Enobosarm
Enobosarm, also known as ostarine or GTx-024, is a nonsteroidal, orally bioavailable selective androgen receptor modulator (SARM) that binds to androgen receptors to promote anabolic effects in muscle and bone tissue while minimizing androgenic side effects in other organs.[1] Developed initially by GTx, Inc. in the late 1990s for treating muscle-wasting conditions like cancer cachexia and sarcopenia, it demonstrated increases in lean body mass and improvements in physical function in phase II trials among elderly subjects and cancer patients.[2][3] However, phase III trials (POWER 1 and 2) met endpoints for lean mass preservation but failed to improve overall survival, resulting in FDA non-approval for those indications in 2013.[4] Currently under development by Veru Inc., enobosarm has received FDA fast-track designation for androgen receptor-positive, estrogen receptor-positive, HER2-negative advanced breast cancer, where phase II data showed antitumor activity, and for preserving lean mass during weight loss with GLP-1 agonists like semaglutide.[5][6] Despite lacking FDA approval for any use, it is prohibited by the World Anti-Doping Agency due to its performance-enhancing potential and has been subject to FDA warnings regarding unapproved SARMs' risks, including cardiovascular events.[7][8]
Chemical and Pharmacological Profile
Chemical Structure and Properties
Enobosarm (GTx-024, ostarine) is a synthetic non-steroidal selective androgen receptor modulator (SARM) characterized by the molecular formula C₁₉H₁₄F₃N₃O₃ and a molecular weight of 389.33 g/mol.[9] Its structure features a chiral center at the 2-position of a propanamide backbone, with the active (S)-enantiomer bearing a hydroxy and methyl group at C2, a 4-cyanophenoxy substituent at C3, and an N-linked 4-cyano-3-(trifluoromethyl)phenyl amide.[10] The IUPAC name is (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide.[9] Physicochemically, enobosarm exists as a white to off-white solid.[11] Predicted octanol-water partition coefficients (logP) range from 2.82 to 3.27, suggesting moderate lipophilicity suitable for oral bioavailability.[9] Water solubility is low at approximately 0.00563 mg/mL, consistent with its hydrophobic aryl and trifluoromethyl moieties, but it exhibits good solubility in organic solvents such as DMSO (up to 80 mg/mL) and ethanol (40 mg/mL).[9][12] Experimental melting point data remains undetermined in peer-reviewed chemical databases, with supplier-reported values varying and lacking independent verification.[13] The compound is typically stored at -20°C to maintain stability.[14]Mechanism of Action
Enobosarm, also known as GTx-024 or ostarine, functions as a nonsteroidal selective androgen receptor modulator (SARM) by binding with high affinity to the androgen receptor (AR), a nuclear receptor that regulates gene expression in response to androgens.[1] Upon binding, enobosarm induces a conformational change in the AR, promoting its dimerization, nuclear translocation, and recruitment to androgen response elements (AREs) in DNA, thereby activating transcription of AR target genes associated with anabolic processes.[15] This interaction occurs with an EC50 of less than 10 nM, indicating potent agonist activity comparable to dihydrotestosterone in activating AR-mediated pathways, though with modulated efficacy across tissues.[15] The tissue selectivity of enobosarm arises from its partial agonist profile and differential co-regulator recruitment, enabling robust AR activation in anabolic tissues such as skeletal muscle and bone while exhibiting minimal agonist or even antagonistic effects in androgen-sensitive organs like the prostate.[1] In preclinical models, this selectivity manifests as increased levator ani muscle weight and bone mineral density without significant prostate enlargement, contrasting with non-selective androgens like testosterone that promote growth across all AR-expressing tissues.[1] Such properties stem from enobosarm's ability to stabilize AR conformations that favor anabolic gene programs in muscle and osteoblasts over those driving prostatic hyperplasia or virilization in skin and hair follicles.[1] In muscle cells, enobosarm's AR agonism drives myogenic proliferation and differentiation by upregulating key transcription factors including myogenin, MyoD, and myosin heavy chain (MyH), with effects blocked by AR antagonists.[16] This process involves activation of the ERK1/2 signaling pathway, enhancing cell viability and fusion into myotubes in models like C2C12 and L6 myoblasts, ultimately contributing to increased lean body mass.[16] Similar mechanisms support its bone-anabolic effects through AR-mediated osteoblast activity, though detailed downstream pathways in bone remain less characterized compared to muscle.[1]Pharmacokinetics
