Ligandrol

Ligandrol (VK5211, LGD-4033)[2] is a novel nonsteroidal oral selective androgen receptor modulator (SARM) for treatment of conditions such as muscle wasting and osteoporosis,[3] discovered by Ligand Pharmaceuticals and under development by Viking Therapeutics.[4][5]

Ligandrol
Clinical data
Other namesVK5211; LGD-4033
Routes of
administration		By mouth
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life24-36 hours [1]
Identifiers
  • 4-[(2R)-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H12F6N2O
Molar mass338.253 g·mol−1
3D model (JSmol)
  • FC([C@H](O)[C@H]1CCCN1C2=CC(=C(C#N)C=C2)C(F)(F)F)(F)F
  • InChI=1S/C14H12F6N2O/c15-13(16,17)10-6-9(4-3-8(10)7-21)22-5-1-2-11(22)12(23)14(18,19)20/h3-4,6,11-12,23H,1-2,5H2/t11-,12-/m1/s1
  • Key:OPSIVAKKLQRWKC-VXGBXAGGSA-N

Ligandrol has been found in World Anti-Doping Agency (WADA) samples and in racehorses too. Like anabolic steroids, it can stimulate muscle growth. "SARMs have shown superior side effect profiles compared with anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors".[6]

WADA control

At least since June 2015, ligandrol has been available via the internet. In that month, German scientists proposed a new test to detect its metabolites present in human urine, and suggested an expansion of the WADA regime.[7]

Misbranded as dietary supplement

On 23 October 2017, a nutritional supplement company in Missouri called Infantry Labs was warned by the FDA that the distribution of two of its products violated the Federal Food, Drug, and Cosmetic Act. One of the substances was ligandrol. The company advertised as benefits of the ligandrol: "increases in lean body mass and decrease in body fat" and "increases in strength, well being, as well as healing possibilities". The company mislabeled as "dietary supplements" what should have been "new drugs" or "prescription drugs" and were instructed to document the steps they would take in order to cease the violation.[8]

Also on 23 October 2017, the FDA sent a warning letter to a New Jersey company called Panther Sports Nutrition. The company's marketing approach for the product was similar to that of the Infantry Labs case, and the product was advertised as a "mass builder" and "physique enhancing agent".[9]

Clinical Research

According to a clinical trial conducted at the Boston Medical Center's Section of Endocrinology, Ligandrol can help improve lean body mass and muscle strength.[10]

Another study conducted in January 2013 found that Ligandrol can help increase lean muscle mass, and was generally well tolerated by test subjects.[10]

Adverse health effects

The FDA claims that "liver toxicity, adverse effects on blood lipid levels, and a potential to increase the risk of heart attack and stroke" are among the adverse health effects of SARMs.[8]

Illicit use

Though not an approved drug, ligandrol has been sold on the black market in countries where it is classified as an illegal substance.[11][12]

Ligandrol is on the World Anti-Doping Association list of prohibited drugs[13] and has been found in drug testing samples of some athletes.[14]

In 2015, the quarterback of the Florida Gators, Will Grier, was suspended for testing positive for ligandrol, a claim that the University of Florida denies.[15]

In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for ligandrol.[16]

In 2019, Australian swimmer Shayna Jack tested positive for ligandrol. She denies knowingly taking the substance.[17]

In August 2019, it came to light that Canadian sprint canoeist Laurence Vincent Lapointe tested positive for ligandrol; the athlete denies knowingly taking a forbidden substance that resulted in her suspension from competition. The athlete remarked that the National Team Training Centre purchased nutritional supplements for its athletes and denied buying or taking nutritional supplements on her own. [18] On January 27, 2020, she was cleared of all charges. The substance was found in her results because of an exchange of bodily fluids with her boyfriend, who took Ligandrol.[19]

In January 2020, Chilean ATP tennis singles competitor Nicolás Jarry tested positive for both ligandrol and stanozolol. He protested at the time that the multi-vitamins from Brazil that he took on the advice of an unnamed doctor were contaminated.[20]

3 September 2022, Nzubechi Grace Nwokocha was provisionally suspended for the use of banned substances [21][22] by the Athletics Integrity Unit (AIU).

Commercial environment

Regulatory information

In the United States, ligandrol is an Investigational New Drug.

