Selective Androgen Receptor Modulators (SARMs) promised to build muscle and bone with fewer side effects than traditional anabolic steroids. Yet despite early optimism, SARMs trials struggled to gain regulatory approval. A key hurdle was defining clear clinical endpoints – the measurable outcomes used to prove a drug’s benefit. This article explores why establishing those endpoints was so challenging for SARMs, how it impacted clinical trials, and what it means for future research.
Understanding Clinical Endpoints in Drug Trials
Definition and Importance: In drug development, a clinical endpoint is a specific measurable outcome that indicates whether a treatment is effective and safe. Endpoints can be clinical events (e.g. survival or fracture occurrence), laboratory measures, or functional assessments. They are crucial in clinical trials because they define the trial’s clinical objectives and determine success or failure. Regulatory agencies like the FDA require endpoints that demonstrate therapeutic effectiveness and clinical relevance – in other words, improvements in how a patient feels, functions, or survives. Well-chosen endpoints ensure that treatment outcomes are meaningful for patients, not just statistically significant changes with little real-world benefit.
Common Endpoints in Muscle-Related Therapies: Trials for muscle-wasting conditions or strength disorders have used a variety of endpoints to evaluate clinical efficacy and treatment outcomes:
- Lean Body Mass: An increase in muscle mass (often measured by DXA scan) is a typical endpoint indicating anabolic effect. Gaining muscle mass can signal that a therapy is building tissue, but by itself it’s considered a biomarker or surrogate – it doesn’t guarantee improved strength or quality of lifefile-s69ysggvhakzxzq5l144ek.
- Muscle Strength: Improvements in strength (e.g. handgrip strength or leg press force) are direct measures of functional benefit. Strength gains reflect that added muscle is translating into measurable outcomes that could help patients in daily activities.
- Physical Function Tests: Endpoints like walking speed, chair-rise time, or stair-climbing power gauge a patient’s mobility and endurance. For example, one SARM trial used a timed stair-climb test as an endpoint to assess physical performancefile-s69ysggvhakzxzq5l144ek. These tests connect muscle gains to real functional treatment outcomes.
- Quality of Life and Symptoms: Patient-reported outcomes (fatigue levels, ability to perform daily tasks) and composite scores (e.g. cachexia appetite and fatigue scales) can serve as endpoints. They capture whether patients feel better or can do more, beyond what objective tests show.
- Clinical Events: In severe conditions, endpoints might include rates of mortality, hospitalizations, or progression of an illness. For muscle-wasting in cancer (cachexia), an ultimate goal would be improving survival or treatment tolerance – though these are challenging to demonstrate in short trials.
Each type of endpoint has pros and cons. Surrogate endpoints like muscle mass are easy to quantify and respond quickly to an anabolic drug, but regulators insist that endpoint definitions also reflect meaningful benefit (e.g. improved physical function). Conversely, functional endpoints are clinically meaningful but can be harder to measure or achieve in very sick patients. Successful trial design requires balancing these to satisfy both scientific and regulatory expectations.
Specific Challenges in Defining SARMs Clinical Endpoints
Difficulty in Selecting Measurable Outcomes: Designing SARMs trials raised a fundamental question: what should count as a successful outcome? SARMs were developed to combat muscle wasting (e.g. in cancer, aging, or other chronic diseases), so increases in lean muscle were expected. However, choosing muscle mass as the primary endpoint was problematic. Drug developers worried that building muscle without improving patient function would not convince regulators. On the other hand, picking a functional endpoint (like improved walking speed or grip strength) as primary risked trial failure if patients’ performance didn’t improve despite added muscle. SARMs trials often tried to satisfy both by using co-primary endpoints – for example, requiring significant gains in lean body mass and a functional improvement. This high bar made trials difficult to win. In a Phase III trial of the SARM enobosarm (Ostarine) for cancer cachexia, researchers set dual primary endpoints: increased lean mass and better physical function (measured by a stair-climb test)file-s69ysggvhakzxzq5l144ek. Enobosarm did significantly increase muscle mass, but the improvement in stair-climbing ability was not statistically significant – the drug “worked” in one sense but not the other. This highlights the challenge of measurable outcomes: a SARM can produce the intended anabolic effect, yet translating that into functional gain proved elusive.