Enobosarm is orally bioavailable with rapid absorption following ingestion, allowing for once-daily administration without regard to food in clinical settings.[1] Phase I trials in healthy male volunteers demonstrated linear pharmacokinetics over doses ranging from 1 mg to 3 mg, with favorable tolerability and no significant accumulation beyond expected steady-state levels after repeated dosing.[1] The compound exhibits a mean elimination half-life of approximately 22 hours in humans, supporting its dosing regimen in therapeutic investigations.[17] Preclinical studies in rats confirmed high oral bioavailability, moderate plasma clearance (74.5–117.7 mL/h/kg), and extensive tissue distribution, though human distribution data remain limited to inferred selectivity via its SARM mechanism.[18] Metabolism occurs primarily via hepatic pathways, including O-glucuronidation, hydroxylation at benzonitrile or propyl moieties, ether cleavage, and sulfation, as identified in human hepatocyte models and urine samples from administered individuals.[19] Major metabolites, such as ostarine-glucuronide, predominate in excretion, which is chiefly renal in humans with detection persisting up to 62 hours post-dose in urine; preclinical rodent data suggest fecal elimination as a secondary route.[19] Enobosarm shows low potential for cytochrome P450-mediated drug interactions, consistent with phase I evaluations.[20]Clinical Investigations
Initial Indications and Early Trials
Enobosarm, developed by GTx, Inc., was initially targeted for the prevention and treatment of muscle wasting conditions, including sarcopenia in the elderly and cachexia linked to chronic illnesses, due to its selective anabolic effects on muscle and bone tissues.[1] Phase I trials in healthy young adult males and elderly males with truncal obesity established a favorable safety profile and pharmacokinetics, involving open-label administration of oral doses over 14 days to 71 participants, with observations of lean body mass increases and absence of prostate or skin-related adverse effects.[1] A multicenter, double-blind, placebo-controlled phase II trial assessed enobosarm's efficacy in 120 healthy elderly men over age 60 and postmenopausal women, randomized equally to placebo or daily doses of 0.1 mg, 0.3 mg, 1 mg, or 3 mg for 12 weeks.[1] The primary endpoint, change in total lean body mass via dual-energy X-ray absorptiometry, demonstrated dose-dependent gains, with the 3 mg cohort achieving a 1.3 kg increase (P < 0.001 versus placebo).[1] Secondary measures of physical function, including stair climb power, showed significant improvement in the 3 mg group (P = 0.013 versus placebo), alongside stable body weight and no clinically meaningful changes in insulin resistance.[1] Safety data indicated comparable adverse event incidence to placebo, primarily mild issues like headache and back pain, with no serious adverse events attributed to the drug.[1]Oncology Applications
Enobosarm has been investigated primarily for its potential to mitigate cancer-associated muscle wasting (cachexia), a condition affecting up to 80% of advanced cancer patients, characterized by progressive loss of skeletal muscle mass and function independent of nutritional status.[21] In phase II trials involving patients with non-small cell lung cancer, colorectal cancer, breast cancer, or other malignancies, oral enobosarm at doses of 1 mg or 3 mg daily increased lean body mass by 1.0–1.5 kg over 16 weeks compared to placebo, while also trending toward improvements in physical function measures like the stair climb test, without stimulating prostate-specific antigen levels.70055-X/fulltext) However, the subsequent phase III POWER 1 and POWER 2 trials, enrolling over 650 patients with advanced non-small cell lung cancer or other solid tumors experiencing cachexia, demonstrated statistically significant gains in lean body mass (primary endpoint met) but failed to achieve the co-primary endpoint of improved stair climb power, leading to FDA rejection of approval for this indication in 2013.[22] These results highlighted enobosarm's tissue-selective anabolic effects but underscored the challenge of translating muscle mass gains into functional outcomes in cachectic patients.[23] Beyond supportive care for cachexia, enobosarm has shown direct antitumor activity in androgen receptor (AR)-expressing breast cancers, leveraging its selective AR agonism to inhibit proliferation in AR-positive, estrogen receptor (ER)-positive, HER2-negative advanced disease. In a phase II trial of 136 heavily pretreated patients, enobosarm monotherapy at 9 mg or 18 mg daily yielded clinical benefit rates of 32% and 29%, respectively, defined as complete response, partial response, or stable disease for at least 24 weeks, with higher AR expression levels correlating to greater efficacy (e.g., objective response rates up to 33% in AR-high subgroups).[24] Median progression-free survival reached 5.6 months, and the drug was well-tolerated, with grade 3+ adverse events primarily fatigue (3%) and anemia (3%), attributed to disease rather than treatment.[25] These findings contrast with standard endocrine therapies, suggesting AR activation as a novel mechanism to overcome resistance in ER+ breast cancer, though larger confirmatory trials are needed.[26] Ongoing investigations explore enobosarm combinations in oncology, including with CDK4/6 inhibitors like abemaciclib for ER+/HER2- metastatic breast cancer, where preliminary open-label data indicate safety and potential synergy in preserving lean mass during therapy.[27] In AR-positive triple-negative breast cancer, a phase II trial combining enobosarm with pembrolizumab reported modest activity, though enrollment challenges limited powering.[28] Despite these advances, regulatory hurdles from prior cachexia failures and the need for AR biomarker validation temper enthusiasm, with Veru Inc. (successor to original developer GTx) prioritizing breast cancer development as of 2024.[29]Muscle Preservation in Obesity and Cachexia
