Selective Androgen Receptor Modulator (SARM)
Hip Fracture, Muscle Wasting
Overview & Profile
VK5211 is an orally available, non-steroidal selective androgen receptor modulator, or SARM, in development for the treatment of patients recovering from non-elective hip fracture surgery. VK5211 is designed to selectively produce the therapeutic benefits of testosterone in muscle and bone tissue with improved safety and tolerability due to a tissue-selective mechanism of action and an oral route of administration.
We have completed a Phase 2 proof-of-concept clinical trial of VK5211 in patients recovering from non-elective hip fracture surgery. The trial demonstrated statistically significant increases in total lean body mass less head, appendicular lean body mass, and total lean body mass, following treatment with VK5211 as compared to placebo. Patients receiving VK5211 demonstrated numerical improvements in certain exploratory assessments of functional performance, including the 6-minute walk test (6MWT) and short physical performance battery (SPPB), compared with placebo. These endpoints were not powered for significance. VK5211 demonstrated encouraging safety and tolerability in this study, with no drug related serious adverse events (SAEs) reported. In 3 previous Phase 1 clinical trials, VK5211 was shown to be safe and well-tolerated at all doses following daily oral administration for up to 21 days.
Androgens, of which the most predominant is testosterone, are important for the proper regulation of the reproductive system and play critical roles in the homeostasis of the muscular, skeletal, cardiovascular, metabolic and central nervous systems. Testosterone stimulates the growth of muscle and bone (anabolic effects), as well as the growth of the prostate and sebaceous gland (androgenic effects) and, as such, testosterone is considered a non-tissue-selective androgen.
Tissue selectivity is critical in treating patients recovering from hip fracture. These patients experience elevated rates of metabolic breakdown of muscle tissue and loss of bone mineral density, or BMD. This results in a loss of muscle strength, an increased risk of additional fractures and increased mortality. SARMs such as VK5211 are a class of small molecules designed to elicit the benefits of androgens on tissues such as muscle and bone, without the undesirable effects on prostate and sebaceous glands, by selectively activating androgen receptors in certain tissues. We believe that, based on their robust activity on muscle and bone, SARMs can be used for the potential treatment of a number of diseases or disorders, including hip fracture, muscle wasting, osteoporosis, frailty and hormone deficiency in both men and women in cases where testosterone supplements or anabolic steroid treatments are ineffective or where the side effect profile is inappropriate.
Goals of SARM Therapy
- Improve Lean Body Mass (LBM)
- Improve Muscle Strength
- Improve Muscle Strength
- Improve Bone Strength
- Improve Physical Performance
- Enhance Quality of Life (QOL)
We have announced positive top-line results from our 12-week, proof-of-concept Phase 2 clinical trial of VK5211 in patients who recently suffered a hip fracture.1,2,3 Top-line data showed that the trial achieved its primary endpoint, demonstrating statistically significant, dose dependent increases in lean body mass, less head (placebo-adjusted increases of 4.8%-9.1%), following treatment with VK5211 as compared to placebo. The study also achieved certain secondary endpoints, demonstrating statistically significant increases in appendicular lean body mass (placebo-adjusted increases of 6.1%-10.2%), and total lean body mass (placebo-adjusted increases of 4.7%-8.3%) for all doses of VK5211, compared to placebo. In addition, patients receiving VK5211 experienced dose-dependent decreases in mean fat mass (placebo-adjusted decreases of 2.2%-6.2%) following 12 weeks of treatment, which reached statistical significance at the study’s highest dose of 2.0 mg. The observed reductions in mean fat mass were coupled with dose-dependent increases in mean body weight following 12 weeks of treatment, demonstrating beneficial changes in overall body composition among VK5211-treated subjects. Patients receiving VK5211 also demonstrated dose-dependent improvements in the 6MWT distance as compared to placebo, though this exploratory endpoint was not powered for significance. For patients in the 2.0 mg VK5211 treatment arm, the mean distance increased by approximately 22 meters compared to placebo. VK5211 demonstrated encouraging safety and tolerability in this study, with no drug-related SAEs reported.
