Global InformationEnobosarm information
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| Other names | Ostarine; GTx-024; MK-2866; S-22; VERU-024[1] |
| Routes of administration | By mouth[2] |
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| Bioavailability | 100% (rats)[3] |
| Metabolism | CYP3A4, UGT1A1, UGT2B7[4] |
| Metabolites | Enobosarm glucuronide[4] |
| Elimination half-life | 14–24 hours[5][6][4][7] |
| Excretion | Feces (70%), urine (21–25%) (rats)[3] |
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| Formula | C19H14F3N3O3 |
| Molar mass | 389.334 g·mol−1 |
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| Melting point | 132 to 136 °C (270 to 277 °F) |
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Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition (e.g., prevention of muscle loss) in people taking GLP-1 receptor agonists like semaglutide.[1][5][7][8][9] It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued.[1][10][2] Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength.[11][2][12][10][13] As a result, enobosarm was not approved and development for this use was terminated.[2] Enobosarm is taken by mouth.[2]
Known possible side effects of enobosarm include headache, fatigue, anemia, nausea, diarrhea, back pain, adverse lipid changes like decreased high-density lipoprotein (HDL) cholesterol levels, changes in sex hormone concentrations like decreased testosterone levels, elevated liver enzymes, and liver toxicity, among others.[6][14][15][16][12] The potential masculinizing effects of enobosarm, for instance in women, have largely not been evaluated and are unknown.[17] The potential adverse effects and risks of high doses of enobosarm are also unknown.[17] Enobosarm is a nonsteroidal SARM, acting as an agonist of the androgen receptor (AR), the biological target of androgens and anabolic steroids like testosterone and dihydrotestosterone (DHT).[10] However, it shows dissociation of effect between tissues in preclinical studies, with agonistic and anabolic effects in muscle and bone, agonistic effects in breast, and partially agonistic or antagonistic effects in the prostate gland and seminal vesicles.[7][10][2][18][19] The AR-mediated effects of enobosarm in many other androgen-sensitive tissues are unknown.[18][20]
Enobosarm was first identified in 2004[11] and has been under clinical development since at least 2005.[1][18] It is the most well-studied SARM of all of the agents that have been developed.[21] According to GTx, its developer, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100 mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2] As of November 2023, it is in phase 3 clinical trials for the treatment of breast cancer and is in phase 2 studies for improvement of body composition in people taking GLP-1 receptor agonists.[1][9] Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.[1]
Aside from its development as a potential pharmaceutical drug, enobosarm is on the World Anti-Doping Agency list of prohibited substances and is sold for physique- and performance-enhancing purposes by black-market Internet suppliers.[10][17] In one survey, 2.7% of young male gym users reported using SARMs.[23] In addition, a London wastewater analysis found that enobosarm was the most abundant "pharmaceutical drug" detected and was more prevalent than recreational drugs like MDMA and cocaine.[24] Enobosarm is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness and safety.[17] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances.[17][25] Social media has played an important role in facilitating the widespread non-medical use of SARMs.[26]
- ^ a b c d e f g "Enobosarm - GTx". Adis Insight. Springer Nature Switzerland AG. Retrieved 22 December 2023.
- ^ a b c d e f g Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW (March 2020). "Selective androgen receptor modulators: the future of androgen therapy?". Translational Andrology and Urology. 9 (Suppl 2): S135–S148. doi:10.21037/tau.2019.11.02. PMC 7108998. PMID 32257854.
Unfortunately, results of recent clinical trials of the SARM GTx-024 (Enobosarm) have tempered expectations for its utility as a therapy for muscle wasting. Early on, GTx-024 appeared to have a very bright future as a treatment for sarcopenia/cachexia. Preliminary clinical trials demonstrated that GTx-024 could increase lean body mass and improve physical function without androgenic side effects (27). However, Enobosarm was dealt a blow after the phase III Prevention and treatment Of muscle Wasting in patients with cancER (POWER) I and II trials, where increases in lean body mass were once again observed, but without improved stair climb power (79,80). Failure to attain both primary endpoints led to a lack of approval by the Food and Drug Administration (FDA), which has cast doubt on the previously charted course for SARMs and has tempered enthusiasm regarding the role of SARMs in the treatment of muscle wasting conditions.
- ^ a b Cite error: The named reference
pmid24074268was invoked but never defined (see the help page). - ^ a b c Cite error: The named reference
pmid27105861was invoked but never defined (see the help page). - ^ a b Srinath R, Dobs A (February 2014). "Enobosarm (GTx-024, S-22): a potential treatment for cachexia". Future Oncology. 10 (2): 187–194. doi:10.2217/fon.13.273. PMID 24490605.