Enobosarm has been investigated for preserving lean body mass in cachexia, a syndrome characterized by involuntary muscle wasting often associated with cancer. In a phase II multicenter trial involving 120 healthy elderly men and postmenopausal women, enobosarm at doses of 0.1, 0.3, 1, and 3 mg daily increased total lean body mass by up to 1.4 kg over 12 weeks, alongside improvements in stair-climbing power, without significant androgenic side effects.[1] A subsequent phase II trial in 159 patients with cancer cachexia demonstrated dose-dependent gains in lean body mass (1.0–1.5 kg at 1–3 mg doses over 16 weeks) and enhanced physical function, as measured by the stair climb test, supporting its potential to mitigate muscle loss without the toxicity of traditional anabolic agents.[21]70055-X/abstract) The phase III POWER 1 and POWER 2 trials evaluated enobosarm (3 mg daily) for preventing and treating muscle wasting in over 1,000 patients with non-small cell lung cancer, advanced breast cancer, or cachexia-related weight loss. Both trials met the co-primary endpoint of significant lean body mass increase (POWER 1: +1.3 kg vs. placebo at day 84; POWER 2: +0.9 kg), persisting through 147 days in some subgroups, but failed to achieve statistical significance on the functional co-primary endpoint of stair-climbing power.[22][30] These results highlighted enobosarm's efficacy in building muscle but underscored the challenge of translating mass gains into functional outcomes in advanced disease states, leading to FDA non-approval for cachexia in 2013 despite the lean body mass benefits.[31] In obesity management, enobosarm addresses the muscle loss accompanying caloric restriction or pharmacotherapy, where up to 40% of weight reduction can involve lean mass depletion. A subset analysis of older obese patients treated with enobosarm showed fat mass reductions while preserving lean body mass, yielding improved body composition ratios compared to weight loss alone.00333-1/fulltext) Recent efforts combine enobosarm with GLP-1 receptor agonists (GLP-1 RAs) like semaglutide (Wegovy), which promote substantial fat loss but risk sarcopenia; a meta-analysis of enobosarm data indicated potential for higher-quality weight loss by prioritizing fat over muscle reduction when paired with such agents.[32] A phase 2b trial (September 2024–January 2025) in 168 obese patients on Wegovy demonstrated that enobosarm (9 mg daily) statistically significantly reduced lean mass loss (p=0.002) versus Wegovy monotherapy, preserving muscle during induced weight reduction while enhancing fat loss and body composition.[6] Safety data supported advancement to phase 3, with enobosarm showing no exacerbation of GLP-1 RA side effects and potential to overcome weight loss plateaus via direct muscle anabolic and indirect fat-metabolizing effects.[33] In September 2025, the FDA provided regulatory clarity affirming lean mass preservation as a viable endpoint for enobosarm-GLP-1 RA combinations in obesity, paving the way for trials focused on muscle-sparing weight management.[34][35]Other Therapeutic Explorations
Enobosarm underwent evaluation in a phase II double-blind, placebo-controlled trial for improving lean body mass and physical function in 120 healthy elderly men (aged over 60 years) and postmenopausal women, targeting age-related muscle decline akin to sarcopenia. Participants received daily oral doses of 0.1 mg, 0.3 mg, 1 mg, or 3 mg for 12 weeks, resulting in dose-dependent gains in total lean body mass, with the 3 mg dose yielding a statistically significant increase of 1.4 kg versus placebo (P < 0.001).[1] Stair climb power, a measure of physical performance, also improved significantly at higher doses (P < 0.05 for 1 mg and 3 mg versus placebo).[1] These findings supported enobosarm's anabolic effects without substantial androgenic side effects, though development for sarcopenia was not advanced due to regulatory challenges in defining the indication.[2] Explorations extended to stress urinary incontinence in postmenopausal women, leveraging enobosarm's tissue-selective androgenic activity on pelvic floor muscles. A phase II proof-of-concept open-label trial involving 17 participants treated with enobosarm for 12 weeks reported a clinically meaningful reduction of 50% or more in daily incontinence episodes across all completers.[36] The subsequent phase II ASTRID trial (NCT03241342), a randomized, placebo-controlled study assessing episode frequency reduction as the primary endpoint, completed enrollment but did not demonstrate sufficient efficacy to proceed to phase III, halting further pursuit in this area.[37] In androgen receptor-positive, estrogen receptor-positive, HER2-negative advanced breast cancer, a phase II randomized, open-label trial tested enobosarm monotherapy at 9 mg daily versus standard care. Among 55 evaluable patients previously treated with endocrine therapy, the drug achieved a clinical benefit rate of 39% (duration ≥12 weeks), including one partial response, with manageable toxicity and no new safety signals.[5] This suggested potential for AR agonism in suppressing tumor growth, distinct from cachexia management, though larger confirmatory studies are required.[24]Safety Profile
