After FibroGen's FDA rejection in anemia, Akebia CEO aims to seize first-in-class opening with vadadustat

In the race for novel oral drugs to treat anemia of chronic kidney disease, AstraZeneca and FibroGen’s roxadustat held the front-runner position for quite some time. But as that program has now stumbled, rival Akebia Therapeutics sees a first-in-class opportunity for its underdog vadadustat.

Despite roxadustat’s recent FDA rejection, Akebia remains confident its Otsuka-partnered vadadustat can at least get an FDA approval in patients who are dependent on dialysis, CEO John Butler said in an interview.

Still, after roxa’s FDA rejection, Akebia has some convincing to do. As the company’s stock performance suggests, investors seem to believe that vada will follow a similar path to roxa and ultimately be turned away by U.S. drug regulators. Akebia’s stock price was nearly halved in July and hasn’t recovered since.

Akebia's vadadustat has already won approval in Japan for anemia from chronic kidney disease in both dialysis-dependent and nondialysis-dependent patients. The company’s local partner Mitsubishi Tanabe Pharma is selling the drug there under the brand name Vafseo. If eventually approved by the FDA, vadadustat would be the first in the HIF-PH inhibitor to enter the U.S. market.

Is heart safety a classwide problem?

HIF-PHIs, a drug class that includes roxa and vada, leverage the body’s natural response to a reduction in the level of oxygen to induce red blood cell production. Scientists hope this novel mechanism of action can help patients avoid the dangerous heart-related side effects seen in the current standard-of-care injectable erythropoiesis-stimulating agents (ESAs), such as Amgen’s Epogen and Johnson & Johnson’s Procrit.

RELATED: Surprise, surprise: AstraZeneca and FibroGen's once-hyped anemia drug roxadustat hits an FDA wall

But in a stunning revelation earlier this year, the FDA linked roxa to increased risk of blood clots, death, serious infections and other complications compared with erythropoietin therapy in the dialysis population and with placebo in nondialysis-dependent patients. The safety concerns prompted a key FDA advisory committee to vote against a potential approval, and the FDA rejected the drug last week.

About a year ago, vada also failed on a safety marker of a composite of heart-related events when compared with Amgen’s ESA Aranesp in healthier, nondialysis-dependent patients in the phase 3 Pro2tect trial. That flop, paired with roxa’s safety signal, made many market watchers believe HIF-PHIs share the same heart safety problem.

Akebia begs to differ.

“We obviously don’t think that there’s a class-wide issue here,” Butler said. As the CEO pointed out, vada matched up to Aranesp in the dialysis-dependent population in the phase 3 Inno2vate study on the major adverse cardiovascular event (MACE) marker, which includes death, heart attack and stroke. Some of the safety problems that cropped up in roxa’s trial, including thromboembolic events, seizures and serious infections, weren’t seen in vada’s program, Butler noted.

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

For roxa, the FDA and FibroGen suspect that the blood clots might be related to a hemoglobin overshoot. While the hemoglobin overreaction could theoretically be managed by lowering the drug’s dose, the FDA still need hard data to show that doing so could solve the cardiovascular safety problem. In vada’s phase 3 trials, the drug instead showed a more “gradual increase” in hemoglobin, Butler pointed out. 

Close communication with the FDA

Butler’s confidence in vada’s approval also comes from the fact that the company designed vada’s registrational trials while in dialogue with the FDA. As the agency expressed concerns about hemoglobin overdrive and its potential risks, Akebia lowered vada’s starting dose to 300 mg once daily from the 450 mg strength used in its phase 2 trial.

Akebia CEO John Butler (Akebia Therapeutics)

Still, even though Akebia may have run vada’s clinical program under the FDA’s advice, the agency lately has become somewhat unpredictable. Just a few days ago, the FDA rejected Adrelyx's chronic kidney disease prospect tenapanor even though the drug hit all of the clinical endpoints agreed upon by the FDA. Plus, the agency convened roxa’s advisory committee meeting late into its review, surprising industry watchers.

Butler noted that vada’s application is under consideration at the FDA’s non-malignant hematology division, which is different team than the tenapanor review group. On a potential advisory committee meeting, the CEO said the company is preparing for that possibility even though the agency said it didn’t expect one. The drug is set for an FDA decision by March 29, 2022.

RELATED: GSK's Duvroq, Akebia's Vafseo win global first nods in Japan to challenge Astellas' anemia drug

As for the nondialysis population, Butler said Akebia is “more cautious” about its drug’s approvability in those patients given the negative phase 3 data. Still, the eight-year Akebia veteran sees a window for vada to score a go-ahead in that use.

In the Pro2tect trial, vada matched up to Aranesp on the MACE endpoint in nondialysis patients in the U.S., who made up about half of the trial participants, the CEO pointed out. The different outcome in ex-U.S. patients might be caused by inconsistent clinical practices for managing nondialysis patients in different parts of the world, he said.

From competition underdog to first-in-class opportunity

An FDA approval based on subgroup analysis is never a certainty at the FDA. Analysts at BTIG, Cantor Fitzgerald, Mizuho and Piper Sandler all figured vada can win over the FDA in the dialysis population but that it’s not likely in nondialysis patients.  

Even so, a limited nod would crown vada the first HIF-PHI to land on the U.S. market. That’s good enough to get analysts excited over vada’s commercial potential, especially since the drug was once thought to not stand a chance against then first-in-class candidate roxa.

After roxa’s thumbs-down at the advisory committee in July, Cantor’s Alethia Young said vada’s peak sales in U.S. dialysis patients could reach $1.2 billion, assuming a market penetration of 40%. Piper Sandler’s Christopher Raymond has put the drug’s 2025 sales at $629 million worldwide. BTIG’s Bert Hazlett has calculated nearly $500 million U.S. dialysis sales for that year.

Although roxa isn’t getting to the U.S. market in the foreseeable future—if ever—AZ and Daiichi are exploring next steps after the rebuff. And a third player isn’t far off.

RELATED: While FibroGen and AstraZeneca stumble, cheeky GSK drops competing data for anemia drug

GlaxoSmithKline last June snatched a Japanese nod for its HIF-PHI candidate daprodustat under the brand name Duvroq for patients regardless of their dialysis status. In July, the British pharma touted topline data from its global phase 3 program dubbed Ascend. In the study, dapro was non-inferior to ESAs on MACE for both dialysis and nondialysis groups.

GSK’s topline message at least refuted the notion that heart safety represents a class concern for all HIF-PHIs, Butler said. As for the potential threat from this fast follow-up, the Akebia CEO said he looked forward to seeing detailed data to make a judgment.

In the U.S. and EU, Akebia has partnered with Otsuka. The two firms are currently working through the details of the marketing strategy and the split of responsibilities, Butler said.

In addition, Akebia in 2019 expanded a licensing deal with Vifor Pharma to provide vada to the Fresenius Medical Care dialysis clinics and other third-party dialysis organizations in the U.S. The collaboration gives vada access to up to 60% of U.S. dialysis patients, Akebia says.

Editor's Note: The story has been updated in the second paragraph to show that Akebia's confidence for vadadustat is in patients who are on dialysis.