This article was updated on April 12, 2013, and includes responses from WADA and GSK.
In an alert published yesterday, the agency claimed the substance – also known online by its supplement name, Endurobol – was being sold on the black market as an endurance booster and was being abused by athletes.
There is no indication as yet as to how prevalent the use of the drug is, nor what the specific health concerns of the substance were that prompted the global alert, but according to WADA:
The side effect of this chemical compound is so serious that WADA is taking the rare step of warning “cheats” to ensure that there is complete awareness of the possible health risks to athletes who succumb to the temptation of using GW501516 for performance enhancement.
GW501516 was described by WADA as:
a developmental drug that was withdrawn from research by the pharmaceutical company and terminated when serious toxicities were discovered in pre-clinical studies.
Unfortunately, 2009 document provided by WADA did not shed any light on the reason for the drug termination by the pharmaceutical company and/or WADA’s latest concern.
What we do know is that GW501516 is a developmental drug that was being developed by the major pharmaceutical company GlaxoSmithKline (GSK).
And we know a little about its chemical make-up and potential uses.
Endurobol’s mechanism of action
They belong to a group of receptors called the NHR super family, which also includes receptors for thyroid hormones, steroid hormones and vitamin D.
GW501516 (also known as GW501, GW516, GW1516) belongs to family of drugs that act on the PPARD receptors and is an oral drug that is bioactive (has interaction with or effect on cell tissue) in humans.
PPARD is believed to work at the gene level and affects skeletal muscle metabolism. In one laboratory study, PPARD activation seemed to nearly double the performance of running endurance in untrained adult mice.
Other potential functions of GW501516 include its regulation of fat metabolism, glucose uptake in skeletal muscle tissue and an increase in muscle gene expression.
The combined effects of these various functions suggest it has a role in burning fat for energy instead of carbohydrates or muscle protein.
As such, it fits within an area of research into clinical applications for obese patients to lose fat effectively without experiencing muscle catabolism or the effects and satiety issues associated with low blood sugar.
In studies on mice, GW501516 led to increases in muscle mass, which improved glucose tolerance and reduced fat mass accumulation even in mice fed a very high fat diet.
Further rodent studies suggest there may be an increased risk of some forms of tumours in rats and mice administered GW501516. The implication of this finding is at present unknown as the in vitro therapeutic effects of GW501516 on human pancreatic cancer cells is also postulated.
Human health risks
The terminated Phase I study evaluated the usefulness of the drug in treating patients with heart disease. It also measured a number of other potential markers of drug activity, including levels of lipids and proteins in participants’ blood.
A phase IV clinical study was completed in Australia in 2008. It assessed the application of GW5015156 in the treatment of high blood cholesterol in insulin resistance and obesity.
No adverse events were reported by the authors for the phase IV trials. The authors also cited two earlier clinical studies that showed no significant adverse effect of the drug, including liver or muscle responses in participants treated with GW501516.
Peroxisome proliferator-activated receptors have been listed as a specific class of substances banned under WADA’s prohibited list since 2009.
Prior to this, the ban was effective only under the generic header of “gene doping” as GW501516 affects gene expression.
According to the Australian Sports Anti-Doping Authority (ASADA) website, PPARs are banned both in and out of competition. But searching the site for GW501516, GW501, GW516, GW1516, GSK-516 and Endurobol all returned negative results.
This, in and of itself, offers little in the way of explanation for the current – and seemingly urgent – WADA warning. Like many people, I’m hoping for more clarification from WADA in the coming days.
I am also waiting for further updates from representatives at GSK, who I contacted today.
Update, April 12, 2013:
Since the global announcement by WADA on March 21, 2013, various online discussion forums have speculated on WADA and GSK’s potential new information on the health effects in humans.
This author has received official clarification from WADA and GSK on the matter, and their responses are reproduced below.
According to Dr Olivier Rabin (WADA Science Director) as relayed through WADA’s Communications Director to this author:
The decision to release this communiqué came from a combination of factors catalysed by the collaboration agreement signed between GSK and WADA which facilitates exchange of information between our two organisations. As part of our collaboration, GSK came to realise that GW501516 was now available on the internet and WADA was recently made aware of several cases of abuse of GW501516. These two recent facts led to further discussions between GSK and WADA. The exceptional warning was then communicated by WADA to protect the health of the athletes … WADA relies on the information and expertise of GSK concerning the health effects in relation to the use of the substance.
The Global External Communications representative from GSK also provided the following information to this author:
GW501516 was an experimental drug being developed to raise HDL or “good” cholesterol in patients with dyslipidemia via its action on muscle. However, all clinical development of GW501516 was stopped when toxicities were found in routine, long-term animal studies that were being conducted in parallel with the clinical studies. The animal studies are required by regulatory authorities as part of the marketing application process.
The long-term effect of GW501516 with chronic dosing in patients is unknown as the initial clinical studies in man were of limited duration and involved small numbers of patients …
Subsequently, the Investigational New Drug application with the FDA was withdrawn in 2009 and GSK has not conducted any further clinical research …
The most recent WADA announcement was not prompted by any new clinical data from studies investigating GW501516. GSK proactively contacted WADA after becoming aware of internet reports in January 2013 suggesting potential abuse of GW501516 by athletes. Independently, WADA had also found several positive cases indicating abuse with the agent in early 2013 as part of their testing. GW501516 has been on the Prohibited List for several years and this action was independent of GSK. In light of the information of abuse given by GSK combined with WADA’s positive test results indicating abuse, WADA took the unusual step of issuing the alert.
The recent WADA warning was therefore not prompted by recent findings of adverse human health effects per se, but rather the concern of the substance’s ready availability and abuse by athletes.
It is understood that a Russian cyclist (European track champion Valery Kaikov) has yesterday been named as the first athlete to be tested positive for the drug.
Human studies on the effects of GW501516 include the following:
- Phase I trial: multicentre trial conducted between 2004-12.
- Phase II trial: trial approved in Belgium and conducted between 2004-11. Results not published.
- Phase IV trials: conducted in Australia between 2003-08.
- Non-GSK-affiliatied anti-doping research: conducted between 2009-12.
- High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor.
- Research into Peroxisome Proliferator–Activated Receptor effects in obese men.
There were no side-effects reported in the human studies.
But this may be due to short study durations. It may also be due to the small doses used in humans.
The side-effects of GW501516 from animal studies were based on large doses of the drug.
There are at present at least eight separate clinical trials being conducted using other drugs of the PPAR class and they are in various stages of development.
Endurobol is currently being sold “legally” in the unregulated “grey market” by Australian entities as either a (non-medication) supplement or a chemical reagent for scientific purposes (although the intention for the sale under this category is clear).
Based on the known mechanism of action of GW501516 and PPARs, these substances are unlikely to be classified under the category of Selective Androgen Receptor Moderators (SARMs) — restricted drugs that have effects similar to steroids – highlighted in the recent Australian Crime Commission (ACC) report.
According to the ACC report, the scheduling of SARMs was recently considered by the Therapeutic Goods Administration’s (TGA) Advisory Committee on Medicines and Scheduling.
The committee determined that SARMs will be classified as a Schedule 4 medicine and included in Appendix D in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) (The Poisons Standard).
This will make it illegal to possess SARMs without a prescription.
This change in scheduling will take effect on May 1, 2013.
In view that it is already been confirmed as a substance of abuse as well as its potential carcinogenic effects, this author has urged the TGA to consider if GW501516 (and potentially various PPARs) should be classified within the Customs (Prohibited Imports) Regulations.