Pharmacokinetics & metabolism: Enobosarm was shown to have linear pharmacokinetics in single-dose studies in healthy male subjects using doses of 1, 3, 10, 30 and 100 mg. In another study enobosarm was given to healthy subjects at doses of 1, 3, 10 and 30 mg over 14 days. Per data from GTx, Inc., the halflife ranged from 14–21 h with similar mean maximum plasma concentration and exposure in subjects of varying ages (Table 1) [20].
- ^ a b Zilbermint MF, Dobs AS (October 2009). "Nonsteroidal selective androgen receptor modulator Ostarine in cancer cachexia". Future Oncology. 5 (8): 1211–1220. doi:10.2217/fon.09.106. PMID 19852734.
- ^ a b c Jones A, Coss CC, Steiner MS, Dalton JT (2013). "An overview on selective androgen receptor modulators: Focus on enobosarm". Drugs of the Future. 38 (5): 309–316. doi:10.1358/dof.2013.038.05.1970866. ISSN 0377-8282. S2CID 75202407.
- ^ Dai C, Ellisen LW (May 2023). "Revisiting Androgen Receptor Signaling in Breast Cancer". The Oncologist. 28 (5): 383–391. doi:10.1093/oncolo/oyad049. PMC 10166165. PMID 36972361.
- ^ a b Cite error: The named reference
Biospace2024was invoked but never defined (see the help page). - ^ a b c d e f Fonseca GW, Dworatzek E, Ebner N, Von Haehling S (August 2020). "Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials". Expert Opinion on Investigational Drugs. 29 (8): 881–891. doi:10.1080/13543784.2020.1777275. PMID 32476495. S2CID 219174372.
[...] to proceed with enobosarm into a phase III clinical trial in patients with sarcopenia, the FDA requested a cardiovascular safety study, which the manufacturer refused to undertake due to considerable costs and decided to test enobosarm in cancer cachexia patients in whom the FDA was more tolerant to the long-term cardiovascular side effects [67]. [...] Enobosarm promotes a similar anabolic response compared with DHT via muscle AR activation, [...] [35]. In a recent study with ovariectomized mice, the weight of the musculus gastrocnemius has been shown to be higher in all groups treated with ostarine as well as bone mineral density and bone biomechanical properties [15]. Moreover, the stimulation of reproductive organs with enobosarm seems to be less pronounced compared to testosterone administration [36] due to its partial agonist and antagonist effect on other androgen-dependent tissues such as prostate and seminal vesicles [37]. [...] In the POWER trials (POWER 1, NCT01355484 and POWER 2, NCT01355497; Table 1), double-blind, placebo-controlled, and multi-center phase III studies [40], patients with non-small-cell lung cancer were given 3 mg of enobosarm or placebo for five months. Despite a lower rate of decline in body weight in the group treated with enobosarm in POWER 1, patients increased LBM at day 84 and day 147 in POWER 1 (+0.41 kg) and POWER 2 (+0.47 kg) compared with patients receiving placebo. However, no physical function improvement has been reported in both studies [41].
- ^ a b Wu C, Kovac JR (October 2016). "Novel Uses for the Anabolic Androgenic Steroids Nandrolone and Oxandrolone in the Management of Male Health". Current Urology Reports. 17 (10): 72. doi:10.1007/s11934-016-0629-8. PMID 27535042. S2CID 43199715.
Enobosarm has also been evaluated in two phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer 1 and 2 (POWER1 (NCT01355484) and POWER2 (NCT01355497)). [...] The co-primary endpoints of this trial were lean body mass (LBM) response and physical function response for enobosarm vs. placebo after 3 months of treatment. Beneficial effects on both LBM and physical function were found in POWER1, and benefit to LBM but equivocal effects on physical function were found in POWER2.
- ^ a b Mohideen H, Hussain H, Dahiya DS, Wehbe H (February 2023). "Selective Androgen Receptor Modulators: An Emerging Liver Toxin". Journal of Clinical and Translational Hepatology. 11 (1): 188–196. PMC 9647117. PMID 36479151.
17α-alkylated AASs have been modified to be more resistant to liver degradation so that they have decreased first-pass metabolism, allowing for better oral bioavailability and more stable serum levels. However, reduced liver clearance increases the potential for hepatotoxicity.19 Much like this class of AASs, SARMs have been designed for adequate oral bioavailability with decreased liver degradation which would likely create a similar potential for hepatotoxicity.8,15 [...] Ostarine was the first SARM to undergo a phase III clinical trial. The POWER1 and POWER2 trials were two identical randomized, double-blind, placebo-controlled studies to evaluate the efficacy of Ostarine for the treatment of muscle wasting in non-small cell lung cancer. Participants were given 3 mg of Ostarine versus placebo. No study results were published; but GTx Incorporated reported that Ostarine failed to meet endpoints for improvement in lean body mass and physical function compared with placebo.