In three Phase 1 clinical trials, VK5211 was shown to be safe and well-tolerated at all doses following daily oral administration for up to 21 days. There were no reported SAEs determined to be related to treatment, and no clinically significant changes in liver function tests, prostate-specific antigen, hematocrit or electrocardiogram readings were observed. Moreover, subjects treated with VK5211 for 21 days experienced statistically significant increases in lean muscle mass, and positive dose dependent trends in functional exercise and strength measures were consistent with anabolic activity.4
In animal models, VK5211 has demonstrated improvements in bone mineral density, bone mineral content, and bone strength, as well as anabolic activity in muscles, anti-resorptive and anabolic activity in bones, and robust selectivity for muscle and bone versus prostate and sebaceous glands. The tissue-selectivity of VK5211 was examined in a castrated rat model.5 In this model, VK5211 demonstrated greater than 500-fold selectivity for maintaining muscle weight at non-castrated levels relative to the effects on prostate weight. By comparison, testosterone shows similar effects on both muscle and prostate tissue. These data suggest that VK5211 is highly tissue-selective for muscle, potentially leading to an improved therapeutic profile relative to testosterone.
In a primate model, VK5211 treatment resulted in a dramatic increase in muscle growth compared to a placebo group. VK5211 was shown to be safe and well-tolerated in this model.
Hip Fracture: A Significant Medical Challenge
Each year over 300,000 older people, those 65 and older, are hospitalized for hip fractures.6 Most hip fractures occur in the elderly, often resulting from minimal trauma, such as a fall from standing height. Unfortunately, elderly individuals are at higher risk of substantial morbidity and mortality as a result of higher rates of frailty and undernourishment. Furthermore, the rate of hip fracture is known to increase with age, doubling every 5-6 years after age 60 years.7 Fractures of the hip can have devastating consequences. Disability frequently results from persistent pain and limited physical mobility. Hip fractures are also associated with substantial morbidity and mortality, with approximately 21% of patients dying within 1-year after sustaining a hip fracture.8 There are currently no approved therapies in the U.S. for restoration or preservation of lean body mass, bone mineral density or physical function in patients who have suffered a hip fracture.
- Magaziner J, Ristic B, Harhaji V, Sirbu PD, et al. VK5211, a Novel Selective Androgen Receptor Modulator (SARM), Significantly Improves Lean Body Mass in Hip Fracture Patients: Results of a 12 Week Phase 2 Trial. Plenary oral presentation at the American Society for Bone and Mineral Research (ASBMR) 2018 annual meeting.
- Viking Therapeutics Presents Results from Phase 2 Study of VK5211 in Patients Recovering from Hip Fracture in Plenary Oral Presentation at ASBMR 2018 Annual Meeting. Viking Therapeutics press release, 10/1/2018 (link).
- Viking Therapeutics Announces Positive Top-Line Results from Phase 2 Study of VK5211 in Patients Recovering from Hip Fracture. Viking Therapeutics press release, 11/28/2017 (link).
- Basaria S, Collins, L, Dillon EL, Orwoll K, et al. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men. J Gerontol A Biol Sci Med Sci. 2013;68(1):87-95 (link).
- Vajda EG, Marschke K, van Oeveren A, Zhi L, et al. LGD-4033 Builds Muscle and Bone with Reduced Prostate Activity and may be Beneficial in Age-related Frailty. Poster presented at the 62nd Annual Meeting of the Gerontology Society of America (November 2009) (link).
- CDC: Hip Fractures Among Older Adults (link); and HCUPnet. Healthcare Cost and Utilization Project (HCUP). 2012. Agency for Healthcare Research and Quality, Rockville, MD (link)
- Kim SH, Meehan JP, Blumenfeld T, Szabo RM. Hip Fractures in the United States: 2008 Nationwide Emergency Department Sample. Arthritis Care Res (Hoboken). 2012;64(5):751-757 (link).
- Schnell S, Friedman SM, Mendelson DA, Bingham KW, Kates SL. The 1-Year Mortality of Patients Treated in a Hip Fracture Program for Elders. Geriatr Orthop Surg Rehabil. 2010;1(1):6-14 (link).