Ambiguity in FDA Guidelines and Regulatory Expectations: A major difficulty was the lack of clear regulatory guidance on endpoints for muscle-wasting conditions. Unlike diseases with well-established endpoints (e.g. blood glucose levels in diabetes or tumor shrinkage in oncology), conditions like cancer cachexia or age-related sarcopenia had no precedent. What magnitude of muscle gain is clinically meaningful? Which functional tests will the FDA accept, and how much improvement is enough? These questions had no definitive answers during early SARMs development. In fact, an absence of consensus on proper endpoints became a noted obstacle. As one review summarized, one of the most significant obstacles for approval of SARMs for cachexia was “a lack of consensus on proper endpoints for clinical trials and a drought of regulatory direction”tau.amegroups.org. Pharmaceutical sponsors found themselves in a guessing game – they had to propose endpoints they hoped regulators would find persuasive. The FDA had not issued specific guidelines for cachexia trial endpoints (researchers even formally petitioned for guidance on this mattertau.amegroups.org), leading to uncertainty. This endpoint definition ambiguity meant trial planners often erred on the side of caution, including multiple endpoints (muscle mass, strength, physical function, etc.) to cover all bases. Doing so, however, increased the complexity and risk of trials. Additionally, different stakeholders had different views: clinicians might value improved physical function or quality of life most, whereas some researchers argued that halting muscle loss (even without functional gain) could be beneficial in itself. Without clear FDA guidelines, SARMs trial designers struggled to align on the one primary endpoint that would define success.
Other challenges compounded the issue. In cachexia, patients are often very ill (advanced cancer, severe chronic disease), so even if a SARM adds muscle, other disease factors (fatigue, organ failure, treatment side effects) might mask any functional improvement. Trials had to decide if stabilizing a patient’s decline could count as success – but regulators indicated that merely preventing deterioration in performance was not sufficient for approvaltau.amegroups.org. Furthermore, short trial durations (a few months) may be too brief to show functional changes even if muscle is gained. All these factors made defining endpoints for SARMs a moving target and a core challenge in drug development for this new class of therapeutics.
Impact of Endpoint Definition Challenges on SARMs Clinical Trials
Uncertainty around endpoints directly influenced how SARMs trials were designed and carried out, often with unfortunate results. Trial Design and Execution: Because researchers weren’t confident which outcomes would demonstrate clinical efficacy, many SARMs trials built in multiple primary and secondary endpoints. This “belt and suspenders” approach was meant to capture a broad picture of efficacy but made trials harder to succeed. For example, the Phase III enobosarm trials (known as the POWER trials) in non-small cell lung cancer patients set two primary goals: (1) increase in total lean body mass and (2) improvement in physical function (stair climb speed). The trial was considered a success only if the drug met both endpoints. Enobosarm achieved significant lean mass gains (around +3% vs placebo) – confirming the drug’s anabolic effect – but patients did not show a significant improvement in stair-climbing abilityfile-s69ysggvhakzxzq5l144ek. Consequently, the trial failed to meet its combined endpoint criteria, and the drug was deemed ineffective for approval purposes. This outcome underscored how an endpoint issue (functional improvement not tracking with muscle gain) derailed a promising therapy.
Examples of Affected SARMs Trials: The difficulties were not limited to enobosarm. Other SARMs trials also illustrate the endpoint problem:
- Ligandrol (LGD-4033): In a Phase II trial, LGD-4033 was tested in elderly patients recovering from hip fracture to see if it could aid rehabilitation. The SARM did cause a dose-dependent increase in lean muscle mass, validating its anabolic action. However, improvements in muscle strength and functional mobility (e.g. walking speed or power) were modest or inconsistentfile-s69ysggvhakzxzq5l144ek. The lack of clear functional benefit meant that, despite gains in muscle mass, the overall treatment outcomes were ambivalent. This result made it hard to claim a definitive clinical benefit to regulators.
- Enobosarm in Cancer Cachexia: Even prior to Phase III, a Phase IIb study of enobosarm in cancer patients hinted at the endpoint dilemma. Patients on enobosarm showed statistically significant increases in lean mass and even some improvement in a physical function test compared to placebo. But the question remained: was the functional gain enough to matter clinically? The Phase III trials tried to confirm this, only to find that the functional gains were too small to be convincing, despite the drug’s clear effect on muscle massfile-s69ysggvhakzxzq5l144ek.
- (Other SARMs: While Ostarine and LGD-4033 are the most prominent examples, development of other SARMs likely faced similar issues. For less advanced candidates, companies may have learned from these trials and adjusted their endpoint strategies accordingly.)
Influence on Trial Outcomes: The endpoint selection challenges had practical consequences. Several high-profile SARM trials failed to meet their primary endpoints, not necessarily because the drugs had no effect, but because the chosen endpoint thresholds were not reached. In the case of enobosarm, hitting one endpoint (muscle gain) but missing the other (function) meant the entire trial was negativefile-s69ysggvhakzxzq5l144ek. Such outcomes are expensive setbacks – sponsors had to reconsider their development programs and sometimes abandon indications. Additionally, the need to capture functional benefits often required larger sample sizes or longer trials to detect changes, making studies more costly and complex. In sum, ambiguous endpoints made it harder to demonstrate clinical efficacy, and several SARMs trials that otherwise showed physiological effects ended without a clear success, primarily due to endpoint issues.