Observed Adverse Effects
In clinical trials of enobosarm at doses of 1-3 mg daily, the most frequently reported adverse effects were mild to moderate, including headache, fatigue, nausea, diarrhea, back pain, and anemia, with incidences comparable to placebo groups.[1][38] In a phase II trial for cancer-related muscle wasting involving elderly patients, treatment-emergent adverse events occurred in 89-91% of enobosarm recipients versus 88% on placebo, but drug-related events were limited to 13% (1 mg dose) and 28% (3 mg dose), primarily consisting of fatigue (15-20%), nausea (11-23%), and anemia (9-17%); no serious adverse events were attributed to the drug.[38] Higher doses in oncology settings, such as 9 mg or 18 mg daily, have shown increased rates of grade 3 or higher treatment-related adverse events, occurring in 8% and 16% of participants, respectively, though specific events were not detailed beyond general tolerability.[39] Recent phase IIb trials combining enobosarm (3 mg) with GLP-1 receptor agonists for obesity-related muscle preservation reported no treatment-related serious adverse events and reduced gastrointestinal effects (e.g., diarrhea, nausea) compared to GLP-1 monotherapy, with enobosarm monotherapy exhibiting negligible gastrointestinal issues.[40] Isolated cases of cholestatic liver injury, presenting with jaundice, anorexia, lethargy, and elevated bilirubin/ALT, have been linked to enobosarm use outside clinical protocols, resolving gradually upon discontinuation after approximately 2 months of exposure; such hepatotoxicity mirrors patterns seen with anabolic steroids and has not been prominently observed in controlled trials at therapeutic doses.[41] No discontinuations due to adverse effects exceeded placebo rates in early phase II studies, and overall profiles indicate good tolerability without signals of cardiovascular, renal, or severe endocrine disruption in short-term use.[38][1]Toxicity and Overdose Data
In clinical trials of enobosarm at therapeutic doses of 1-3 mg/day, toxicity profiles were characterized by mild, dose-related adverse effects, including transient elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, typically resolving without intervention, and reductions in high-density lipoprotein (HDL) cholesterol without significant impacts on low-density lipoprotein (LDL) or total cholesterol.[38] No instances of severe hepatotoxicity or overdose were documented in phase II or III studies involving cancer patients or elderly subjects, where the drug was administered for up to 16 weeks and monitored for safety endpoints such as physical function and lean body mass preservation.[5] Post-marketing and recreational use, often involving unregulated supplements with doses exceeding 10-25 mg/day, has been linked to drug-induced liver injury (DILI), predominantly cholestatic in nature. Case reports describe acute onset of jaundice, pruritus, hyperbilirubinemia (e.g., total bilirubin up to 20 mg/dL), and modest transaminase elevations (ALT 100-500 U/L), with histological findings of bile duct proliferation and portal inflammation upon biopsy, resolving over weeks to months after discontinuation and supportive care like ursodeoxycholic acid.[41] [42] A systematic review identified 15 such DILI cases associated with selective androgen receptor modulators (SARMs) including enobosarm, alongside rare reports of rhabdomyolysis and tendon rupture, attributing severity to higher doses and impurities in non-pharmaceutical products.[43] Overdose data remain limited, with no controlled human studies or verified acute overdose fatalities reported; toxicity appears cumulative rather than acutely dose-proportional beyond trial ranges, potentially exacerbating endocrine disruptions (e.g., suppressed testosterone) and cardiovascular risks like altered lipid profiles or cardiomyocyte cytotoxicity observed in vitro at supraphysiologic concentrations.[44] [45] In the absence of specific antidotes, management focuses on discontinuation, monitoring liver function, and addressing symptoms, as evidenced by resolution in documented cases without long-term sequelae.[46]Pharmacological Interactions
Enobosarm is primarily excreted unchanged in feces, with metabolism occurring mainly through glucuronidation via uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes such as UGT1A1 and UGT2B7, and minimal contribution from cytochrome P450 (CYP) pathways including CYP3A4.[20] This profile limits the potential for pharmacokinetic interactions driven by CYP induction, inhibition, or competition, as the drug exhibits low affinity for CYP enzymes and does not substantially rely on them for clearance.[20] Dedicated Phase I open-label studies assessed enobosarm's interactions with itraconazole (a strong CYP3A4 inhibitor), rifampin (a CYP3A4 inducer), probenecid (an inhibitor of organic anion transporters involved in renal excretion), celecoxib (a CYP2C9 substrate), and rosuvastatin (a substrate for hepatic uptake transporters like OATP1B1). Co-administration with itraconazole produced no meaningful changes in enobosarm's area under the curve (AUC) or maximum concentration (C_max), confirming negligible CYP3A4 dependence. Rifampin slightly reduced enobosarm AUC by approximately 20-30% due to potential induction effects, but this did not reach clinical significance thresholds (e.g., <50% change). Probenecid had no impact, consistent with enobosarm's predominant fecal elimination route over renal secretion.