Patients with severe anaemia, frequently caused by a life-threatening illness like chronic kidney disease or cancer, are faced with few treatment options. This is why the market for erythropoiesis-stimulating agents (ESAs) like Epogen and Aranesp is still worth billions of dollars, despite the products’ serious safety issues and need for transfusion.
Now hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitors – agents that work by mimicking the reaction of the body to high altitude – are emerging as a potential new option. The decision by AstraZeneca last month to pay $350m up front for rights to the most advanced candidate in this class signals that progress is being taken seriously; two other agents are behind in phase II. Safer and more convenient anaemia treatments should be greeted with high demand, and data due in the coming months and years will be closely watched (see table).
Amgen’s Epogen and Johnson & Johnson’s Procrit were launched in 1989, and the market for these and rival ESAs had ballooned to $12bn by 2006. However, by last year the branded market had shrunk to $7.61bn - demand was dented by restrictions on use in cancer and kidney disease prompted by serious safety concerns. In the case of cancer ESAs were linked to blood clots, accelerated tumour growth and reduced survival rates, while in kidney disease it was heart attack and stroke.
All ESAs now carry black box warnings highlighting these risks. In chronic kidney disease, the warning cites risk of death and cardiovascular events when dosed to increase haemoglobin to above 11g/dl – in the past much higher haemoglobin levels were targeted, and patients were given much larger doses of the drugs.
It is now thought that aggressively boosting haemoglobin alone does not cause the problems – the big peaks and troughs in haemoglobin often seen after the otherwise very effective ESAs are administered are now assumed to be doing the damage.
Developers of the HIF-PH inhibitors believe that they will avoid this issue.
Whereas in the case of ESAs synthetic erythropoietin – the hormone that stimulates the production of new red blood cells – is transfused into a patient, HIF-PH inhibitors activate this pathway further upstream. They do this by preventing the breakdown of hypoxia-inducible factors (HIFs), transcription factors that respond to decreases in oxygen, by inhibiting the enzyme prolyl hydroxylase.
Activating these HIFs – as would happen naturally at high altitude, for example – prompts erythropoiesis, of which the production of erythropoietin is one part.
As well as prompting the production of endogenous erythropoietin, this mechanism has the advantage of triggering a much more gradual and controllable rise in haemoglobin levels, says Joseph Gardner, chief executive and co-founder of Akebia Therapeutics, which has an HIF-PH compound in phase IIb.
“With our drug we can control the rise in haemoglobin by dose, and that is an attractive feature that should allow us to avoid the safety issues of Epo,” he says.
“It is much more similar to taking someone up in altitude. And the altitude literature has demonstrated quite clearly that chronic kidney disease patients on dialysis do better at higher altitude; they require less Epo and they have fewer cardiovascular events.”
|Phase III||FG-4592/ASP1517||Astellas Pharma/AstraZeneca/Fibrogen||FibroGen|
|Phase II||YM311/FG-2216||Astellas Pharma/Fibrogen||FibroGen|
|AKB-6548||Akebia Therapeutics||Procter & Gamble|
|Phase I||BAY 85-3934||Bayer||Bayer|
|JTZ-951||Torii Pharmaceutical||Japan Tobacco|
There are three HIF-PH inhibitors in mid to late-stage development; Fibrogen’s FG-4592 is the most advanced, having entered phase III last December. Glaxo’s GSK1278863 has completed three phase II studies in anaemia, according to clinicaltrials.gov, but the company has released few details about its compound.
Oral administration is another big advantage with HIF-PH inhibitors – a pill would be much more convenient, as well as substantially lowering the overall cost of treating an anaemic patient compared with the transfusions required with ESAs. Mr Gardner reckons AKB-6548 will be a once-daily drug; Fibrogen is testing various doses including twice and three times weekly, and GlaxoSmithKline’s compound also appears to be once daily, although again details are scant.
The deal Fibrogen struck with AstraZeneca last month means FG-4592 is now a high-profile asset – the sum the pharma giant agreed to pay for restricted marketing rights highlights the potential.
For $350m in up-front and non-contingent payments and $465m in potential milestones, the company gained rights in the US, China and other markets not included in an earlier deal that Fibrogen had signed with Astellas Pharma. Back in 2006 the Japanese company bought rights for Europe, the CIS, Middle East and South Africa, having secured Japan rights the previous year. It paid $300m up front, and agreed to further milestones of $465m.
Fibrogen and Astellas have already started two phase III studies with FG-4592, one in the US and one in Europe, seeking to recruit 1,050 pre-dialysis patients.
AstraZeneca intends to invest heavily in this project – a company spokesperson says the global pivotal programme it will run will involve eight phase III studies recruiting more than 7,000 patients. Two settings will be tested: the pre-dialysis, chronic kidney disease indication and end-stage renal disease, where patients are undergoing dialysis.
Akebia last month started a phase IIb trial with its candidate, AKB-6548, seeking to recruit 200 chronic kidney disease patients not yet on dialysis. These will be dosed for 20 weeks, the longest study period conducted with the agent so far.
With regulators actively discouraging ESA use in pre-dialysis patients the need for safer, more effective products has grown in the past few years. In fact there are many more pre-dialysis patients who would benefit from an increase in haemoglobin levels than there are patients already on dialysis.
According to figures quoted by Fibrogen, of the 5.6 million later-stage CKD cases in the US, 1.1 million pre-dialysis patients could benefit from a haemoglobin boost. Around 350,000 of the CKD cases are end-stage renal disease patients already receiving dialysis who become anaemic owing to the treatments and for whom the need of ESAs outweighs the risks.
Developers of HIF-PH inhibitors have largely focused on the much bigger pre-dialysis opportunity, where an oral pill also represents a major advance in convenience. But with rich partners on board Fibrogen has already started moving into the dialysis space, and Akebia intends to follow, thanks to a $41m Series C venture round in June.
“If the safety profile on cardiovascular event rate is improved, then we think there would be an opportunity to cannibalise a significant portion of Epo usage,” says Mr Gardner.
Oral administration is certainly a major boon, but it is safety that will ultimately define the market potential of the HIF-PH class, as it did with the ESAs. Phase III data are now eagerly awaited and Fibrogen is likely to report first – it hopes to file in China in 2015 and in the US in 2017 – while Akebia will have results from its phase IIb by late 2014.
As Akebia has the only non-partnered asset in this promising class, much depends on the data readouts in the next couple of years. And although Mr Gardner says the company has had interest, he is biding his time for now.
“We haven’t started looking for a partner; we plan on waiting until we have the results and are phase III ready,” he says.
If longer-terms trials confirm the potential, Mr Gardner should not have a shortage of suitors.