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Akebia crashes on vadadustat flop in larger anemia indication. Will AZ, FibroGen own the market?

What was previously expected to be a three-way battle in the novel HIF-PHI renal anemia drug class now has one man down. Akebia Therapeutics has posted a surprise trial flop, which one analyst said could hand the rival FibroGen-AstraZeneca team an early monopoly of the market.

On Thursday, Akebia said its Otsuka-partnered vadadustat was linked to increased heart risks compared with Amgen’s standard erythropoietin therapy Aranesp in nondialysis-dependent patients with anemia due to chronic kidney disease.

The primary safety flop in the phase 3 PRO2TECT trial shocked Akebia investors, who sent the company’s stock southward by about 75% on Thursday. The failure was unexpected mainly because the drug already boasts an approval in Japan as Vafseo in broader kidney disease-related anemia, and its INNO2VATE dialysis data were positive on every front; the drug even matched up to Aranesp on time to first occurrence of major adverse cardiovascular events.

Calling the vadadustat result a “Goldilocks scenario” for AstraZeneca and FibroGen, SVB Leerink analyst Geoffrey Porges said the pair’s roxadustat could not only head to an early monopoly in the larger nondialysis-dependent indication, but might also squeeze out the Akebia drug in the dialysis population as well.

Traditional erythropoietin-stimulating injections from Amgen and Johnson & Johnson aren’t approved for the less sick nondialysis patients because of their cardiovascular risks. The hope for the HIF-PHI agents is to offer more convenient oral options with hemoglobin-boosting efficacy that’s at least as good—and without the accompanying heart problems.

Previously, pooled phase 3 analyses showed the risk of major CV side effects was comparable between roxadustat and placebo. But vadadustat has now shown it fared even worse than the already risky Aranesp in that department.

“We think today’s data have ended vada’s opportunity in [nondialysis-dependent patients], at least from a commercial standpoint, although Akebia management continued to guide to an alternative path forward in this indication,” Porges wrote in a Thursday note to client.

According to Piper Sandler analyst Christopher Raymond, Akebia management is now looking at subgroup analyses as its potential regulatory next step, though he acknowledged the feeling of a “collective investor-eye-roll” when this proposal was put forward.

Despite vadadustat still having a “credible path forward” in dialysis anemia, shares behaved as if the drug was completely dead, Raymond noted. That may just be the case. To SVB Leerink’s Porges, the nondialysis safety scare is likely to significantly limit the product’s adoption in dialysis, too, since he figures roxadustat will win a broad and clean label.

Roxadustat has already launched in China for both nondialysis- and dialysis-dependent renal anemia, and an FDA decision is expected in December. The drug is also sold in Japan as Evrenzo in the dialysis-dependent population, and FibroGen’s local partner Astellas in January filed for the nondialysis indication.

There’s a third player in the ring, and that’s GlaxoSmithKline’s daprodustat, sold in Japan as Duvroq. It will likely arrive later in the U.S. The primary completion dates of Ascend-D and Ascend-ND, the two global phase 3 trials supporting its FDA filing in dialysis and nondialysis, have been delayed until November 2021 and March 2022, respectively.