The Selective Androgen Receptor Modulator Gtx-024
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J Cachexia Sarcopenia Muscle (2011) 2:153–161 DOI 10.1007/s13539-011-0034-6 ORIGINAL ARTICLE 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 Received: 20 April 2011 /Accepted: 11 July 2011 /Published online: 2 August 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract resistance (P=0.013, 3 mg vs. placebo). The incidence of Background Cachexia, also known as muscle wasting, is a adverse events was similar between treatment groups. complex metabolic condition characterized by loss of Conclusion GTx-024 showed a dose-dependent improve- skeletal muscle and a decline in physical function. Muscle ment in total lean body mass and physical function and was wasting is associated with cancer, sarcopenia, chronic well tolerated. GTx-024 may be useful in the prevention obstructive pulmonary disease, end-stage renal disease, and/or treatment of muscle wasting associated with cancer and other chronic conditions and results in significant and other chronic diseases. morbidity and mortality. GTx-024 (enobosarm) is a nonste- roidal selective androgen receptor modulator (SARM) that Keywords Muscle wasting . Selective androgen receptor has tissue-selective anabolic effects in muscle and bone, modulator . Cachexia . Physical function . Lean body mass while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclini- 1 Introduction cal studies and favorable safety and pharmacokinetic profiles in phase I investigation. Skeletal muscle accounts for nearly half of whole body Methods A 12-week double-blind, placebo-controlled protein mass and plays a critical role in overall health by phase II clinical trial was conducted to evaluate GTx-024 providing strength for daily physical function [1]. In in 120 healthy elderly men (>60 years of age) and healthy individuals, skeletal muscle homeostasis requires a postmenopausal women. The primary endpoint was total balance of anabolic and catabolic processes, resulting in lean body mass assessed by dual energy X-ray absorptiometry, continuous renewal of muscle proteins without a net change and secondary endpoints included physical function, body in overall muscle mass. As the primary reservoir of amino weight, insulin resistance, and safety. acids, muscle is the mediator of whole body protein and is a Results GTx-024 treatment resulted in dose-dependent source of precursors for hepatic gluconeogenesis. increases in total lean body mass that were statistically Muscle also plays an important role in blood glucose significant (P<0.001, 3 mg vs. placebo) and clinically regulation and metabolic health [2]. Muscle loss is a strong meaningful. There were also significant improvements in predictor of physical disability, frailty, and loss of indepen- physical function (P=0.013, 3 mg vs. placebo) and insulin dence and has been linked to poor balance, decreased gait speed, falls, and fractures [3–6]. Healthy adults lose * : : : : – J. T. Dalton ( : ) K. G. Barnette: C. E. Bohl: M. L. Hancock approximately 1 2% of their skeletal muscle mass per year D. Rodriguez S. T. Dodson R. A. Morton M. S. Steiner after the age of 50 [7]. Additionally, Baumgartner et al. GTx, Inc., estimates that 13–24% of persons under the age of 70 and 175 Toyota Plaza, Memphis, TN 38103, USA up to 50% of individuals over the age of 80 suffer from e-mail: [email protected] significant muscle loss [8]. 154 J Cachexia Sarcopenia Muscle (2011) 2:153–161 Accelerated muscle loss occurs in many acute and clinically apparent adverse effects involving the skin or chronic conditions including cancer, chronic kidney disease, prostate (data on file). A phase II, randomized, double- diabetes, acquired immune deficiency syndrome, chronic blind, placebo-controlled study was conducted to evaluate obstructive pulmonary disease, congestive heart failure, the effects of GTx-024 on total lean body mass and rheumatoid arthritis and hypogonadism, sepsis, and burn physical function in elderly men and postmenopausal injury [1, 9–12]. Patients have profound muscle loss because women. Secondary endpoints included safety of GTx-024, of increased protein demand, a heightened inflammatory effects on fat mass, bone mineral density, blood glucose, state, increased resting energy expenditure, and atrophy from and insulin. This study is the first to demonstrate the ability disuse. Muscle wasting is an independent risk factor for poor of a nonsteroidal, orally bioavailable SARM to increase health outcomes in patients with chronic diseases [11]. The lean muscle mass and improve