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| Other names | LGD4033; VK5211; VK-5211; Ligandrol; Anabolicum |
| Routes of administration | By mouth[1][2] |
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| Eliminationhalf-life | 24–36 hours[3][2][4] |
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| Formula | C14H12F6N2O |
| Molar mass | 338.253 g·mol−1 |
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LGD-4033, also known by the developmental code nameVK5211 and by the black-market nameLigandrol, is aselective androgen receptor modulator (SARM) which is under development for the treatment ofmuscle atrophy in people withhip fracture.[5] It was also under development for the treatment ofcachexia,hypogonadism, andosteoporosis, but development for these indications was discontinued.[5] LGD-4033 has been reported todose-dependently improvelean body mass andmuscle strength in preliminaryclinical trials, but is still being developed and has not been approved for medical use.[5][6][7][8] The drug is takenby mouth.[1][2]
Known possibleside effects of LGD-4033 includeheadache,dry mouth, adverselipid changes like decreasedhigh-density lipoprotein (HDL)cholesterol levels, changes insex hormone concentrations like decreasedtestosterone levels,elevated liver enzymes, andliver toxicity.[9][1][10][3][2][11][6] The potential of LGD-4033 and other SARMs for producingmasculinization is largely uncharacterized and hence is unknown.[3] LGD-4033 is anonsteroidal SARM, acting as anagonist of theandrogen receptor (AR), thebiological target ofandrogens andanabolic steroids liketestosterone anddihydrotestosterone (DHT).[10] However, it shows dissociation of effect between tissues inpreclinical studies, with agonistic andanabolic effects in muscle and bone andpartially agonistic orantagonistic effects in theprostate gland.[12][3][13]
LGD-4033 was first described in 2010.[12][4] It is less clinically studied than other SARMs likeenobosarm, with only a few smallclinical trials having been conducted and reported.[14][11][9][2][8] LGD-4033 has not yet completed clinical development or been approved for any use.[5][10][3] As of 2023, it is inphase 2clinical trials for the treatment ofhip fracture andmuscle atrophy.[5] LGD-4033 was developed byLigand Pharmaceuticals, and is now being developed by Viking Therapeutics.[5]
Aside from its development as a potentialpharmaceutical drug, LGD-4033 is on theWorld Anti-Doping Agencylist of prohibited substances[15] and is sold forphysique- and performance-enhancing purposes byblack-market Internet suppliers.[3][9][16] LGD-4033 is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness andsafety.[3][9] Many products sold online that are purported to be LGD-4033 either contain none or contain other unrelated substances.[3][17]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[18]
LGD-4033 is not approved for any medical use and is not available as a licensedpharmaceutical drug as of 2023.[5][10][3]
Side effects of LGD-4033 may includeheadache anddry mouth.[9] LGD-4033 has been found todose-dependently decrease levels oftotal testosterone,free testosterone,follicle-stimulating hormone (FSH),sex hormone-binding globulin (SHBG),HDL cholesterol, andtriglycerides, while not affecting levels ofluteinizing hormone (LH),total cholesterol,LDL cholesterol, orprostate-specific antigen (PSA).[3][2] Due to the decreased ratio of HDL cholesterol to LDL cholesterol, LGD-4033 could theoretically increase the risk ofheart attack andstroke.[19]
Elevated liver enzymes, such as increased levels ofaspartate aminotransferase (AST) oralanine aminotransferase (ALT), have not been reported with LGD-4033 in the few conducted clinical trials thus far.[6][9] However, multiplecase reports ofhepatotoxicity with LGD-4033 in the setting of non-medical use have been published.[11][6][9][20]
LGD-4033 and other SARMs are largely uncharacterized in terms of their potential formasculinizing effects, for example in women.[3] In addition, the effects andsafety of high doses of LGD-4033 and other SARMs, which are often used in non-medical contexts, are unknown.[3] Anecdotal reports of masculinization with black-market SARMs in women exist in online forums.[18]
TheUnited StatesFood and Drug Administration (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 potential adverse health effects of SARMs including LGD-4033.[21]
LGD-4033 has been assessed in clinical trials at single doses ranging from 0.1 to 22 mg and at repeated doses ranging from 0.1 to 2 mg/day for 3 to 12 weeks.[11] The drug sold viablack-market Internet suppliers and used non-medically is often taken at much higher doses than those used in repeated-dose clinical trials (e.g., 5–10 mg/day), with unknown adverse effects and risks.[3][9][11]