[20] Enobosarm did not appreciably alter the pharmacokinetics of celecoxib or rosuvastatin, indicating it lacks substantial inhibitory effects on CYP2C9 or relevant transporters. All combinations were well tolerated, with no serious adverse events attributed to interactions. These results collectively demonstrate enobosarm's low propensity for clinically relevant pharmacokinetic drug-drug interactions in evaluated scenarios.[20] Pharmacodynamic interactions remain underexplored in clinical settings, though enobosarm's selective androgen receptor agonism could theoretically potentiate effects of concurrent androgens or modulators of the hypothalamic-pituitary-gonadal axis; no such studies confirm additive risks beyond expected hormonal perturbations. Combinations with newer agents like GLP-1 receptor agonists have not been formally evaluated for interactions.[47]Regulatory Trajectory
FDA Review Process and Decisions
In June 2011, GTx, Inc. reached an agreement with the FDA on a Phase III clinical development plan for enobosarm to evaluate its efficacy in preventing and treating muscle wasting associated with non-small cell lung cancer.[48] This plan included two pivotal trials, POWER 1 and POWER 2, which assessed lean body mass increase as the primary endpoint and stair climb power as a key secondary endpoint for physical function improvement.[49] On January 8, 2013, the FDA granted Fast Track designation to enobosarm for the prevention and treatment of muscle wasting in patients with non-small cell lung cancer, facilitating expedited development and potential priority review of a future new drug application (NDA).[50] However, topline results from the POWER trials, announced in August 2013, showed that while enobosarm met the primary endpoint of increasing lean body mass, it failed to achieve statistically significant improvement in the key secondary endpoint of stair climb power, leading GTx to conclude that the data did not support NDA submission.[51] No formal NDA was filed, and enobosarm received no approval for cancer cachexia indications.[52] Following GTx's challenges and asset transfer, Veru Inc. advanced enobosarm for new indications. On January 10, 2022, the FDA granted Fast Track designation for its use in androgen receptor-positive, estrogen receptor-positive, HER2-negative metastatic breast cancer that progressed after endocrine and CDK4/6 inhibitor therapy.[53] In February 2024, the FDA cleared an investigational new drug (IND) application to initiate a Phase 2b trial evaluating enobosarm in combination with GLP-1 receptor agonists for preserving muscle mass in sarcopenic obesity during weight loss.[54] As of September 2025, a Type B end-of-Phase 2 meeting with the FDA confirmed the acceptability of the 3 mg daily dose for further development in obesity-related muscle preservation, endorsed incremental weight loss over GLP-1 therapy alone as a potential primary endpoint for approval, and encouraged inclusion of younger patients (aged 40-65) alongside elderly cohorts in future trials.[33] Enobosarm remains unapproved by the FDA for any indication, with ongoing Phase 2b/3 trials required to support potential NDA submission.[55] The agency has also issued public warnings on selective androgen receptor modulators like enobosarm regarding risks of unapproved use, including liver injury and cardiovascular effects.[56]International Regulatory Perspectives
Enobosarm has not received marketing authorization from the European Medicines Agency (EMA) for any therapeutic indication, despite involvement in clinical trials within the European Union.[56] The EMA's rejection of similar agents for cachexia treatment, such as anamorelin in May 2017, underscores regulatory caution toward compounds targeting muscle wasting without established long-term safety profiles.[57] Ongoing phase II and III studies for enobosarm in oncology and other areas have not progressed to approval, positioning it as an investigational selective androgen receptor modulator (SARM) rather than a licensed pharmaceutical.[58] In Canada, Health Canada has issued warnings against the unauthorized sale and use of enobosarm, classifying it alongside other SARMs as unapproved drugs not assessed for safety or efficacy.[59] Products containing enobosarm are deemed unauthorized health products, with regulatory actions targeting their distribution in workout supplements due to risks of serious adverse effects.[60] This stance aligns with broader prohibitions under the World Anti-Doping Agency (WADA), where enobosarm lacks approval from any governmental health authority for human therapeutic use.[61] Australia's Therapeutic Goods Administration (TGA) regards enobosarm as an unapproved medicine, with SARMs generally not evaluated for human consumption and prohibited without prescription.[62] Regulatory delegates have noted its unscheduled status but emphasized the absence of clinical validation for safety, leading to enforcement against illicit marketing.[63] Similar perspectives prevail in other jurisdictions, where enobosarm's development remains confined to research settings amid concerns over hepatotoxicity and endocrine disruption observed in trials.[56] No international agency has endorsed its therapeutic application as of 2025, reflecting a consensus on insufficient evidence for benefit-risk balance.Intellectual Property and Formulation Advances
