The development history of Ostarine (MK-2866): why the drug never reached pharmacies

Ostarine, also known as enobosarm, GTx-024, or MK-2866, is probably the best-known selective androgen receptor modulator (SARM). In gyms it is talked about as if it were a long-familiar drug. In reality, over a quarter-century of development ostarine never obtained registration with any major regulator. The editorial team traced how this molecule traveled from a university laboratory to clinical trials — and why it stopped at the pharmacy door.

Where the idea of SARMs came from

Androgens — testosterone and its derivatives — effectively build muscle and bone mass, but at the same time act on the prostate, skin, hair follicles, blood lipids, and liver. For medicine this is a long-standing problem: patients with sarcopenia, cachexia, or osteoporosis need the anabolic effect, not the whole «package» of androgenic action. That is why pharmacologists spent decades searching for a substance that would separate these effects.

The breakthrough came in the late 1990s in the laboratory of James Dalton and Duane Miller at the University of Tennessee. Studying derivatives of nonsteroidal antiandrogens (in particular structural «relatives» of bicalutamide), the group found that small changes in the molecule turn a blocker of the androgen receptor into its activator. The 1998 publication on the «discovery of nonsteroidal androgens» became the starting point for the entire class of arylpropionamide SARMs.

The key idea lay in tissue selectivity. The nonsteroidal molecule is not a substrate for the enzymes 5-alpha-reductase and aromatase, so it is not converted into dihydrotestosterone or estradiol. In addition, the «SARM–receptor» complex interacts differently with coregulator proteins in different tissues. In theory this made it possible to obtain action on muscle and bone with minimal effect on the prostate.

The first «star» of this chemical series was andarine (S-4), but it had problems, in particular with visual disturbances in preclinical studies. Later the company GTx, founded to advance these developments, focused on the compound S-22, which received the names GTx-024, ostarine, and subsequently the international nonproprietary name enobosarm.

Early studies of ostarine

In the second half of the 2000s, GTx entered into a partnership with the company Merck, within which the compound received the code MK-2866 — it is precisely under this name that it is still most often mentioned on sports forums. The partnership later ended, and the rights to the molecule returned to GTx, but the «Merck» name took hold in informal use.

The best-known early work was a double-blind placebo-controlled phase II study in 120 elderly men and postmenopausal women (Dalton et al., 2011). Over roughly three months, participants received various doses of enobosarm or placebo. In the 3 mg per day group, lean body mass increased by approximately 1.3 kg compared with placebo, and the stair-climb test result also improved.

In parallel, a phase II study was conducted in patients with cancer cachexia (Dobs et al., 2013). Enobosarm at doses of 1 and 3 mg increased lean mass compared with baseline, whereas in the placebo group there was no significant gain. These results seemed convincing enough to move toward registration trials.

Already at this stage researchers noted changes familiar for androgens: a dose-dependent decrease in high-density lipoprotein (HDL) and sex hormone–binding globulin (SHBG). In the short studies these changes were moderate and reversible, but they showed that «full» tissue selectivity had not been achieved.

Phase III and the POWER program

The decisive stage was the POWER program — two large randomized phase III studies in patients with non-small-cell lung cancer who were receiving chemotherapy. The goal was to prove that enobosarm prevents the loss of muscle mass while at the same time preserving physical function. The design of the program is described in detail in the publication by Crawford and colleagues (2016).

The regulators put forward a fundamental requirement: it is not enough to show a gain in lean mass on densitometry, one must prove a clinically meaningful improvement in function — in this case, power during stair climbing. This is precisely where difficulties arose. According to results announced in 2013, both co-primary endpoints could not be achieved simultaneously in the planned analysis.

For regulatory logic this is a verdict: a drug that adds a kilogram of «lean» mass but does not convincingly improve how a patient lives and moves has no proven benefit that would outweigh the risks. The failure of POWER collapsed GTx's market capitalization and effectively closed the path to registration for ostarine under the indication «muscle wasting in cancer».

This episode neatly illustrates the general problem of the entire SARM group. The gain in muscle mass in clinical studies was moderate and did not always translate into function. At the same time, long-term data on cardiovascular safety and effects on lipids and the liver remained limited.

