“Oxygen in a pill”: the next big thing in sports doping?

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Much has been written in recent years about the future of doping in cycling and what drug, if any, will replace EPO as the substance of choice. Previously we published an article that looked at two compounds, GW1516 and AICAR, and considered whether their use might be widespread in the pro peloton, now or into the future.

Recent positive drug tests by two cyclists Fabio Taborre of Italy and Carlos Oyarzun of Chile suggest there is a new substance that’s going through clinical trials that increases production of red blood cells, and still not approved for human consumption. We’re talking about FG-4592/ASP1517. Dr Ben Koh and Matt de Neef first highlighted the potential use of this experimental drug over two years ago. The article is reproduced here in view of new events unfolding and anti-doping organisations finally catching up to testing for the substance.

As far as drug names go FG-4592/ASP1517 isn’t particularly catchy — it’s too young in its development cycle to have been given a name for marketing purposes — but it does tell us which pharmaceutical companies are behind the compound: FibroGen and Astellas. Between them, they’ve developed a pill that can be used for the treatment of anaemia with a particular focus, at present, on anaemia associated with chronic kidney disease.

As a quick refresher: anaemia is a condition in which an individual has a lower red blood cell count than normal. Or more specifically, when an individual has less than the normal amount of haemoglobin — iron-containing, oxygen-transporting molecules inside the red blood cells — in their blood.

So FG-4592/ASP1517 is a compound that can increase an individual’s red blood cell count, leading to a greater capacity to transport oxygen around the body. You might even refer to it as “oxygen in a pill”.

| Related: Tour de France samples to be retested for EPO-booster FG4592

As we’ve touched on, this compound has benefits for patients who have a lower-than-normal red blood cell count. But, of course, the compound could also be (ab)used by athletes, in much the same way EPO has been used in the past. That is, to potentially increase their red blood cell count, thereby improving oxygen transport to the muscles and potentially creating a boost in aerobic sporting performance.

| Related: Blood Doping 101 

So how does FG-4592/ASP1517 actually work? In very broad terms, it works at the genetic level to allow the body’s natural red blood cell production to function more efficiently. Or, to quote from a FibroGen press release, FG-4592/ASP1517 is “an inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase”. To understand that statement, we’ll need to return to a couple of principles that we touched on in an earlier article about gene doping.

You might recall that hypoxia is the condition in which the body (or part of the body) is deprived of an adequate amount of oxygen. In this state, the body can respond in a number of ways. The most immediate way is to convert from aerobic (oxygen) exercise into anaerobic (lack of oxygen) exercise. However, anaerobic exercise is not efficient and soon the lactic acid build-up causes the athlete to stop exercising.

A more efficient solution is to create more red blood cells so as to have more oxygen in the tank at any one time. This is the basis behind altitude training.

Researchers have only recently come to realise the importance of mediators involved in the body’s response to hypoxia and the production of red blood cells. These mediators are known as hypoxia-inducible factors (or HIFs) — a type of transcription factor.

What are transcription factors? Well, they can been seen as proteins that “read the instruction manual” of the genes involved in red blood cell production. Imagine a car factory supervisor (HIF) reading a manual (genes) and instructing the workers (the body/bone marrow) to produce more cars (red blood cells).

| Related: The future of cheating: Gene doping

So HIFs affect the body’s adaptive responses to hypoxia by orchestrating the creation of more red blood cells. But as the name suggests, HIFs only function when the body doesn’t have a normal amount of oxygen to work with. When oxygen levels return to normal, an enzyme called prolyl hydroxylase catalyses (or speeds up) a chemical reaction which breaks down the HIFs, thereby ceasing the production of red blood cells. To return to our analogy, imagine the factory boss asking the factory supervisor to stop reading the manual and giving orders to the workers.

Which brings us back to the description of FG-4592/ASP1517 as “an inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase”. This compound inhibits the prolyl hydroxylase, stopping it from breaking down the HIFs, thereby allowing red blood cell production to continue when the body isn’t starved of oxygen. Imagine the factory boss is home sick and is unable to tell the factory supervisor to stop reading the manual and giving orders.

As discussed above, this is very useful for patients with a low red blood cell count — it allows the body to continue producing red blood cells. But again, this could also be used by athletes with a normal red blood cell count for the same purpose.

As you might expect, the use of FG-4592/ASP1517 is banned by the World Anti Doping Agency (WADA), but not by name, rather by its mechanism of action:

The following substances and their releasing factors are prohibited:

– Erythropoiesis-Stimulating Agents [e.g. erythropoietin (EPO), darbepoetin (dEPO), hypoxia-inducible factor (HIF) stabilizers, methoxy polyethylene glycol-epoetin beta (CERA), peginesatide (Hematide)]

The use of FG-4592/ASP1517 is also prohibited under section S0 in WADA’s prohibited list because it’s a drug with no current approval by any governmental regulatory health authority for human therapeutic use.

So how would taking FG-4592/ASP1517 as a performance-enhancing drug compare to taking EPO? It is potentially better in several ways. Not only can FG-4592/ASP1517 do almost everything EPO can do, clinical trials have suggested that it may have a better “safety profile” than EPO. More specifically, no heart or blood pressure issues have been observed in trials thus far. Furthermore, FG-4592/ASP1517 is available in a pill form and does not have to be injected into the body.

