Everyone was waiting for a European deal, but in the end Akebia delivered on the US, and with a Japanese partner. Importantly, the collaboration with Otsuka puts in place the financing to complete the large pivotal programme of its anaemia treatment vadadustat, and dangles the prospect of another deal sitting on the horizon.
Akebia has struggled to keep up with Fibrogen in this space, on both partnerships and valuation – both are working on hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitors. With Glaxosmithkline putting the third asset in this class into phase III last month, Akebia has signed on the dotted line in the nick of time (see table below).
Akebia has four phase III trials ongoing, and the bills are racking up – it estimates that the pivotal programme will cost $450-480m but ended September with only $161m in the bank, enough to fund operations through the second quarter of 2017.
This transaction puts concerns about immediate financing to bed. Terms include a payment of $125m up front and a further $35m in the first quarter of 2017, to reimburse for past R&D costs. Otsuka will also pay at least $105m towards the R&D programme over the coming months, while potential payments linked to development and commercial milestones could reach $765m.
The Japanese company gains a 50:50 profit share in the US; the two partners will equally share commercialisation costs.
The attraction to Akebia here is clear: HIF-PH inhibitors will be going after the $6bn EPO market in the US, and marketing clout will be needed. Fibrogen signed up Astrazeneca in 2013in the US and China for its candidate, roxadustat, in a deal that came with a huge $350m up-front payment (Therapeutic focus – Big pharma takes high-level interest in anaemia pills, August 28, 2013).
Japanese pharma companies have shown much interest in this space – Astellas has roxadustat rights in Japan, Europe and a few other regions, while Akebia has an existing deal in place with Mitsubishi Tanabe for Japan and other Asian countries.
Akebia has long been trailing a European deal, and with phase III data unlikely to emerge until well into 2018 this remains an event for investors to stay focused on in the meantime.
Down to the data
Data from Fibrogen’s pivotal programme should start to emerge early next year from trials run in China, and later in the year from US and European studies. Then the real potential of these agents can be assessed, and Fibrogen will effectively be showing its rivals what they have to beat.
These oral drugs work by mimicking the reaction of the body to high altitude, triggering the production of endogenous erythropoietin. They promise to solve a number of the issues associated with the transfusion of recombinant erythropoietin, which alongside the inconvenience of administration include the risk of blood clots, accelerated tumour growth, heart attack and stroke.
The three developers in this space are therefore running trials with major adverse cardiac events (MACE) endpoints, to rule out similar risk of harm. The data have shown no signals so far, but should any emerge this could easily prove fatal for these projects.
The table below shows that their developers have taken different approaches to establish the safety and efficacy of this class. While Akebia, and now Glaxosmithkline, have chosen to use co-primary endpoints and an active comparator, Fibrogen has run more specifically designed studies with single endpoints, as well as running placebo-controlled trials.
Akebia bulls contend that Fibrogen’s clinical programme will generate cumbersome data that are difficult to interpret, and point out that regulators will have to rely on the variability of inter-study comparisons to draw conclusions on cardiac safety.
It is too soon to say whether this will indeed hamper its regulatory progress. But the fact remains that Fibrogen is still a good 18 months ahead of the pack. Akebia deserved the 20% jump in its valuation on the Otsuka deal, but it needs to keep up the pace to stay in this race, with Glaxosmithkline now hot on its heels.
|Key phase III trials for the HIF-PH space|
|Trial name||Patient population and comparator||Endpoints||Primary completion||Enrolment||Trial ID|
|Roxadustat - Fibrogen/Astrazeneca/Astellas|
|-||Dialysis-dependent vs Epogen||Mean change in Hgb||Nov 2016||305||NCT02652806 (China)|
|-||Non-dialysis vs placebo||Mean change in Hgb||Dec 2016||154||NCT02652819 (China)|
|-||Dialysis-dependent vs Epogen||MACE||Feb 2017||1,425||NCT02174731|
|-||Non-dialysis vs placebo||MACE||Mar 2017||2,600||NCT02174627|
|-||Non-dialysis vs placebo||Anaemia correction and maintenance||Jun 2017||600||NCT01750190|
|Himalayas||Newly initiated dialysis vs Epogen||Mean change in Hgb/Hgb response||Jun 2017||750||NCT02052310|
|-||Dialysis-dependent ESRD vs Epogen||Mean change in Hgb||Jun 2017||600||NCT02273726|
|Pyrenees||Dialysis-dependent ESRD vs Epogen/Aranesp||Mean change in Hgb||Jun 2017||838||NCT02278341(Europe)|
|Dolomites||Non-dialysis vs Aranesp||Hgb response||Jul 2017||570||NCT02021318|
|ALPS||Non-dialysis vs placebo||Hgb response and maintenance at weeks||Jan 2018||600||NCT01887600|
|Vadadustat - Akebia/Otsuka/Mitsubishi Tanebe|
|Protect-correction||Non-dialysis EPO naïve vs Aranesp||MACE + mean change in Hgb||Oct 2018||1,000||NCT02648347|
|Protect-conversion||Non-dialysis maintenance vs Aranesp||MACE + mean change in Hgb||Oct 2018||2,100||NCT02680574|
|Innovate Correction||Dialysis-dependent EPO naïve vs Aranesp||MACE + mean change in Hgb||Aug 2019||400||NCT02865850 (US)|
|Innovate-conversion||Dialysis-dependent maintenance vs Aranesp||MACE + mean change in Hgb||Aug 2019||2,200||NCT02892149 (US)|
|Daprodustat - Glaxosmithkline|
|Dialysis maintenance vs Aranesp||Mean change in Hgb||Jul 2018||270||NCT02969655 (Japan)|
|Non-dialysis/Peritoneal Dialysis vs Micera||Mean change in Hgb||Jul 2018||320||NCT02791763 (Japan)|
|ASCEND-D||Dialysis maintenance vs Aranesp||MACE + mean change in Hgb||Apr 2020||3,000||NCT02879305 (US)|
|ASCEND-ND||Non-dialysis vs Aranesp||MACE + mean change in Hgb||Jan 2021||4,500||NCT02876835 (US)|