The use of HIF-PH inhibitors to treat anaemia gained much prominence and the buy-in of big pharma, but now the excitement has had to be put on hold: readout of a massive pivotal programme of the industry’s most advanced asset, Fibrogen’s roxadustat, has been delayed by six months.
The signs had been good, with pivotal trials in China yielding sufficiently decent data for a local filing, and a phase III study in Japan also reading out positively. Fibrogen’s two key competitors, Akebia and Glaxosmithkline, must now wait a little longer to find out how data from their own less cumbersome pivotal trials will compare.
Glaxosmithkline’s daprodustat and Akebia’s vadadustat are in phase III trials that largely comprise co-primary endpoints measuring change in haemoglobin as well as major adverse cardiac events (MACE) (Akebia gets high with second Japanese partner, December 21, 2016).
Fibrogen, meanwhile, took a different tack with roxadustat: seven pivotal studies are under way, four in dialysis-dependent and three in non-dialysis patients, enrolling just under 9,000 chronic kidney disease (CKD) subjects. Only one study measures change in haemoglobin and MACE as co-primary endpoints. Anaemia is seen in CKD because injured kidneys make insufficient erythropoietin (EPO), the cytokine that prompts the bone marrow to make red blood cells.
It is still unclear whether the data will be revealed in one presentation, or as each trial reads out in turn. But at its fourth-quarter financials update yesterday Fibrogen revealed that phase III trials would not read out until the fourth quarter, leading to a regulatory filing in the first half of 2019.
Earlier, Astrazeneca, Fibrogen’s US and China partner, said a US roxadustat filing was planned for the second half of this year, implying study readout in early to mid-2018. MACE studies are event driven, and it was already clear that it was taking longer than expected to reach the prespecified number of MACE events.
HIF-PH (hypoxia inducible factor prolyl hydroxylase) inhibitors aim to mimic the body’s reaction to high altitude, preventing the degradation of HIFα and leading to increased production of EPO. It is hoped that the class could replace EPO-stimulating agents in the dialysis setting and open up the market for non-dialysis CKD patients.
Roxadustat and the other HIF-PH inhibitors are going after an EPO market worth some $6bn a year. However, Fibrogen insists that its asset could be more than just an oral alternative to injectable EPO-stimulating agents, citing its potential to overcome the suppressive effects of inflammation, non-requirement of IV iron co-treatment, and better safety profile.
The dialysis and non-dialysis settings require different standards of proof to be met, Stifel analysts reckon. Dialysis-dependent CKD studies should demonstrate non-inferior efficacy and superior safety versus EPO-stimulating agents, while non-dialysis CKD trials need to show superior efficacy and non-inferiority in safety – in roxadustat’s case versus placebo.
A key point to bear in mind is that Glaxo and Akebia have set a tougher standard, employing active comparators in both settings.
|Roxadustat phase III studies awaiting readout|
|Trial||Design||Primary endpoint||Enrolment target||Sponsor & status||Trial ID|
|Himalayas||Newly initiated dialysis vs Epogen||Change in Hb||900||Fibrogen, enrolment exceeded target||NCT02052310|
|Sierras||ESRD vs Epogen||Change in Hb||820||Fibrogen, enrolment exceeded target||NCT02273726|
|Rockies||ESRD vs Epogen||Change in Hb & MACE||2,100||Astrazeneca, enrolment exceeded target||NCT02174731|
|Pyrenees||ESRD vs Epogen/Aranesp||Change in Hb||838||Astellas, completed enrolment||NCT02278341 (Europe)|
|Andes||Vs placebo||Anaemia correction & maintenance||900||Fibrogen, enrolment exceeded target||NCT01750190|
|Olympus||Vs placebo||MACE||2,700||Astrazeneca, enrolment exceeded target||NCT02174627|
|Alps||Vs placebo||Hb response & change in Hb||597||Astellas, completed enrolment||NCT01887600|
|CKD=chronic kidney disease; ESRD=end-stage renal disease; Hb=haemoglobin; MACE=major adverse cardiac events.|
Read-across from the pivotal programme that led to roxadustat’s filing in China should give Fibrogen hope. In dialysis-dependent patients roxadustat was non-inferior to – and numerically superior to – Kirin’s EPO product. In non-dialysis subjects it comfortably beat placebo in terms of haemoglobin increase and response.
Fibrogen has also pointed to phase II data showing anaemia correction in both patient groups, and to the first phase III study to have been completed in Japan; this showed haemoglobin levels being maintained within a target range in 92.3% of EPO-stimulating agent-naive patients and in 74.4% of subjects converting from EPO-stimulating drugs, with good tolerability.
In addition to Astrazeneca Fibrogen has Astellas as a roxadustat partner, for Japan and the EU. The tie-ups have together made the biotech company $890m in up-front fees, equity investments and milestones, and up to a further $1.7bn could be payable in future milestones.
Akebia has licensed vadadustat to Otsuka and Mitsubishi Tanabe, while Glaxo put daprodustat into phase III in 2016. Astra separately showed its continuing commitment to kidney disease in striking a licensing deal with Ionis last week covering the antisense project IONIS-AZ5-2.5Rx/AZN2373 for $30m up front.
Given the sums involved and the size of the market these agents are playing for, roxadustat’s lead over the competition is not something its developers will want to give up without a fight.