Enobosarm (GTx-024), a selective androgen receptor modulator originally developed by GTx, Inc., is covered by patents exclusively licensed from the University of Tennessee Research Foundation, with U.S. composition-of-matter patents expiring in 2024.[64] Additional method-of-use patents for specific indications, such as Duchenne muscular dystrophy, are pending issuance with potential expiration in 2024 if granted.[64] Following GTx's restructuring and asset acquisition by Veru Inc. in 2020, the intellectual property portfolio has been expanded to include protections for enobosarm's applications in oncology and metabolic disorders, with some U.S. patents extending to 2029 and potential new chemical entity extensions to 2034.[65] Veru maintains that this portfolio sufficiently safeguards enobosarm's development in areas like breast cancer and obesity.[66] In response to challenges with the original immediate-release oral formulation, including variable pharmacokinetics when combined with GLP-1 receptor agonists, Veru selected a novel modified-release oral formulation of enobosarm 3 mg in August 2025 for phase 3 trials targeting sarcopenia in obesity patients.[67] This formulation aims to enhance tissue selectivity for fat loss over muscle preservation during weight reduction therapy, demonstrating improved stability and reduced gastrointestinal interactions in preclinical assessments.[40] Patent applications for this modified-release version have been filed, with projected expiration in 2046 if issued, extending commercial exclusivity beyond the core compound patents.[67] These advances address bioavailability limitations of earlier SARM formulations while supporting combination regimens with agents like semaglutide.[68]Non-Clinical Applications
Recreational and Performance-Enhancing Use
Enobosarm, also known as ostarine or MK-2866, is employed recreationally by bodybuilders, fitness enthusiasts, and athletes seeking anabolic effects such as increased lean muscle mass, enhanced strength, and reduced body fat, with claims of fewer androgenic side effects than traditional anabolic-androgenic steroids.[69][19] It is typically sourced from online vendors marketing it as a research chemical or supplement, bypassing regulatory oversight for human use.[19] This off-label application stems from its selective androgen receptor modulation, which preclinical and early clinical data indicate promotes muscle protein synthesis and hypertrophy via androgen receptor agonism in skeletal muscle tissue.[70] Recreational protocols commonly involve oral doses of 10 to 30 mg per day, administered in cycles lasting 8 to 12 weeks, often followed by post-cycle therapy involving selective estrogen receptor modulators to counteract potential testosterone suppression.[69] These dosages exceed those in clinical trials (typically 1 to 3 mg daily), where enobosarm demonstrated dose-dependent lean body mass increases of 1.0 to 1.4 kg over 12 weeks in elderly or cachectic populations, alongside modest fat mass reductions averaging 0.6 kg.[1][69] User reports in fitness forums describe 4.5 to 9 kg of lean mass gains, improved endurance, faster recovery, and preserved muscle during caloric deficits, though such outcomes rely heavily on anecdotal evidence rather than controlled studies in healthy young adults.[69][19] The appeal for performance enhancement is evident in its prevalence as a doping agent, with enobosarm accounting for 306 adverse analytical findings in anti-doping tests from 2016 to 2022, reflecting widespread adoption among both amateur and elite athletes for competitive advantages in strength and recovery without overt virilization.[19] In vitro studies further support its myogenic potential by inducing muscle cell proliferation and differentiation through androgen receptor activation.[71] However, evidence for superior efficacy over placebo in vigorous training regimens remains limited to extrapolations from therapeutic contexts, underscoring the experimental nature of recreational application.[70]Market Availability and Legal Status
Enobosarm remains unapproved by the United States Food and Drug Administration (FDA) for any medical indication as of October 2025, classifying it as an investigational new drug restricted to clinical trials.[8][72] Despite ongoing phase 2b trials, including combinations with GLP-1 receptor agonists for muscle preservation in obesity treatment, no new drug application has been approved, and it lacks marketing authorization.[6] In the U.S., enobosarm cannot be legally marketed or sold as a dietary supplement, drug, or for human consumption under the Federal Food, Drug, and Cosmetic Act, with the FDA issuing warnings against its distribution due to unproven safety and efficacy.[8] Commercially, enobosarm is unavailable through legitimate pharmaceutical channels but circulates in gray-market channels as a research chemical, often labeled "not for human use" and sold online by chemical suppliers for laboratory purposes.