LGD-4033 is aselective androgen receptor modulator (SARM), or atissue-selective mixedagonist orpartial agonist of theandrogen receptor (AR).[10] This receptor is thebiological target ofendogenousandrogens liketestosterone anddihydrotestosterone (DHT) and ofsyntheticanabolic steroids likenandrolone andoxandrolone.[22][23][24] LGD-4033 shows highaffinity andselectivity for the AR, with an affinity (Ki) value of 0.9 nM.[12][3][13] It did not meaningfully interact with theprogesterone receptor,glucocorticoid receptor, ormineralocorticoid receptor (all Ki > 4,000 nM), whereas theestrogen receptor α was not assessed.[13] In terms ofin vitrotranscriptional activity at the AR, theefficacy (Emax) of LGD-4033 was 132% to 133% and itsEC50 was 3.6 to 4.4 nM.[12][13] The AR is widely expressed intissues throughout the body, including in theprostate gland,seminal vesicles,genitals,gonads,skin,hair follicles,muscle,bone,heart,adrenal cortex,liver,kidneys, andbrain, among others.[23][24] LGD-4033 has been found to have varyingfull agonist andpartial agonist AR-mediated effects in different tissues, includingpotent agonistic andanabolic activity inmuscle andbone and weaker partial agonist activity in theprostate gland andsebaceous glands.[12][3][13][25][26]
LGD-4033 has shown robust selectivity for stimulation of thelevator ani muscle relative to stimulation of the prostate in rats.[12] At the highest assessed dose in castrated male rats, levator ani weight was increased to around 140% of that of gonadally intact controls, whereas prostate weight was only increased to around 45% of that of intact controls.[13] The tissue selectivity of LGD-4033 was independent of local tissue drug concentration, suggesting that its selectivity was intrinsic.[12][13] The muscle-stimulating effects of LGD-4033 have also been confirmed in humans in preliminary clinical trials.[10][27] The data also allow comparison between different SARMs and other AR agonists.[10][27] In aphase 1 clinical trial in 76 healthy young men, 1 mg/day LGD-4033 increasedlean body mass by 1.2 kg after 3 weeks of treatment.[10][27][2] For comparison,enobosarm, another SARM, increased lean body mass by 1.3 kg at a dose of 3 mg/day after 12 weeks in healthy elderly men and postmenopausal women.[2][27][28] It was concluded that the employed dose of LGD-4033 produced similar increases in lean body mass compared to enobosarm despite a substantially shorter treatment period.[2] In aphase 2 clinical trial in 108 women and men withhip fracture, LGD-4033 increased lean body mass by 4.8% at 0.5 mg/day, 7.2% at 1 mg/day, and 9.1% at 2 mg/day after 12 weeks of treatment.[8] For comparison, lean body mass with enobosarm 3 mg/day after the same time period of 12 weeks increased by about 0.30% at 0.1 mg/day, 0.40% at 0.3 mg/day, 1.2% at 1 mg/day, and 3.1% at 3 mg/day, with only the latter change achievingstatistical significance.[28] Relative to SARMs, supraphysiological doses of testosterone (300–600 mg/week intramuscular testosterone enanthate) over similar timeframes, like 20 weeks, have been found to result in lean body mass gains of 5 to 8 kg in healthy young men.[29][3][30]
In addition to selectivity for muscle and bone over the prostate gland, LGD-4033 has also been stated by Ligand Pharmaceuticals researchers to have reduced strength in thesebaceous glands.[12][4] Reduced activity in stimulating sebaceous gland formation, to about 30 to 50% of that produced by DHT at doses with similar anabolic potency in rats, has also been reported for certain other SARMs, like the steroidal agentsTFM-4AS-1 andMK-0773.[12] In addition, enobosarm and MK-0773 have been reported to limitedly stimulate the sebaceous glands in small short-term clinical studies in women.[31][28][32]
LGD-4033 showedlinear or dose-proportionalpharmacokinetics across doses of 0.1 to 1 mg/day over 21 days of administration.[2] Levels of LGD-4033 were 3-fold higher at day 21 compared to day 1, indicating significantaccumulation with repeated administration.[2] The meanarea-under-curve levels of LGD-4033 on day 21 were 19 ng•day/mL at 0.1 mg/day, 85 ng•day/mL at 0.3 mg/day, and 238 ng•day/mL at 1 mg/day.[2] Theelimination half-life of LGD-4033 is 24 to 36 hours.[3][2][4] Pharmacokinetic studies of LGD-4033 for purposes ofdoping detection have also been conducted.[33][34][35][36]
LGD-4033 is anonsteroidal SARM with apyrrolidinyl-benzonitrile corestructure and is also referred to as aquinoline orquinolinone SARM.[3][12]LG121071 (LGD-121071), atricyclic quinoline, was the predecessorcompound of LGD-4033.[10] Thechemical structure of LGD-4033 had not been disclosed as late as 2013.[12][27] LGD-4033 has sometimes been confused with other structurally relatedLigand Pharmaceuticals SARMs includingLGD-2226,LGD-2941, andLGD-3303,[10][5] but is a different compound from these agents.[12][10]
