VK5211 for Hip Fracture

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Overview and Profile

Our lead clinical program is VK5211, a novel, orally available, non-steroidal selective androgen receptor modulator, or SARM, in Phase 2 development for the treatment of patients recovering from non-elective hip fracture surgery. VK5211 belongs to a family of novel non-steroidal SARM compounds based on tissue-specific gene expression and other functional, cell-based technologies. We expect VK5211 to produce the therapeutic benefits of testosterone with improved safety, tolerability and patient acceptance due to a tissue-selective mechanism of action and an oral route of administration. In Phase 1 clinical trials, VK5211 demonstrated statistically significant increases in lean body mass among treated subjects following 21 days of treatment.1 In a pre-clinical model of osteoporosis, VK5211 demonstrated improvements in bone mineral density, bone mineral content, bone strength, and other measures.2 We believe VK5211’s potential stimulatory effect on lean body mass and bone mineral density could result in benefits to patients recovering from hip fracture surgery.

Goals of SARM Therapy

  • Improve Lean Body Mass (LBM)
  • Improve Muscle Strength
  • Improve Bone Strength
  • Improve Physical Performance
  • Enhance Quality of Life (QOL)

potential-therapeutics-benefits-sarms


Clinical Data

In two Phase 1 clinical trials,1,3 VK5211 was shown to be safe and well-tolerated at all doses following daily oral administration for up to 21 days, with no reported clinically significant drug-related adverse events, and no clinically significant changes in liver function tests, prostate-specific antigen, hematocrit or electrocardiogram readings.

In the Phase 1 multiple ascending dose clinical trial, 76 healthy young men in three cohorts were dosed daily with placebo, 0.1 mg, 0.3 mg or 1 mg of VK5211 for 21 days. The average body mass index in all cohorts ranged from 24.6 kg/m2 to 27.0 kg/m2. In this clinical trial, VK5211 demonstrated statistically significant increases in lean body mass with a positive trend in strength and performance measurements. There were no significant changes or trends in fat mass among cohorts. VK5211 was shown to be safe, with a similar frequency of adverse events between the treated and placebo (PBO) groups. VK5211 also displayed a favorable pharmacokinetic profile, without any changes in prostate-specific antigen.

 

Highlights from Phase 1 Data

vk5211-clinical-highlights
*p<0.5
Statistically significant improvement in lean body mass, with positive trends in strength and performance measurements. Safe, well-tolerated, no SAEs.


Preclinical Data

VK5211 has also demonstrated anabolic activity in muscles, anti-resorptive and anabolic activity in bones and robust selectivity for muscle and bone versus prostate and sebaceous glands in animal models. The tissue-selectivity of VK5211 was examined in a castrated rat model.2 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.


Effects of VK5211 in Muscle and Prostate Tissue in Castrated Rats

vk5211-tissue-selectivity
Highly tissue selective: muscle vs. prostate
A potentially best-in-class androgen receptor (AR) modulator


Hip Fracture: A Significant Medical Challenge

Over 300,000 people are hospitalized for hip fracture in the U.S. annually.4 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 60.5 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 20% of patients dying within one year of fracture.6 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.


References

  • Basaria S, Collins, L, Lichar Dillon E, Orwoll K, Storer W, Miciek R, Ulloor J, Zhang A, Eder R, Zientek H, et al. 2013. 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. Jan 68(1):87-95.
  • Vajda EG, Marschke K, van Oeveren A, Zhi L, Chang WY, Lopez FJ, Meglasson MD. LGD-4033 builds muscle and bone with reduced prostate activity and may be beneficial in age-related fraility. Poster presented at: 62nd Annual Meeting of the Gerontology Society of America 2009 Nov 19-21; Atlanta, GA.
  • Kapil R, Leibowitz MT, Peterkin JJ, Chen Y, Lee KJ, Lee YH, Meglasson MD, Vajda EG. Phase I clinical trial of LGD-4033, a novel selective androgen receptor modulator (SARM). Poster presented at: 14th International Congress of Endocrinology 2010 Mar 26-30; Kyoto, Japan.
  • Magaziner J, Hawkes W, Hebel JR, Zimmerman SI, Fox KM, Dolan M, Felsenthal G, Kenzora J. Recovery from hip fracture in eight areas of function. 2000. J Gerontol A Biol Sci Med Sci.55:M498-M507.
  • Kim SH, Meehan JP, Blumenfeld T, Szabo RM. 2012. Hip fractures in the United States: Nationwide emergency department sample, 2008. Arthritis Care Res. 64(5):751-7.
  • Keene GS, Parker MJ, Pryor GA. 1993. Mortality and morbidity after hip fractures. BMJ. 307:1248.