In the quest to find an alternative anaemia treatment, Fibrogen has been sitting pretty for some time. With big name partners AstraZeneca and Astellas, and with its hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor roxadustat already in phase III, it had what looked like an unassailable lead over its smaller rival Akebia Therapeutics.
But Akebia’s recent $100m boost, in the shape of a partnership with Mitsubishi Tanabe Pharma, should fund a phase III programme of its HIF-PH blocker vadadustat and give it a shot at approval in what is becoming an increasingly competitive segment (see table below).
Most of the companies involved are working towards a new option for anaemia caused by chronic kidney disease (CKD), which is currently treated with erythropoiesis-stimulating agents (ESAs) like Epogen and Aranesp.
Although these are still blockbusters, serious side effects and resulting black box warnings have dented sales. It is thought that HIF-PH-targeting drugs – which mimic the body’s reaction to high altitude – could provide a less risky alternative. Furthermore, the likes of roxadustat and vadadustat are dosed orally, thereby avoiding the transfusions required with ESAs.
With Astra bagging rights to roxadustat in the US and China in 2013, it looks like attention is now shifting to HIF-PH-blocking agents earlier in development, with Akebia the latest beneficiary of big pharma interest in the field.
As well as up-front development costs, the Mitsubishi deal includes up to $250m in milestones and tiered royalties of up to 20% on sales in Japan, Taiwan, South Korea, India, Indonesia and other Asian countries.
Perhaps just as importantly it also gives Akebia’s project credibility and ould help it attract a partner in Europe, JMP analysts believe – while others think it could make Akebia a takeover target. The company’s share price climbed 7% on Monday and another 13% yesterday.
Akebia has already agreed the Pro2tect phase III programme with the FDA and EMA, and expects to start this by the end of 2015, encompassing two trials involving 3,100 patients with non-dialysis dependent CKD.
The correction study will enrol those not already being treated by recombinant ESAs, while the conversion study will evaluate patients converted from recombinant ESAs to either vadadustat or active control. Primary endpoints include haemoglobin response and major adverse cardiovascular events.
Akebia is also planning the Inno2vate programme in CKD patients undergoing dialysis. Some analysts expect a US launch in both indications as early as 2020.
Vadadustat is still a way behind roxadustat, the first HIF-PH to enter phase III and Fibrogen’s most advanced asset. This is supported by Astra and Astellas, and is being tested in a huge phase III programme involving 10 trials in around 8,000 patients in CKD, in both the pre-dialysis and dialysis settings. Regulatory filings are expected in 2016 in China and in 2018 in the US.
Being a fast follower might not be a bad thing for Akebia, but there are some worrying signs from phase II data, where on the face of it roxadustat seems to have performed better (Fibrogen shoots for the stars as Akebia falls to earth, November 03, 2014).
While 55% of patients receiving vadadustat met the primary endpoint in a phase II trial in non-dialysis dependent patients, a response was seen in 93% of those getting roxadustat in one study. Both endpoints were based on patients achieving or maintaining certain haemoglobin levels.
But on closer inspection Akebia’s trial was more rigorous, including a placebo arm, which Fibrogen’s did not. More worrying was an increase in serious adverse events with vadadustat – although these concerns seem to have been allayed by more recent phase II data in dialysis patients.
Phase III results might give us a better idea of how the two agents stack up, but as usual caution is needed when comparing across trials.
While vadadustat is progressing, other HIF-PH inhibitors have also moved on (Therapeutic focus – Big pharma takes high-level interest in anaemia pills, August 28, 2013).
Bayer has taken molidustat, formerly known as BAY 85-3934, into phase II, putting it on track to become the third drug in the class to get approval.
|Phase III||Roxadustat||Astellas/ AstraZeneca/ Fibrogen||Anaemia in CKD|
|Phase II||Vadadustat||Akebia Therapeutics||Anaemia in CKD|
|Molidustat||Bayer||Anaemia in CKD|
|GSK1278863||GlaxoSmithKline||Anaemia in CKD|
|Anaemia in CKD|
|Phase I||DS-1093||Daiichi Sankyo||Anaemia in CKD|
|FG-6874||Fibrogen||General inflammatory disorders|
But others seem to have stalled. There are still few details available about GlaxoSmithKline’s GSK1278863, but according to clinicaltrials.gov the company has completed several phase II studies in anaemia and is currently carrying out another.
While Akebia is not at the front of the HIF-PH race, it is still in a fairly good position. Positive phase III results could see it battling it out with Fibrogen and Astra – unless it is acquired first.