LGD-4033 is asmall-molecule (molecular weight = 338.3 g/mol) and highlylipophilic (predictedlog P = 3.6–3.7)compound.[37][38]
The predecessor of LGD-4033,LG121071 (LGD-121071), was discovered byLigand Pharmaceuticals and was first described in the literature in January 1999.[10][39] It was the firstorally activenonsteroidalandrogen receptoragonist to be discovered.[40][39] LG121071 is atricyclicquinolinederivative, and is structurally distinct from arylpropionamide SARMs likeandarine andenobosarm (ostarine).[40]LGD-2226, abicyclic quinoline SARM, was subsequently developed by Ligand Pharmaceuticals andTAP Pharmaceuticals in 2001.[40] Other quinoline SARMs, likeLGD-2941 andLGD-3303, were also subsequently developed by Ligand Pharmaceuticals prior to the development of LGD-4033.[12][41]
LGD-4033 was developed by Ligand Pharmaceuticals and was first described in the literature in 2010.[5][12][4] On the basis of a favorablepreclinical profile,phase 1clinical trials of LGD-4033 began in 2009.[12] The results of a single-dose phase 1 clinical trial were published as aconference abstract in 2010 and the findings of a multi-dose phase 1 trial were published as ajournal article in 2013.[11][1][4][2] A third phase 1 trial was also conducted.[6][14] By 2012, aphase 2 trial of LGD-4033 for the treatment of muscle wasting related to cancercachexia, acuterehabilitation (e.g.,hip fracture), andacute illness was being prepared by Ligand Pharmaceuticals.[12][1] On 22 May 2014, Viking Therapeutics licensed the developmental rights of LGD-4033 from Ligand Pharmaceuticals and intended to advance the compound into mid-to-late-stage clinical trials.[10] The phase 2 study of LGD-4033 for muscle wasting was finally initiated in November 2016[42] and was completed with results reported in 2017 and 2018.[14][10][8] As of March 2023, LGD-4033 (VK5211) continues to be under development by Viking Therapeutics and continues to be in phase 2 clinical trials for treatment of muscle atrophy and hip fracture.[5]
In the United States, LGD-4033 is anInvestigational New Drug and is not approved for any medical use.[5]
Though not an approved drug, LGD-4033 (Ligandrol) has beensold on the black market as adesigner drug in countries where it is classified as an illegal substance.[43][44][16] Along withenobosarm (ostarine; GTx-024, S-22),andarine (GTx-007; S-4), andvosilasarm (RAD140; "testolone"), LGD-4033 is one of the most popular and common non-medically-used SARMs.[9][45] Many products sold online that are purported to be LGD-4033 either contain none or contain other unrelated substances, and doses are also frequently not as labeled.[3][17]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[18]
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 theFederal Food, Drug, and Cosmetic Act. One of the substances was LGD-4033. The company advertised as benefits of the LGD-4033: "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.[21]
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".[46]
LGD-4033 is on theWorld Anti-Doping Association (WADA) list of prohibited drugs[15] and has been found in drug testing samples of some athletes.[47] Since at least June 2015, LGD-4033 has been available via the internet. In that month, German scientists proposed a new test to detect itsmetabolites present in humanurine, and suggested an expansion of the WADA regime.[48] LGD-4033 has been found in WADA samples and in racehorses as well.[49]
On 15 March 2024 cyclistChristos Volikakis was informed of an Adverse Analytical Finding on a re-analysis of a sample from the 2016 Rio Olympics. The athlete has since requested an analysis of the B sample.[50]
In 2015, the quarterback of theFlorida Gators,Will Grier, was suspended for testing positive for LGD-4033, a claim that theUniversity of Florida denies.[51]
In 2017,Joakim Noah was banned for twenty games by theNBA for testing positive for LGD-4033.[52]
In 2019, Australian swimmerShayna Jack tested positive for LGD-4033. She denies knowingly taking the substance.[53]
In August 2019, it came to light that Canadian sprint canoeistLaurence Vincent Lapointe tested positive for LGD-4033; 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.[54] On 27 January 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 LGD-4033.[55]
In January 2020, ChileanATP tennis singles competitorNicolás Jarry tested positive for both LGD-4033 andstanozolol. He protested at the time that the multi-vitamins from Brazil that he took on the advice of an unnamed doctor were contaminated.[56]
On 3 September 2022, sprinter Nzubechi Grace Nwokocha was provisionally suspended for the use of banned substancesenobosarm and LGD-4033[57] by the Athletics Integrity Unit (AIU).
