Is the much-hyped oral HIF-PH inhibitor class of drugs destined to disappoint?
By rejecting Akebia Therapeutics and Otsuka’s bid for approval of vadadustat, the FDA has swatted away a second HIF-PHI following its denial of FibroGen and AstraZeneca’s roxadustat back in August. Akebia had applied for approval for its medicine to treat anemia due to chronic kidney disease (CKD) in both dialysis-dependent and nondialysis patients.
In issuing its complete response letter (CRL) Wednesday for vadadustat, the U.S. regulator noted safety concerns for drug—including higher risks of thromboembolic events and liver injury.
During a conference call hours after the decision, Akebia CEO John Butler did little to hide his exasperation. After hitting a wall at the agency, the company will have to restructure to cut costs, he added.
“I want to express my extreme disappointment and frustration at this outcome,” Butler said. “Our team is deeply aware of the unmet needs of CKD patients with anemia, and we’re disheartened that we can not deliver a therapeutic that we believe could address those needs.”
With the news, Akebia’s stock plummeted more than 60% on Wednesday.
Butler said Akebia will request a meeting with the FDA. When asked whether an appeal was in the works, Butler said everything was “on the table.”
After the rejection, Piper Sandler analyst Chris Raymond wrote to clients that this is "likely the end of the road for vadadustat development in the US" because his team believes the FDA will want to see more data before a potential approval. Raymond and his team "had long believed" the drug had a "good chance of approval in the dialysis setting," he wrote.
Vadadustat has been endorsed in Japan for both dialysis and non-dialysis patients. Last month, anticipating an approval in the U.S., Akebia expanded its licensing deal with Swiss company Vifor which would have facilitated quick access of vadadustat to CKD patients.
“We believe it is critical that we engage in a discussion with the FDA,” Butler said. “The notification of the CRL came as a surprise, especially with respect to the dialysis patient population. The dialysis data from our global phase 3 clinical development program were clear and consistent. Those trials met both primary and secondary efficacy endpoints and the primary safety endpoint.”
In the study, while more vadadustat patients had thromboembolic events than those on a comparator drug, the overall rate of events was the same—6.6 per 100 patient years.
“You really need to look at the rate of events,” Butler said. “From our perspective it was the new analysis the FDA did. They simply prioritized a different way of looking at the data.”
Another stumbling block Akebia and Otsuka are trying to overcome is a vadadustat patient in a phase 2 trial in 2014 who developed jaundice. The patient was never hospitalized and recovered. In the subsequent phase 3 trial, careful screening of patients prevented another such incident.
“We thought that either of these issues could certainly be handled with putting labeling in, letting physicians understand the data and make a choice with the patients,” Butler said.
Before the pair of recent HIF-PH inhibitor rejections, market watchers had optimism for a drug class with the ability to leverage the body’s natural response to a reduction in the level of oxygen to induce red blood cell production. Scientists hope this mechanism of action can help patients avoid heart-related side effects seen in the current standard-of-care injectable erythropoiesis-stimulating agents, such as Amgen’s Epogen and Johnson & Johnson’s Procrit.
Up next to the plate with a candidate from the HIF-PHI class is GlaxoSmithKline. After success with daprodustat in trials for both dialysis and non-dialysis patients, the company is expected to submit applications for approval in the U.S. and Europe in the first half of this year.
As for Massachusetts-based Akebia, it has a marketed product in liver disease med Auryxia, which generated sales of $142 million last year, an increase of 10% from 2020. But after the rejection of potential blockbuster vadadustat, the company will have to undergo restructuring, Butler said.
“We will be making adjustments to our cost structure to reduce spend while still enabling us to invest in the future,” Butler said.