Given the lack of
doping interest at the winter Olympics, I thought I should turn to a story I
have meant to cover for a while.
GW501516 is the name
of a Glaxo Wellcome drug (the GW stands for the company and the number is that
of the product). It is also known as GW-501,516, GW1516, GSK-516). It is a PPARδ receptor agonist that was not taken further than clinical
trials. As such it is banned in sport. It fits in a number of places on the
list, including specifically as “a peroxisome
Proliferator Activated Receptor δ (PPARδ) agonists (e.g. GW501516)”. But
it would also come under WADA’s new catch all “non approved substances” section
that aims to stop any unlicensed drug being used by athletes:
“Any pharmacological substance which is not
addressed by any of the subsequent sections of the List and with no current
approval by any governmental regulatory health authority for human therapeutic
use (e.g drugs under pre-clinical or clinical development or discontinued, designer drugs,
substances approved only for veterinary use) is prohibited at all times.”
GW501516 gained
notoriety when WADA took the unusual, but not unprecedented, step of warning
users of its potential health risk in a press release in March, 2013 [1]. This
was not triggered by new safety data (this information had been known for a while)
but by the fact that it was being marketed as a supplement touted to endurance
training (called Endurobol) and that, probably because of this there had been
several positive doping tests for it. Endurobol is clearly a name targeted at
athletes. So it is seems inappropriate for companies to market a drug with this
name, even if they say it is not intended for human consumption [2]. It should
be sold as GW501516. By the way there is no chance of banning this compound in
wider society. Like other drugs that modify cell function, it is a legitimate
tool in biomedical research (I could see why I might use it in my laboratory
studies for example). There are over 200
research papers on this drug, and the majority are not about its alleged
performance enhancing effects [3].
So what is GW501516 and
what is its possible relationship to sporting performance? The key paper [4] was
published in 2004 by US and Korean scientists entitled
“Regulation
of Muscle Fiber Type and Running Endurance by PPARδ. PPARδ is a transcription factor i.e. a gene that can make a protein
that controls many other genes. So making more PPARδ can elicit wide ranging
developmental, physiological and biochemical outcomes. In this particular paper
the amount of the PPARδ gene was dramatically increased in the skeletal muscle
of mice. The resultant mice had more type 1 (endurance-type) muscle fibres and were
resistant to obesity. The gene doped mice could run longer than normal mice on
a treadmill (almost three times as long – you can see the videos here).
The gene doping was done in the mouse embryo so is not directly applicable to
what could be done in an athlete. However, the authors did show that activating
the PPARδ gene in normal adult mice (using GW501516) showed the same gene expression effects as in the genetically
altered mice. To the scientists this is good confirmation that
the PPARδ gene controls the genes that determine muscle fibre type.
However, this does not show that GW501516
can improve performance; in the adult mice it may be too late to make this
change – their fibre type ratio having already been fixed during development.
Indeed no performance effect was measured in this paper, nor has there been any
significant paper published since claiming that GW501516 can change fibre type
and improve performance in normal adult mice (or indeed humans).
What the 2004 paper
did show was an effect of GW501516 on reducing obesity induced by a high fat
diet. And of course this is why the drug companies were interested in this
product. As I note repeatedly in my book, medical markets are much larger than
any sports performance market for pharmaceutical companies.
So what became of GW501516?
Glaxo has stopped the development of the product. You have to search around a
bit to find out why. In two rather obscure short abstracts published in The Toxicologist, it was shown that,
when rats and mice were given the drug for two years, they was a significantly
increased risk of developing a range of cancer [5]. Normally bloggers concerned
with evidence-based science would be wary of taking too much credence from
reports that are not published in full peer-reviewed science journals. These
two papers, however, are abstracts of reports presented at a scientific
meeting; they describe negative results about a drug and are being published by
the drug company and the toxicology service that did the work. So we can be
pretty much sure they report a clear risk to health.
An effect of long-term
use on cancer risk might not immediately rule out a drug if it was intended as
a one off life-saving acute intervention. But as a long-term treatment for
obesity or obesity-related syndromes it is clearly a disaster. Glaxo Wellcome
stopped developing the drug and halted a clinical trial, although interestingly
one Australian trial (not Glaxo Wellcome funded) did seem to show some positive
effects [6].
This is becoming a
long blog (for which my apologies). So perhaps a summary is in order at this
point:
- There is scientific evidence from animal studies that GW501516 (Endurobol) has the theoretical potential to improve performance in aerobic sports
- However, when taken by adult humans GW501516 is unlikely to be directly effective in endurance sport, though it might affect body fat content
- There are no reliable studies that demonstrate a performance enhancement with GW501516
- Long term use of GW501516 is very dangerous and can cause cancer
WADA have become very
aggressive in targeting the dangers of using drugs that are in preclinical
animal trials, but have never been tested in humans. Even an absence of
evidence of harm in the scientific literature does not mean that a drug is safe
(drug companies do not necessarily publish all their toxicology data). For
example, a drug I use in my laboratory biochemistry research was never taken
forward by the pharmaceutical company. I know that the reason was they once tested
a slightly higher dose and the animal dropped dead instantly. There was clearly
an additional mechanism operating at doses just above normal that proved fatal.
They could not take the risk that some people would be more sensitive to this
effect and die at the normal therapeutic dose. So drug development was stopped.
But I don’t think this was ever reported; they just moved on to test safer
alternatives.
The moral is very
clear. If you take a drug that has not been approved for human use, you are
taking a risk.
Notes:
[3] I should note in passing that Glaxo
themselves were only interested in this drug for human use - they do not sell it for biomedical research
and, of course especially not for, athletic use. But once a drug formula is
known the manufacturing process can usually be copied or adapted by other
companies. So long as they are not claiming a benefit that infringes Glaxo’s
patents, selling this compound is perfectly legal (ad in fact this benefits
biomedical research science). Selling it for human consumption of course is not
legal.