[72] These products, typically in liquid or powder form at concentrations like 25 mg/mL, evade direct regulatory scrutiny by disclaiming consumptive intent, though trace contamination in supplements has prompted FDA enforcement actions.[8] Illicit sales for performance enhancement persist despite crackdowns, with no standardized quality controls ensuring purity or accurate dosing. Internationally, enobosarm holds no regulatory approvals for therapeutic use in major jurisdictions, mirroring U.S. restrictions and prohibiting over-the-counter or prescription sales.[72] In the United Kingdom, it is not authorized for human consumption and is treated as an unlicensed medicine, with availability limited to unregulated online sources.[73] Australia classifies selective androgen receptor modulators like enobosarm under Schedule 4 (prescription-only) but enforces bans on unapproved imports and sales, aligning with global patterns where it functions primarily as a prohibited research substance outside controlled studies. Efforts like the proposed U.S. SARMs Control Act of 2019 underscore attempts to impose stricter controls, though enforcement relies on existing unapproved drug statutes.[74]Sports Doping Implications
Prohibitions and Testing Protocols
Enobosarm, also known as ostarine, is prohibited under section S1.2 (Other Anabolic Agents) of the World Anti-Doping Agency (WADA) Prohibited List as a selective androgen receptor modulator (SARM), with the ban applying at all times, both in- and out-of-competition.[75][61] This classification stems from its anabolic effects, which provide unfair performance advantages in muscle growth and recovery without the full androgenic side effects of traditional steroids.[7] The prohibition is enforced by all WADA signatories, including the International Olympic Committee (IOC), national anti-doping agencies such as the United States Anti-Doping Agency (USADA) and United Kingdom Anti-Doping (UKAD), and international federations overseeing sports like athletics and cycling.[7][73] In the United States, the Department of Defense (DoD) also lists all SARMs, including enobosarm, as prohibited dietary supplement ingredients for military personnel.[76] The National Collegiate Athletic Association (NCAA) bans enobosarm within its broader anabolic agents category, subjecting violators to sanctions ranging from suspensions to eligibility loss.[77] Testing protocols for enobosarm adhere to WADA's International Standard for Laboratories (ISL), which mandates sample collection—primarily urine, occasionally supplemented by blood—under strict chain-of-custody procedures during competitions or out-of-competition testing. Initial screening employs liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect enobosarm and its primary urinary metabolites, including the glucuronide conjugate and hydroxyostarine, as the parent compound is excreted mainly in conjugated form.[78][79] WADA-accredited laboratories must routinely identify these markers above their validated limits of detection, with enobosarm classified as a non-threshold substance, meaning any confirmed concentration triggers an adverse analytical finding (AAF) without a specified allowable limit.[78][19] Confirmation testing, required for presumptive positives, utilizes high-resolution mass spectrometry with isotope dilution for structural elucidation and quantification, ensuring specificity against potential interferences.[80] WADA's Technical Letter TL12 provides specific guidance on reporting enobosarm findings, emphasizing the detection of deconjugated parent ostarine for screening efficiency and major phase II metabolites for confirmation.[78] Laboratories achieve this through validated methods capable of identifying microdosed administrations, with elimination studies showing detectability in urine for up to several days post-ingestion, even at low doses mimicking contamination scenarios.[81] Between 2015 and 2019, global anti-doping efforts recorded 178 AAFs for ostarine, underscoring its prevalence and the protocols' sensitivity.[73]Detection Challenges and Contamination Claims
Detection of enobosarm (also known as ostarine) in sports doping tests primarily relies on identifying the parent compound or its glucuronide-conjugated metabolite in urine via liquid chromatography-mass spectrometry (LC-MS/MS), with the unmodified parent and glucuronide serving as primary markers of ingestion.[82] Analytical challenges arise from structural similarities to permitted drugs like bicalutamide, whose metabolites (e.g., O-dephenyl-ostarine) can appear in low abundance and complicate interpretation; thus, WADA guidelines specify that only confirmed parent or glucuronide findings trigger adverse analytical findings (AAFs), excluding isolated minor metabolites.[78] Additionally, microdosing—single or repeated low doses (1–50 μg)—produces urinary concentrations below 6 ng/mL with detection windows up to 15 days, exhibiting high inter-individual variability in metabolite ratios (e.g., hydroxylated forms like M1a detectable for 44–72 hours at higher microdoses), which overlaps with profiles from trace contamination and hinders definitive attribution of intentional use.[83] Contamination claims frequently invoke dietary supplements as the source of trace enobosarm detections, with USADA documenting 13 such doping cases involving possession or use since 2014, often at levels consistent with inadvertent exposure rather than therapeutic dosing.