Consequences for SARMs Regulatory Approval and Market Entry
The difficulty in defining and achieving appropriate endpoints had a ripple effect on regulatory approval prospects. To date, no SARM has earned FDA approval for clinical usefile-s69ysggvhakzxzq5l144ek. A major reason is that no trial has yet definitively proven a clinical endpoint that satisfies regulators in terms of patient benefit. Enobosarm, the frontrunner, was not approved by the FDA after Phase III because it did not convincingly improve functional outcomes, despite increasing muscle. This outcome signaled that the FDA’s drug approval process for a muscle-wasting therapy would require evidence beyond surrogate markers. The regulatory message was clear: an effective cachexia drug must show patients function better or feel better, not just have more muscle on scansfile-s69ysggvhakzxzq5l144ek. Because early SARMs trials struggled to meet this bar, regulatory approval was effectively on hold.
Regulatory Hurdles: The lack of established endpoints became a regulatory hurdle in itself. Companies developing SARMs faced a Catch-22: without prior approved drugs in this space, regulators provided only broad guidance, yet without guidance, it was exceedingly hard to design a trial that the FDA would definitively accept. This uncertainty likely contributed to delays – for instance, developers spent extra time consulting with FDA and European agencies to agree on trial designslink.springer.com. Even then, as seen with the POWER trials, meeting those agreed endpoints proved challenging. After the Phase III failures around 2013, it took years for any company to re-attempt late-phase trials for muscle wasting. The field saw setbacks: some sponsors (like GTx Inc., the company behind enobosarm) halted or pivoted their programs, and investors grew cautious due to the perceived regulatory risk. Essentially, unclear endpoint expectations translated into a higher chance of trial failure, which in turn made the path to regulatory approval and market entry longer and more uncertain.
Market Entry Delays: The consequence of these endpoint-related failures is that patients have no approved SARM therapies available. Conditions like cancer cachexia or age-related frailty still lack FDA-approved anabolic treatments. The promising SARMs remain investigational, delaying their entry into the medical marketplace. Meanwhile, as an unintended side effect, some SARMs compounds leaked into the market as unapproved supplements or doping agents, precisely because formal approval was stalled. Regulatory agencies issued warnings about such products, but the drug approval process for legitimate use continues to face hurdles. The FDA’s stance, shaped by earlier trial outcomes, is that a SARM must demonstrate clear treatment outcomes (improved patient function or health status) to be approved – a high standard that has yet to be met. This has set a precedent that future SARMs developers must plan for more rigorous trials with well-justified endpoints, inevitably slowing down how fast SARMs might reach patients in need.
Broader Implications for SARMs Research
The challenges with endpoints in past trials have strongly influenced how researchers approach SARMs going forward. One immediate effect was to learn from failure: the SARMs research community recognized that simply building muscle is not enough – the clinical objectives must align with meaningful patient improvement. This realization has shaped new trial strategies in several ways:
- Refining Endpoint Strategies: Ongoing and future trials are now more carefully choosing endpoints that reflect both therapeutic effectiveness and patient benefit. Researchers are working to establish consensus criteria for conditions like cancer cachexia and sarcopenia. International expert groups have defined cachexia and suggested multi-faceted endpoint measures (combining weight, strength, and symptoms) to capture true clinical benefittau.amegroups.org. Such efforts aim to ensure that trials measure what truly matters for patients, using composite endpoints or validated functional tests to demonstrate improvement.
- Emphasizing Functional Outcomes: There is a greater focus on functional and quality-of-life endpoints from the outset. Rather than treating lean mass gain as sufficient, new SARMs trials build in endpoints like six-minute walk distance, stair-climb power, or patient-reported outcome scores as primary or co-primary goals. The hope is that by designing studies to achieve functional gains (possibly by longer treatment durations, rehab programs alongside the drug, etc.), the trials will show the clinical relevance needed for approval. Essentially, future studies are prioritizing therapeutic effectiveness in daily life, not just lab measurements.
- Exploring Alternative Indications: The endpoint hurdle in muscle-wasting conditions has prompted exploration of other uses for SARMs where endpoints may be clearer. For example, SARMs are being investigated in osteoporosis (where bone density and fracture rates are established endpoints), and in certain hormonal conditions (like stress urinary incontinence or androgen-responsive breast cancer)tau.amegroups.org. In these cases, the endpoint definitions (e.g. improved bone mineral density, reduced incontinence episodes, tumor progression delay) are more straightforward. Success in an alternate indication could allow a SARM to reach the market, after which off-label or additional studies might revisit muscle-wasting uses with more confidence.