On 23 January 2024,Tristan Thompson was suspended for 25 games by the NBA for testing positive foributamoren and LGD-4033.[58]
On 12 March 2024, curlerBriane Harris was provisionally suspended for up to four years after testing positive for LGD-4033. She denies this after being tested by doping control officers on Jan. 24 and notified of her positive test on Feb. 15. A second sample, called the B sample, also confirmed the positive test. She appealed the ban to the Court of Arbitration for Sport (CAS), arguing she was unknowingly exposed to it through bodily contact.[59] CAS ruled that "Harris has established that she bearsNo Fault or Negligence for the anti-doping rule violation. No period of Ineligibility is imposed."[60]
Oral administration of LGD-4033 tocynomolgus 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 totoxicity concerns, but this did not negatively impact development of the drug as this dose is significantly higher than the doses being utilized in aphase 2clinical trial.[61]
Twophase 1clinical trials of LGD-4033 have been conducted and reported.[11] The first was a single-dose study published as aconference abstract in 2010 and the second was a multi-dose study published as ajournal article in 2013.[11][4][2] The multi-dose phase 1 trial published in 2013 reported that LGD-4033dose-dependently improvedlean body mass andmuscle strength in 76 healthy young men over 21 days.[2] It was generally well-tolerated in this study, with no significant adverse effects reported.[2]
A phase 2 clinical trial, initiated on 3 November 2016, consisted of 108 women and men recovering from hip fracture surgery.[8] The randomized study participants received either placebo or varying doses of LGD-4033 over a period of 12 weeks, with improved lean body mass as the primary endpoint.[8] Other endpoints included satisfactory results in terms ofquality of life,safety, andpharmacokinetics.[42] This study was completed and results reported in 2017 and 2018.[14][10][8] In the trial, LGD-4033dose-dependently improvedlean body mass andmuscle strength and was reported to be safe andwell-tolerated.[6][7][8] Placebo-adjusted lean body mass was increased by 4.8% at 0.5 mg/day, 7.2% at 1 mg/day, and 9.1% at 2 mg/day after 12 weeks.[8]
As of 2023, LGD-4033 has been less studied than other SARMs likeenobosarm, with only three small phase 1 clinical trials and one phase 2 trial, or a total of four clinical studies, having been conducted and reported.[14][11][9][2][8]
LGD-4033 is a potent SARM that binds the human androgen receptor with Kd =0.9 nM. In animal models, it has anabolic effects on skeletal muscle and bone, but spares prostate, sebaceous glands, and female genitalia. In a double-blind, placebo-controlled, first-in-human Phase I trial, ascending single oral doses of LGD-4033 ranging from 0.1 mg to 22 mg were administered to healthy males. LGD4033 was safe and well tolerated up to the highest tested dose with no serious adverse events reported. LGD-4033 exhibited dose-proportional, sustained systemic exposure (AUC0-48hr: 24 to 7000 ng. hr/ mL for 0.1 and 22 mg doses, respectively). The elimination half-life (t1/2) was 31 hrs, indicating LGD-4033 is amenable for once daily dosing. PK-PD studies were conducted in orchiectomized (ORDX) rats, a model of androgen action, to determine the LGD-4033 efficacious exposure level. Subcutaneous minipumps were used to mimic the 10-fold longer t1/2 in humans vs. rats. A dose that produced an AUC of 80 ng. hr/mL restored the atrophied muscle mass of ORDX rats to the eugonadal level (270% increase in levator ani muscle weight with LGD-4033 vs. vehicle) and reduced the elevated luteinizing hormone level of ORDX rats by 98%. The efficacious range predicted by the preclinical model will be achieved by repeated daily doses ca. 0.25 mg in humans. Conclusion: LGD-4033 is a well-tolerated and highly tissue-specific, potential new treatment for sarcopenia (e.g., cancer cachexia or the frail elderly) and osteoporosis that is predicted to be effective using low, daily oral doses. A Phase I multi-dose study is in progress.