Pre-clinical

Oral administration of the drug to cynomolgus monkeys at daily doses varying from 0 to 75 mg/kg over 13 weeks demonstrated significant body weight gain in both males and females. After 48 days, the 75 mg/kg dose testing was halted due to toxicity concerns, but this did not negatively impact development as the dose is significantly higher than those being utilized in the Phase 2 clinical trial.[23]

Clinical trials

In a Phase 1 clinical trial of 76 adult male humans in which the dose size was varied, a dose-dependent increase in lean body mass was observed with no significant adverse events over 21 days.[2]

The Phase 2 clinical trial, initiated on 3 November 2016, consists of 120 patients recovering from hip fracture surgery. The randomized study participants will receive either a placebo or varying dose sizes of LGD-4033 over a period of 12 weeks, with improved lean body mass as the primary endpoint. Other endpoints include satisfactory results in terms of quality of life, safety, and pharmacokinetics.[24]

References
  1. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. (January 2013). "The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 68 (1): 87–95. doi:10.1093/gerona/gls078. PMC 4111291. PMID 22459616.
  2. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. (January 2013). "The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 68 (1): 87–95. doi:10.1093/gerona/gls078. PMC 4111291. PMID 22459616.
  3. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. (January 2013). "The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 68 (1): 87–95. doi:10.1093/gerona/gls078. PMC 4111291. PMID 22459616.
  4. "Ligand Presents New Preclinical Data on its Lead SARM Molecule LGD-4033 at the Gerontological Society of America Annual Meeting" (Press release). San Diego: Ligand Pharmaceuticals. November 20, 2009. Archived from the original on November 23, 2014. Retrieved November 23, 2014.
  5. "Viking Signs Broad Licensing Deal With Ligand Pharmaceuticals for Rights to Five Novel Therapeutic Programs". 22 May 2014. Archived from the original on 5 March 2016.
  6. Hansson A, Knych H, Stanley S, Berndtson E, Jackson L, Bondesson U, et al. (February 2018). "Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 1074–1075: 91–98. doi:10.1016/j.jchromb.2017.12.010. PMID 29334634.
  7. Thevis M, Lagojda A, Kuehne D, Thomas A, Dib J, Hansson A, et al. (June 2015). "Characterization of a non-approved selective androgen receptor modulator drug candidate sold via the Internet and identification of in vitro generated phase-I metabolites for human sports drug testing". Rapid Communications in Mass Spectrometry. 29 (11): 991–999. Bibcode:2015RCMS...29..991T. doi:10.1002/rcm.7189. PMID 26044265.
  8. "WARNING LETTER Infantry Labs LLC MARCS-CMS 535333 — OCT 23, 2017". FDA. 23 October 2017.
  9. "WARNING LETTER Panther Sports Nutrition MARCS-CMS 535341 — OCT 23, 2017". FDA. 23 October 2017.
  10. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. (January 2013). "The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 68 (1): 87–95. doi:10.1093/gerona/gls078. PMC 4111291. PMID 22459616.
  11. Geldof L, Pozo OJ, Lootens L, Morthier W, Van Eenoo P, Deventer K (February 2017). "In vitro metabolism study of a black market product containing SARM LGD-4033". Drug Testing and Analysis. 9 (2): 168–178. doi:10.1002/dta.1930. PMID 26767942.
  12. Krug O, Thomas A, Walpurgis K, Piper T, Sigmund G, Schänzer W, et al. (November 2014). "Identification of black market products and potential doping agents in Germany 2010-2013". European Journal of Clinical Pharmacology. 70 (11): 1303–1311. doi:10.1007/s00228-014-1743-5. PMID 25168622. S2CID 111542.
  13. "Prohibited List". 2014-07-22.
  14. Cox HD, Eichner D (January 2017). "Detection of LGD-4033 and its metabolites in athlete urine samples". Drug Testing and Analysis. 9 (1): 127–134. doi:10.1002/dta.1986. PMID 27168428.
  15. Trahan K (12 October 2015). "Florida starting QB Will Grier suspended for at least 2015 after taking banned substance". SB Nation. Retrieved 20 October 2015.
  16. "NBA bans Joakim Noah 20 games for drug violation". Fox Sports. March 25, 2017. Archived from the original on 26 October 2019.
  17. Maasdorp J (July 28, 2019). "Shayna Jack reveals banned substance Ligandrol was behind her doping suspension from swimming". Australian Broadcasting Corporation. Retrieved July 28, 2019.
  18. "Canada's Vincent Lapointe reveals she tested positive for muscle-building substance". CBC. 20 August 2019.
  19. "Dopage : Laurence Vincent Lapointe blanchie et soulagée" [Doping: Laurence Vincent Lapointe cleared and relieved]. Radio Canada (in French). 27 January 2020.
  20. Briggs S (15 January 2020). "Wimbledon doubles champion Robert Farah fails drugs test". Telegraph Media Group Limited.
  21. Ostarine and Ligandrol
  22. "Commonwealth gold medallist Nwokocha provisionally suspended for doping". Reuters. 2022-09-03. Retrieved 2023-05-09.
  23. Bautz D (21 November 2016). "VKTX: Additional Preclinical Data Shows Robust and Durable Weight Gain for VK5211-Treated Primates". Yahoo. Yahoo, Inc.
  24. "Viking Therapeutics Initiates Phase 2 Trial of VK5211 in Patients Recovering From Hip Fracture". FierceBiotech. Questex LLC. 21 November 2016.
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