–3462. doi: 10.1210/jc.84.10.3459.
    1. Bohl CE, Chang C, Mohler ML, Chen J, Miller DD, Swaan PW, et al. A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor. J Med Chem. 2004;47(15):3765–3776. doi: 10.1021/jm0499007.
    1. Chen J, Hwang DJ, Chung K, Bohl CE, Fisher SJ, Miller DD, et al. In vitro and in vivo structure-activity relationships of novel androgen receptor ligands with multiple substituents in the B-ring. Endocrinology. 2005;146(12):5444–5454. doi: 10.1210/en.2005-0732.
    1. Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-prop ionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J Pharmacol Exp Ther. 2005;315(1):230–239. doi: 10.1124/jpet.105.088344.
    1. Gao W, Kim J, Dalton JT. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharm Res. 2006;23(8):1641–1658. doi: 10.1007/s11095-006-9024-3.
    1. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52(12):3597–3617. doi: 10.1021/jm900280m.
    1. 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(5):604–609. doi: 10.1016/j.apmr.2007.02.004.
    1. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440–1447. doi: 10.1210/jcem-21-11-1440.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–419. doi: 10.1007/BF00280883.
    1. SAS Institute Inc . SAS/STAT user's guide, version 8. Cary: SAS Institute Inc.; 1999.
    1. Bulcao C, Ribeiro-Filho FF, Sanudo A, Roberta Ferreira SG. Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. Am J Cardiovasc Drugs. 2007;7(3):219–224. doi: 10.2165/00129784-200707030-00007.
    1. Eriksson JG, Lehtovirta M, Ehrnstrom B, Salmela S, Groop L. Long-term beneficial effects of glipizide treatment on glucose tolerance in subjects with impaired glucose tolerance. J Intern Med. 2006;259(6):553–560. doi: 10.1111/j.1365-2796.2006.01633.x.
    1. Choi BG, McLaughlin MA. Why men's hearts break: cardiovascular effects of sex steroids. Endocrinol Metab Clin North Am. 2007;36(2):365–377. doi: 10.1016/j.ecl.2007.03.011.
    1. Guay A, Jacobson J. The relationship between testosterone levels, the metabolic syndrome (by two criteria), and insulin resistance in a population of men with organic erectile dysfunction. J Sex Med. 2007;4(4 Pt 1):1046–1055. doi: 10.1111/j.1743-6109.2007.00530.x.
    1. Lunenfeld B. Testosterone deficiency and the metabolic syndrome. Aging Male. 2007;10(2):53–56. doi: 10.1080/13685530701390800.
    1. Adams SG, Smith PK, Allan PF, Anzueto A, Pugh JA, Cornell JE. Systematic review of the chronic care model in chronic obstructive pulmonary disease prevention and management. Arch Intern Med. 2007;167(6):551–561. doi: 10.1001/archinte.167.6.551.
    1. Jamerson KA. Preventing chronic kidney disease in special populations. Am J Hypertens. 2005;18(4 Pt 2):106S–111S. doi: 10.1016/j.amjhyper.2004.11.018.
    1. Peralta CA, Kurella M, Lo JC, Chertow GM. The metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens. 2006;15(4):361–365. doi: 10.1097/01.mnh.0000232875.27846.7e.
    1. Cantrill JA, Dewis P, Large DM, Newman M, Anderson DC. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984;21(2):97–107. doi: 10.1111/j.1365-2265.1984.tb03448.x.
    1. Thompson PD, Cullinane EM, Sady SP, Chenevert C, Saritelli AL, Sady MA, et al. Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. JAMA. 1989;261(8):1165–1168. doi: 10.1001/jama.261.8.1165.
    1. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335:1–7. doi: 10.1056/NEJM199607043350101.
    1. von Haehling S, Morley JE, Coats AJS, Anker SD. (2010) Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8. doi: 10.1007/s13539-010-0003-5.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe