Ligandrol (VK5211, LGD-4033)
is a novel nonsteroidal oral
selective androgen receptor modulator
Selective Androgen Receptor Modulators or SARMs are a class of androgen receptor ligands that maintain some of the desirable effects of androgens, such as preventing osteoporosis and muscle loss while reducing risks of developing prostate cancer ...
(SARM) for treatment of conditions such as
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
wasting and
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
,
discovered by
Ligand Pharmaceuticals
Ligand Pharmaceuticals is a biopharmaceutical company located in San Diego, California. Founded in 1987 as Progenix Inc., the company went public in 1992. Initially focused on developing its own drugs, a period of turbulence in the early 2000s cul ...
and under development by
Viking Therapeutics
Vikings ; non, víkingr is the modern name given to seafaring people originally from Scandinavia (present-day Denmark, Norway and Sweden),
who from the late 8th to the late 11th centuries raided, pirated, traded and se ...
.
Ligandrol has been found in
World Anti-Doping Agency
The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...
(WADA) samples and in racehorses too. Like
anabolic steroids
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects t ...
, it can stimulate muscle growth. "SARMs have shown superior side effect profiles compared with
anabolic steroids
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects t ...
, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors".
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
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
present in human
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
, and suggested an expansion of the WADA regime.
Misbranded as dietary supplement
On 23 October 2017, a nutritional supplement company in Missouri called Infantry Labs was warned by the
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
that the distribution of two of its products violated the
Federal Food, Drug, and Cosmetic Act
The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C) is a set of laws passed by the United States Congress in 1938 giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of f ...
. 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
A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill (pharmacy), pill, capsule (pharmacy), capsule, tablet (pharmacy), tablet, powder, or liquid. A supplement can provide nutrients either extr ...
" what should have been "
new drugs" or "
prescription drugs
A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...
" and were instructed to document the steps they would take in order to cease the violation.
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".
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.
Another study conducted in January 2013 found that Ligandrol can help increase lean muscle mass, and was generally well tolerated by test subjects.
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
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
and
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
" are among the adverse health effects of SARMs.
[
]
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.
Ligandrol is on the World Anti-Doping Association list of prohibited drugs and has been found in drug testing samples of some athletes.
In 2015, the quarterback of the Florida Gators
The Florida Gators are the intercollegiate athletic teams that represent the University of Florida, located in Gainesville. The University of Florida, its athletic program, its alumni and its sports fans are often collectively referred to as t ...
, Will Grier
William Grier (born April 3, 1995) is an American football quarterback for the Dallas Cowboys of the National Football League (NFL). He played college football at Florida and West Virginia and was drafted by the Carolina Panthers in the third ro ...
, was suspended for testing positive for ligandrol, a claim that the University of Florida
The University of Florida (Florida or UF) is a public land-grant research university in Gainesville, Florida. It is a senior member of the State University System of Florida, traces its origins to 1853, and has operated continuously on its ...
denies.
In 2017, Joakim Noah
Joakim Simon Noah ( ; born February 25, 1985) is an American-born French-Swedish former professional basketball player. He played college basketball for the Florida Gators, winning back-to-back NCAA championships in 2006 and 2007. The Chicago B ...
was banned for twenty games by the NBA
The National Basketball Association (NBA) is a professional basketball league in North America. The league is composed of 30 teams (29 in the United States and 1 in Canada) and is one of the major professional sports leagues in the United St ...
for testing positive for ligandrol.
In 2019, Australian swimmer Shayna Jack tested positive for ligandrol. She denies knowingly taking the substance.
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. On January 27th 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.
In January 2020, Chilean ATP tennis singles competitor Nicolás Jarry
Nicolás Jarry Fillol (; born 11 October 1995) is a professional tennis player from Chile. He has won one tournament in singles and two in doubles on the ATP Tour. He achieved his highest ATP singles ranking of World No. 38 in July 2019, after ...
tested positive for both ligandrol and stanozolol
Stanozolol (Abbreviation, abbrev. Stz), sold under many brand names, is an androgen and anabolic steroid (AAS) medication derived from dihydrotestosterone (DHT). It is used to treat hereditary angioedema. It was developed by American pharmaceuti ...