This new compound has another advantage too, relating to iron absorption.

HIF promotes the body’s own EPO secretion from the kidneys and other non-renal sources (e.g. the liver) and up-regulates EPO receptors in the bone marrow to produce more red blood cells. HIF also activates factors that improve iron absorption from the gut, that mobilise iron from storage sites within the body, and that effectively transport all the needed iron to the bone marrow for red blood cell production. As such, FG-4592/ASP1517 has an advantage over EPO injections in that athletes need not also supplement themselves with iron at the same time as EPO administration.

We are not sure at this time if there is a specific blood or urine test used to detect FG-4592/ASP1517 in an athlete’s body as this has not yet been reported in the scientific literature. However, because the drug potentially increases the body’s red blood cell levels above an individual’s normal range, this upwards trend can be detected by way of WADA’s Biological (Haematological) Passport. By charting an athlete’s baseline blood (and other biological) values over time, any sudden/recent anomalous readings (of increased red blood cells) would ring alarm bells.

In researching this article we contacted a number of anti-doping experts and none had heard of FG-4592/ASP1517, let alone heard of its use among athletes. But Dutch anti-doping expert Dr Klaas Faber, did offer a provocative observation about the state of anti-doping:

Current anti-doping is a total failure. Success rate is extremely poor. Perhaps the best proof of its failure is a statement by WADA’s director general David Howman, from 2011: “We are catching the dopey dopers, but not the sophisticated ones.”

We also spoke to a leading Australian biochemist who has worked in sports science for several years and who preferred to remain anonymous. He told us he was familiar with the therapeutic use of compounds such as FG-4592/ASP1517, but said of its use in a sporting context:

I would be very surprised if anyone is using this compound or was going to use it, but nothing should surprise me. Drugs such as these are most effective for their therapeutic uses and any uses in sport would likely be very hit-and-miss. I can only see it being effective at the high end of sport.

He also indicated that the use of compounds such as FG-4592/ASP1517 for doping is a big step up from existing doping methods — a leap from blood doping (in the case of EPO) to gene doping:

When we start talking about HIF-stabilisers we’re really to get to the pointy end of some serious biochemistry. It’s not just a case of injecting a drug into the muscle.

So where is the development of this drug up to? And is it available yet?

In November last year FibroGen announced that they had completed a Phase II clinical trial on the efficacy of FG-4592/ASP1517 — that is, a study of how the drug affected kidney disease patients with anaemia. Thomas B. Neff, Chief Executive Officer of FibroGen said in a statement:

“We continue to see signs of potential therapeutic advantages, including the ability of FG-4592 to effectively treat anemia and to do so safely, by modest increases in erythropoietin levels to within physiologic range, while promoting iron bioavailability.

A month after releasing the results of their Phase II study, in December 2012, FibroGen and Astellas announced they were about to begin Phase III clinical trials on the compound — a trial with greater patient numbers.

In total there have now been seven completed human trials on FG-4592/ASP1517, with three more in progress. The results have so far been encouraging, with patients seeing an increase in haemoglobin levels. In addition, no major side-effects have been reported.

So where to from here?

Well, assuming the various clinical trials continue to show the compound to be safe for human use and of therapeutic benefit for anaemia — a process which could take a few years — we could potentially see FG-4592/ASP1517 approved by various governmental regulatory health authorities for therapeutic use on humans.

Unfortunately in the world of sports doping, many (ab)users do not wait for official approval of drugs. Much like GW1516 and AICAR, a quick online search reveals that FG-4592/ASP1517 is readily available for purchase online, on the grey market, as a “research chemical”. Looking at the online prices for the compound, and assuming an athlete uses the maximum dose tested in the clinical trials — 3.0 mg/kg twice weekly for a month — it would cost the athlete about $3,000 for one cycle of treatment.

Of course, we aren’t suggesting that anyone should do so, nor are we condoning doping in sport. We believe that athletes competing in sports signatory to the WADA Code should, at all times, comply with the rules on anti-doping. Such athletes should therefore be keeping constantly abreast of the science and anti-doping laws to avoid being sanctioned for inadvertent doping violations.

We’d also urge curious athletes who are in pursuit of sporting gains to be wary of experimental drugs not yet clinically approved: long-term side effects are often unknown.

Of course, we recognise the pragmatics of the real world and that in the absence of robust regulation, “research chemicals” are easily available. Sports and anti-doping administrators should therefore be vigilant in keeping their athletes — who may be uninitiated or ill-informed, especially younger athletes — safe, including from themselves.

Further reading:

The new EPO? — GW1516, AICAR and their use in cycling – CyclingTips, April 16 2013
The future of cheating: EPO gene doping – CyclingTips, February 19 2013
Blood doping 101 – CyclingTips, November 29, 2012

Thank you to Dr Benjamin Koh for co-authoring this article. CyclingTips does not advocate or condone the use of performance-enchancing drugs. This article was published with the sole intention of being informative.

This article was first published on CyclingTips on April 24, 2013.

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