New attempts: other indications

After POWER the company looked for a niche where the SARM effect could have clinical significance. One direction was stress urinary incontinence in women: the hypothesis was that androgenic stimulation of the pelvic floor muscles would strengthen their function. Small pilot data were encouraging, but in a controlled phase II study no convincing advantage over placebo was obtained.

The second direction was breast cancer positive for androgen and estrogen receptors. In certain tumor subtypes, activation of the androgen receptor can inhibit growth, and this idea has a historical basis: androgens were used in oncology long before the advent of modern antiestrogens. A randomized phase II study (Palmieri et al., 2024) showed signs of antitumor activity of enobosarm in patients with advanced disease who had previously received endocrine therapy.

In 2019 GTx merged with another biotechnology company, and the rights to enobosarm subsequently passed to the company Veru. It continued the oncology program and proposed one more idea — combining enobosarm with GLP-1 receptor agonists to preserve muscle mass during medically induced weight loss. This direction is being studied in the 2020s, and its final conclusions are still ahead.

So the story of ostarine is not over, but it consists of narrow medical scenarios under the supervision of doctors. None of them concerns healthy athletes, and none has yet ended in registration.

Why the drug is not in pharmacies

The short answer is that the ratio of proven benefit to insufficiently studied risks never satisfied the regulators. To summarize, the editorial team identifies several reasons:

• A modest functional effect.A gain in lean mass of 1–1.5 kg was not always accompanied by an improvement in strength or endurance that mattered to patients.
• Incomplete selectivity.The decrease in HDL and the suppression of the body's own gonadotropins and testosterone showed that SARMs nevertheless affect systems that were supposed to remain «untouched».
• A lack of long-term data.The studies lasted weeks and months; the safety of many years of use remains unknown.
• Commercial risks.After the failure of phase III, investors lost interest, and developing another large trial costs hundreds of millions of dollars.

At the same time, the molecule «leaked» beyond clinical research. Already from the late 2000s ostarine began to appear in products sold online as «research chemicals» or «supplements». The FDA has repeatedly warned that SARMs are not dietary supplements and that their use is associated with risks to the liver and heart. The analysis by Van Wagoner and colleagues (2017) in JAMA showed that the contents of such products often do not match the label.

Sports organizations reacted even earlier: SARMs were placed on the WADA Prohibited List in class S1.2 «Other Anabolic Agents», where enobosarm (ostarine) is named directly. For years ostarine has remained one of the most frequently detected substances of this group in doping control.

So the absence of ostarine from pharmacies is not a bureaucratic accident. It is the result of the fact that even after twenty years of research the manufacturer could not convincingly show that the benefit for specific patients outweighs the risks.

Editorial conclusions

Ostarine was born from an entirely medical idea — to separate the anabolic action of androgens from the undesirable one. The concept turned out to be partly correct: the drug did moderately increase lean mass with less action on the prostate than one might expect from testosterone.

However, the decisive phase III trials did not confirm functional benefit, and the side effects inherent to androgens did not disappear entirely. New indications — from oncology to preserving muscle during weight loss — are being studied, but so far have not led to registration.

What is sold under the name «MK-2866» is a product with no medical status, quality control, or long-term safety data. For an athlete it is also a guaranteed anti-doping rule violation.

If this topic interests you, we recommend reading our materials on the effect of ostarine on bone tissue, on the known risks of ostarine for women, and on comparing ostarine with anabolic steroids.

References

1. Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD. Discovery of nonsteroidal androgens. Biochem Biophys Res Commun. 1998;244(1):1–4.
2. Dalton JT, Barnette KG, Bohl CE, et al. 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. J Cachexia Sarcopenia Muscle. 2011;2(3):153–161.
3. Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14(4):335–345.
4. Crawford J, Prado CM, Johnston MA, et al. Study design and rationale for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER trials). Curr Oncol Rep. 2016;18(6):37.
5. Palmieri C, Linden H, Birrell SN, et al. Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial. Lancet Oncol. 2024.
6. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–142.
7. Van Wagoner RM, Eichner A, Bhasin S, et al. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004–2010.
8. World Anti-Doping Agency. The World Anti-Doping Code: International Standard — Prohibited List. Montreal: WADA; чинна редакція.