physical function. prevalence of muscle wasting in cancer patients increases to greater than 80% prior to death from malignancy and represents the cause of death in over 20% of cancer patients 2 Patients and methods [13–16]. To date, no therapy is approved for the prevention and treatment of muscle wasting. This was a randomized, double-blind, placebo-controlled, Although anabolic steroids and testosterone have been and multicenter study conducted under the World Medical used to treat muscle wasting, their risks often outweigh the Association Declaration of Helsinki, International Conference potential benefits for many patients [17]. The use of these on Harmonization Guidance for Good Clinical Practices. The agents is limited by their inability to separate the desired study documents were reviewed and approved by an anabolic effects of steroids in the muscle and bone from Independent Ethics Committee and Medicines and Healthcare unwanted side effects of testosterone, partly due its products Regulatory Agency, UK. The study was conducted conversion to estrogen in adipose tissue and dihydrotestos- from 11 July 2006 to 20 October 2006. The primary endpoint terone (DHT) in the skin and prostate [18]. Concerns was to assess the effect of GTx-024 on total lean body mass related to increased risk or severity of benign prostatic measured by dual energy X-ray absorptiometry (DXA). hyperplasia or prostate cancer in men, virilization in Secondary endpoints included assessments of the effects of women, and cardiovascular side effects in certain popula- GTx-024 on physical function measured by the Stair Climb tions limit widespread use of testosterone and other Test [27], bone mineral density (BMD), body weight, fat anabolic steroids [19]. Additionally, due to limitations in mass and insulin resistance, sebum production, lipids, serum oral bioavailability, testosterone replacement therapy is only hormones, hair growth in females (hirsutism), and safety available in transdermal and intramuscular formulations and tolerability. which may also limit its usefulness due to adverse skin The subjects included in this study were healthy reactions and wide fluctuations in the serum concentrations volunteers without evidence of disease recruited from the of testosterone that are observed [20]. general population around the phase I study units in London There is an unmet medical need for an anabolic agent (Richmond Pharmacology, Ltd.), Plymouth (Veeda Clinical with an improved benefit/risk profile. The ideal agent Research), and Dundee (Drug Development Solutions, should demonstrate anabolic selectivity in muscle and bone Limited) in the UK, Belfast in Northern Ireland (MDS without suppressing luteinizing hormone (LH), lack cross- Pharma Services), and Hamburg, Germany (MDS Pharma reactivity with other steroid receptors, allow oral dosing, Services). The subjects were recruited through advertisement and avoid conversion to DHT and estradiol [21]. The need and database searches. The subjects were non-obese (body for such an agent has stimulated the development of mass index (BMI) <30) and were not required to have selective androgen receptor modulators (SARMs). mobility disability. The subjects were required to sign an GTx-024 (enobosarm; United States Adopted Names informed consent, agree to return to the study center at least Council official generic name) is an orally bioavailable ten times during the outpatient portion of this study, and have nonsteroidal SARM with tissue-selective anabolic and a white blood cell count ≥3,000/mm3, platelet count androgenic pharmacologic activity [22–26]. In animal ≥100,000/mm3, serum creatinine ≤1.5 mg/dL, alanine studies, GTx-024 increased muscle mass and bone density aminotransferase and aspartate aminotransferase <1.25 while having limited effects on other androgen-responsive times the upper limit of normal, and total bilirubin tissues including the prostate and seminal vesicles. In fact, <1.5 mg/dL. Females required clinical confirmation of prostate size was reduced at doses that increased muscle menopausal status, and males were required to be over mass in intact, male rats. In a phase I study in 48 healthy the age of 60 and have a serum prostate specific antigen 18- to 45-year-old males and 23 elderly males with truncal of ≤4.0 ng/mL or a negative prostate biopsy (no prostate obesity, GTx-024 administered for 14 days increased lean cancer) within 6 months of evaluation. The subjects were body mass and had a favorable tolerability profile without not permitted to initiate diet modification or initiate or J Cachexia