. He protested at the time that the multi-vitamins from Brazil that he took on the advice of an unnamed doctor were contaminated.
3 September 2022, Nzubechi Grace Nwokocha was provisionally suspended for the use of banned substances https://www.reuters.com/lifestyle/sports/commonwealth-gold-medallist-nwokocha-provisionally-suspended-doping-2022-09-03/ by the Athletics Integrity Unit (AIU).
Commercial environment
Viking Therapeutics does not manufacture any pharmaceutical products, but is developing several products to treat metabolic
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
and endocrine
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
disorders. Thus, the company relies upon investments from stockholders and business partners. The company completed its initial public offering in the 2nd quarter of Fiscal Year 2015, generating $22.3M in net proceeds.[Lian, Brian, Ph.D. "Q2 2015." Viking Therapeutics InvestorRoom. Viking Therapeutics, Inc., 3 Aug. 2015. Web. 21 Nov. 2016.] Viking Therapeutics assumed the largest expense in 2014 from cited Research and Development costs ($21.2M), which may be related to purchase of required equipment and facilities to develop the drug candidates licensed by Ligand Pharmaceuticals in that year, including ligandrol.
Financial risks of development
Viking Therapeutics has yet to bring a drug to market. If one or several of their drug candidates does not pass clinical trials before one is successfully brought to market, then a significant amount of stockholders would likely sell their stocks, seriously reducing revenue and capability to continue development of ligandrol. Additionally, as noted in the Form 10-Q submitted on 10 November 2016, Viking relies heavily upon licensed technologies by Ligand Pharmaceutics. If Viking Therapeutics were to lose this license, then its operating capability would be severely impacted.
Other commercial aspects
Ligand Pharmaceutics has disclosed that its royalty fee incurred upon Viking Therapeutics for production and sale of ligandrol would be 7.25-9.25% of the product revenue.
Another promising drug candidate, VK2809, is expected to drive a major shift in the market cap of Viking Therapeutics and its share of the market for TRβ agonists, which is dominated by Madrigal Pharmaceuticals
A madrigal is a form of secular vocal music most typical of the Renaissance music, Renaissance (15th–16th c.) and early Baroque music, Baroque (1600–1750) periods, although revisited by some later European composers. The Polyphony, polyphoni ...
. This would improve the company portfolio as a whole, and would allow for greater capitalization upon the potential success of ligandrol.
Intellectual property
Ligand Pharmaceuticals has patents filed for the manufacture and therapeutic use of certain compounds occupying several stated chemical structures, which are intended for use as selective androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...
receptor modulators. The patent is filed under the following designations: US8519158 B2, US8865918, US9359285, US20070254875, US20140005186, US20150099720, and WO2005090282A1. The patents will expire on March 12, 2025. These patents effectively protect any future capitalization upon ligandrol in the market by Viking and Ligand through their licensing agreement.
Regulatory information
In the United States, ligandrol is an Investigational New Drug.
Pre-clinical
Oral administration of the drug to cynomolgus monkeys
The crab-eating macaque (''Macaca fascicularis''), also known as the long-tailed macaque and referred to as the cynomolgus monkey in laboratories, is a cercopithecine primate native to Southeast Asia. A species of macaque, the crab-eating macaqu ...
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 toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
ity concerns, but this did not negatively impact development as the dose is significantly higher than those being utilized in the Phase 2 clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
.
Clinical trials
In a Phase 1 clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
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.[Basaria, S., L. Collins, E. L. Dillon, K. Orwoll, T. W. Storer, R. Miciek, J. Ulloor, A. Zhang, R. Eder, H. Zientek, G. Gordon, S. Kazmi, M. Sheffield-Moore, and S. Bhasin. "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 (2012): 87-95. Web. 21 Nov. 2016.]
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
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
.["Viking Therapeutics Initiates Phase 2 Trial of VK5211 in Patients Recovering From Hip Fracture." FierceBiotech. Questex LLC, 03 Nov. 2015. Web. 21 Nov. 2016.]
References
{{Androgen receptor modulators
Experimental drugs
Pyrrolidines
Selective androgen receptor modulators
Trifluoromethyl compounds
World Anti-Doping Agency prohibited substances