- Regulatory Collaboration: The past difficulties have encouraged closer dialogue between SARM developers and regulatory bodies. Researchers have literally requested regulatory guidance on cachexia trial designtau.amegroups.org, and agencies have become more involved in advising what endpoints would be acceptable. This collaborative approach should yield clearer targets for trials. For instance, if the FDA were to formally endorse a certain functional test or a composite endpoint as sufficient for approval, companies could design trials accordingly and avoid the guesswork that plagued earlier studies. There is also ongoing work to qualify certain biomarkers or imaging measures as supportive endpoints that correlate with functional improvements, which could bolster the overall evidence package.
- Combining Interventions: Another implication is the idea of combining SARMs with other interventions to amplify clinical outcomes. Since exercise and nutrition also improve muscle function, some propose that pairing a SARM with a structured exercise program in trials might show larger functional gains than drug alone, making it easier to meet endpoints. While this complicates trials, it reflects creative strategies born from the endpoint challenges – the ultimate goal is to ensure measurable outcomes that regulators recognize as a clear benefit.
Overall, the endpoint difficulties experienced in first-generation SARMs trials have provided valuable lessons. They have spurred the field to be more rigorous and patient-centered in trial design. The challenges in drug development for SARMs have, in a sense, raised the standards: any new SARM candidate must now come with evidence that it can make patients not only stronger on paper but healthier and more functional in reality. This will shape the direction of SARMs research for years to come. There is optimism that with refined endpoints and trial methods, SARMs can eventually demonstrate the clinical efficacy needed for approval. The process may be slow, but it is moving forward with a clearer understanding of how to show real patient benefit.
FAQs
Why are clinical endpoints crucial in SARMs trials?
Clinical endpoints are crucial in SARMs trials because they define how success is measured. Endpoints translate the biological effects of a SARM into quantifiable treatment outcomes that matter for patients. For instance, increasing muscle mass is beneficial only if it leads to improved strength, mobility, or health. Well-chosen endpoints ensure that a SARMs trial demonstrates clinical efficacy – showing regulators that the drug makes a meaningful difference (e.g. better physical function or quality of life). In short, clear clinical endpoints are the bridge between a SARM’s lab effects and real-world patient benefits, and they are essential for earning regulatory approval of the drug.
What challenges did researchers face in defining endpoints for SARMs?
Researchers struggled with selecting endpoints that were both measurable outcomes of a SARM’s action and acceptable to regulators as proof of benefit. A key challenge was deciding between surrogate markers like lean muscle gain and direct benefits like improved physical function. Often, SARMs increased muscle size, but showing a corresponding functional improvement (strength, exercise capacity) was difficult, especially in sick or elderly populations. There was also no clear FDA guideline initially on what endpoints a muscle-wasting therapy must meet, leading to ambiguity. This lack of consensus meant trials sometimes used multiple primary endpoints (e.g. muscle mass plus a functional test), raising the bar for success. In summary, defining endpoint criteria for SARMs involved scientific uncertainty (how muscle gains translate to function) and regulatory uncertainty (which endpoints would satisfy approval requirements), making it one of the toughest aspects of SARMs clinical development.
Conclusion
Defining clinical endpoints proved to be a formidable challenge in the development of SARMs, and this had far-reaching consequences. Trials of promising SARMs like enobosarm and ligandrol demonstrated that how you measure success can make or break a study. The difficulty in identifying endpoints that show clear patient benefit (and not just laboratory changes) led to trial failures, which in turn slowed the progress of SARMs toward the clinic. However, these setbacks have provided critical guidance for the field. Researchers now better understand what regulators need to see – evidence of improved clinical outcomes, not just bigger muscles. Consequently, current and future SARMs trials are evolving to include more robust and meaningful endpoints. Though the road has been long and winding, the lessons learned are reshaping strategies and could ultimately help SARMs fulfill their medical potential. By tackling the endpoint problem head-on, scientists and regulators are inching closer to bringing SARMs from the lab to the clinic. The impact of these early challenges is clear: they have raised the standards of evidence, ensuring that when SARMs do achieve regulatory approval, they will truly make a difference for patients. Readers interested in this journey are encouraged to explore more resources on SARMs research and follow new studies that are building on these insights – the story of SARMs is still unfolding, with more chapters yet to come.
References
- Kearbey JD et al. (2013). The safety, pharmacokinetics, and effects of LGD-4033, a novel oral selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci, 68(1): 87–95.
- Dalton JT et al. (2011). 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 clinical trial. J Cachexia Sarcopenia Muscle, 2(3): 153–161.
- Fearon K et al. (2015). Request for regulatory guidance for cancer cachexia intervention trials. J Cachexia Sarcopenia Muscle, 6(4): 272–274.
- Narayanan R et al. (2008). Selective androgen receptor modulators in preclinical and clinical development. Nucl Recept Signal, 6: e010.
Jeffrey Kearbey
Pharmaceutical Scientist
Experienced in androgen receptor modulator research and drug development.
https://www.linkedin.com/in/jeffreykearbey