[84] In UFC anti-doping policy applications, four athletes (Augusto Mendes, Marvin Vettori, Sean O’Malley, and Nicco Montano) tested positive for trace ostarine in out-of-competition samples between March and December 2018, with investigations attributing findings to supplement contamination and no evidence of intentional use, resulting in reduced six-month sanctions per case.[85] Similar assertions surfaced in boxer Ryan Garcia's 2024 case, where two listed supplements pre-fight against Devin Haney tested positive for enobosarm, underscoring persistent adulteration risks despite manufacturer claims of purity; however, strict liability rules under WADA and affiliated codes hold athletes accountable regardless, emphasizing personal responsibility for intake while acknowledging empirical evidence of widespread supplement tainting.[86] These incidents highlight causal factors like inadequate regulatory oversight of non-prescription products, where peer-reviewed analyses confirm SARMs contamination in commercially available supplements, often evading detection until post-ingestion testing.[87]Documented Violations and Case Analyses
In mixed martial arts, the United States Anti-Doping Agency (USADA) has documented multiple violations involving enobosarm under the UFC Anti-Doping Policy, often at trace levels below 0.1 ng/mL, resulting in reduced six-month sanctions after acceptance of no-fault findings due to potential contamination. For instance, on August 6, 2018, Italian fighter Marvin Vettori tested positive following an out-of-competition urine sample, leading to a six-month suspension ending December 6, 2018. Similarly, American fighter Augusto Mendes tested positive on March 7, 2018, from an out-of-competition test, accepting a six-month ban concluding September 7, 2018. Two additional unnamed UFC athletes in the same cohort accepted identical sanctions for comparable trace detections announced on April 23, 2019. Brazilian welterweight Elizeu Zaleski dos Santos faced a provisional suspension after testing positive on March 14, 2022, from an out-of-competition sample, ultimately accepting a sanction under the policy. American featherweight Andre Ewell received a public warning after a positive test on October 15, 2020, from an out-of-competition urine sample, with no competition suspension due to the circumstances. These cases highlight a pattern in combat sports where low concentrations frequently lead to negotiated resolutions rather than full two- or four-year bans, reflecting USADA's consideration of evidentiary thresholds for intent. In boxing, British former world champion Amir Khan was banned for two years by UK Anti-Doping after testing positive for enobosarm following his June 2018 loss to Kell Brook, with the violation confirmed via urine samples showing the metabolite, leading to the sanction starting February 20, 2019, and ending February 19, 2021. While boxer Ryan Garcia did not test positive himself, two supplements he declared prior to his April 2024 fight against Devin Haney contained enobosarm upon independent testing, underscoring risks of undeclared contamination in over-the-counter products but not resulting in a direct athlete violation. In weightlifting, American athlete Amy Hay received a two-year ineligibility period from an American Arbitration Association panel after testing positive for enobosarm (also known as MK-2866) in 2017, with the decision emphasizing strict liability despite her claims of supplement contamination. In collegiate baseball, two Clemson University players tested positive for enobosarm in 2019 from tainted supplements, but their appeal was denied by a World Anti-Doping Agency medical review committee, upholding the findings under strict liability despite recommendations against positives in low-level contamination scenarios. In triathlon, Beth McKenzie and another athlete represented the first documented enobosarm cases in the sport around 2017, with positives attributed to contaminated recovery products, resulting in sanctions that highlighted emerging detection challenges in endurance disciplines. In athletics, a 2024 Court of Arbitration for Sport case (CAS 2024/A/10748) confirmed a violation for an athlete whose A sample revealed enobosarm under WADA's S1.2 prohibited substances, enforcing standard penalties absent evidence overturning the finding. Another athletics case involved an athlete challenging positives below 0.1 ng/mL in 2024, ultimately suspended after analysis ruled out supplement contamination from declared products.| Athlete | Sport | Test Date | Concentration/Notes | Sanction | Source |
|---|---|---|---|---|---|
| Marvin Vettori | MMA (UFC) | Aug 6, 2018 | Trace (<0.1 ng/mL) | 6 months | [85] |
| Augusto Mendes | MMA (UFC) | Mar 7, 2018 | Trace | 6 months | [85] |
| Elizeu Zaleski dos Santos | MMA (UFC) | Mar 14, 2022 | Positive metabolite | Accepted sanction (details per policy) | [88] |
| Andre Ewell | MMA (UFC) | Oct 15, 2020 | Positive | Public warning | [89] |
| Amir Khan | Boxing | Post-Jun 2018 fight | Metabolite detected | 2 years (Feb 2019–2021) | [90] |
| Amy Hay | Weightlifting | 2017 | Positive (MK-2866) | 2 years | [91] |
| Unnamed athlete | Athletics | 2024 | Enobosarm in A sample | Standard WADA penalty | [92] |