- ^ "GTX Reports Results for Enobosarm POWER Trials for the Prevention and Treatment of Muscle Wasting in Patients with Non-Small Cell Lung Cancer" (Press release). 19 August 2013.
- ^ Tauchen J, Jurášek M, Huml L, Rimpelová S (February 2021). "Medicinal Use of Testosterone and Related Steroids Revisited". Molecules. 26 (4): 1032. doi:10.3390/molecules26041032. PMC 7919692. PMID 33672087.
- ^ Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW (January 2019). "Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications". Sexual Medicine Reviews. 7 (1): 84–94. doi:10.1016/j.sxmr.2018.09.006. PMC 6326857. PMID 30503797.
- ^ Choi SM, Lee BM (2015). "Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids". Expert Opinion on Drug Safety. 14 (11): 1773–1785. doi:10.1517/14740338.2015.1094052. PMID 26401842. S2CID 8104778.
Anabolic androgenic steroids (AASs) comprise synthetic derivatives of testosterone. AASs bind directly to the cytosolic androgen receptor (AR), which is widely distributed across reproductive and non-reproductive tissues, including the prostate, skeletal muscle, liver, skin, and central nervous system (CNS). This binding results in various physiological activities [1], the major one being a masculinizing effect in the skeletal muscle via muscle building [2].
- ^ a b c d e Cite error: The named reference
pmid33148520was invoked but never defined (see the help page). - ^ a b c Mohler ML, Nair VA, Hwang DJ, Rakov IM, Patil R, Miller DD (2005-10-28). "Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates". Expert Opinion on Therapeutic Patents. 15 (11). Informa Healthcare: 1565–1585. doi:10.1517/13543776.15.11.1565. ISSN 1354-3776. S2CID 96279138.
- ^ Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA, Traina TA (June 2015). "Targeting the androgen receptor in prostate and breast cancer: several new agents in development". Endocrine-Related Cancer. 22 (3): R87–R106. doi:10.1530/ERC-14-0543. PMC 4714354. PMID 25722318.
Selective AR modulators (SARMs) are a class of drugs in development; unlike androgen synthesis inhibitors, they act as selective androgen agonists and show promise as a potential therapeutic strategy in BCa. Enobosarm (GTx024) is the farthest along in clinical development, and demonstrates an agonist effect that in some populations inhibits BCa growth. Preclinical data show antitumor activity of GTx-024 in ARC stably expressing cell lines MCF-7 (ERC) and MDA-MB-231 (TNBC) implanted subcutaneously into nude mice. Tumor growth was reduced more than 75% in MDA-MB-231-AR cells and 50% in MCF-7-AR cells compared with vehicle-treated tumors, demonstrating benefit (Dalton et al. 2013).
- ^ Cite error: The named reference
pmid25905231was invoked but never defined (see the help page). - ^ Zajac JD, Seeman E, Russell N, Ramchand SK, Bretherton I, Grossmann M, et al. (2020). "Testosterone". Encyclopedia of Bone Biology. Academic Press. pp. 533–550. ISBN 978-0-12-814082-6.
- ^ "GTx, Inc. Release: Enobosarm Meets Pre-Specified Primary Efficacy Endpoint In Ongoing Phase 2 Clinical Trial In ER+/AR+ Breast Cancer". BioSpace. 28 November 2016.
Enobosarm, a selective androgen receptor modulator (SARM) has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1,000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg.
- ^ Leciejewska N, Jędrejko K, Gómez-Renaud VM, Manríquez-Núñez J, Muszyńska B, Pokrywka A (December 2023). "Selective androgen receptor modulator use and related adverse events including drug-induced liver injury: Analysis of suspected cases". European Journal of Clinical Pharmacology. 80 (2): 185–202. doi:10.1007/s00228-023-03592-3. PMC 10847181. PMID 38059982.
- ^ Cite error: The named reference
TheGuardian2018was invoked but never defined (see the help page). - ^ Van Wagoner RM, Eichner A, Bhasin S, Deuster PA, Eichner D (November 2017). "Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet". JAMA. 318 (20): 2004–2010. doi:10.1001/jama.2017.17069. PMC 5820696. PMID 29183075.
- ^ Cite error: The named reference
pmid35574698was invoked but never defined (see the help page).