Other molecules have been developed including LGD-4033 which increased muscle mass and strength in healthy males after 3 weeks (Basaria et al. 2013) [...] Recently, a phase 2 trial on the agent VK211 demonstrated dose-dependent increases in lean body mass, and improvements in physical performance in patients who had sustained hip fracture (Ristic et al. 2018). Whilst SARMs hold great promise as anabolic agents that may offer an effective therapy for osteosarcopenia, long-term side effects of these agents are unknown, studies are generally small and of short duration. Regulation of these products poses immense challenges with their high uptake on the black market and via the internet as performance-enhancing, body-building agents, which may overshadow their potential mainstream application in disorders of aging.
Introduction Hip fractures are a leading cause of disability and morbidity in older people. Post-facture, an increased catabolic state often leads to loss of muscle, which can impair balance and endurance, potentially increasing the risk of further injury. Anabolic steroids have been shown to improve muscle mass in certain settings. Selective androgen receptor modulators (SARMs) could be similarly effective in older patients who have suffered muscle loss following hip fracture, while potentially avoiding undesired side effects associated with broad-acting anabolic agents. VK5211 is a novel, non-steroidal, orally available SARM that has been shown to improve muscle mass and bone mineral density in animal models. In humans, a prior Phase 1 study demonstrated increases in lean body mass after 21 days of dosing. Purpose A 12 week study was conducted to assess the safety and efficacy of VK5211 in patients who had suffered a hip fracture. Methods A randomized, double-blind, placebo-controlled, multicenter, international Phase 2 trial was conducted to evaluate VK5211 in patients recovering from hip fracture. Patients were randomized to receive daily oral VK5211 doses of 0.5 mg, 1.0 mg, 2.0 mg, or placebo, for 12 weeks. The primary endpoint evaluated change from baseline in lean body mass, less head, in patients receiving VK5211 compared with placebo. Secondary and exploratory endpoints included changes in appendicular lean mass, bone density, and functional performance. Results A total of 108 patients were randomized (83 F, 25 M; mean age 77). Patients receiving VK5211 demonstrated significant increases in lean body mass, less head, after 12 weeks. Placebo-adjusted increases were 4.8% at 0.5 mg, 7.2% at 1.0 mg, and 9.1% at 2.0 mg (p < 0.005 for each). The proportions of patients experiencing at least a 2.0 kg increase were 14% with placebo, 57% at 0.5 mg, 65% at 1.0 mg, and 81% at 2.0 mg (p < 0.01 for each). Patients receiving VK5211 demonstrated improvement in certain measures of functional performance, including the 6-minute walk test and short physical performance battery (these endpoints were not powered for significance). The rates of adverse events were similar in cohorts receiving VK5211 as compared with placebo, and no drug-related SAEs were observed in VK5211-treated patients. Conclusion VK5211 was well-tolerated and produced improvements in lean body mass in hip fracture patients following 12 weeks of dosing. Further evaluation in this setting is warranted.
At the doses that have been tested, the first generation SARMs induce modest gains in lean body mass in healthy volunteers, which are nowhere near the much greater gains in skeletal muscle mass reported with supraphysiological doses of testosterone. The modest gains of 1.0 to 1.5 kg in fat-free mass with first generation SARMs over 4–6 weeks should be contrasted with the 5–7 kg gains in fat-free mass with 300 and 600 mg doses of testosterone enanthate. However, it is possible that next generation of SARM molecules will have greater potency and selectivity than the first generation SARMs.
The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001).
