GSK's daprodustat will have to face FDA expert panel first as oral CKD anemia prospect targets nod that stumped AstraZeneca, Otuska rivals

After slapping down two rival drugs, the FDA has elected to first call its independent expert panel to weigh in on GSK's prospect for chronic kidney disease (CKD) related anemia before it passes a verdict. Side effect concerns will be top of mind for the committee as GSK looks to sidestep safety bruises that knocked its would-be rivals out of the ring.

Now, daprodustat's first FDA reckoning is almost at hand. The regulator has decided to summon its Cardiovascular and Renal Drugs Advisory Committee (AdComm) on October 26 to assess the HIF-PH inhibitor. Akebia and Otsuka’s vadadustat and AstraZeneca and Fibrogen’s roxadustat—both also oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors—received complete response letters in March March 2022 and August 2021, respectively. In fact, roxadustat also faced an AdComm, which voted last July 13-1 against its approval in non-dialysis patients and 12-2 against a green light in dialysis-dependent patients. 

GSK is asking the FDA to approve daprodustat for adult CKD patients with anemia whether they are on or off dialysis--the same label sought out for both vadadustat and roxadustat. The agency in April said it planned to make an approval decision on GSK’s oral contender by Feb. 1, 2023. The FDA isn’t required to follow the decisions made in AdComm meetings, though the agency often does. Outside the U.S., daprodustat is also in the running for marketing authorization in Europe. The med boasts a green light in Japan, where it’s approved as Duvroq to treat patients with renal anemia.

Daprodustat’s application leverages data from the phase 3 Ascend clinical program, comprising five studies that run the CKD gamut. The clutch of trials have shown dapropdustat improved and or helped patients maintain target hemoglobin levels, with a non-inferior safety profile versus standard of care erythropoietin stimulating agents (ESAs) on major adverse cardiovascular events (MACE), GSK said.

In vadadustat's study, while the overall rate of thromboembolic events was the same—6.6 per 100 patient years—more vadadustat patients had such problems than those on the comparator drug. FDA's complete response letter flagged the higher risks of thromboembolic events, as well as of liver injury.

And a few months before roxadustat's rejection, the FDA flagged a link between AZ and Fibrogen’s drug to increased risk of death, blood clots, serious infections and more.

Now, the future of Otsuka and Akebia’s and AstraZeneca and Fibrogen’s scorned drugs looks uncertain. The vadadustat rejection prompted Akebia in April to unveil plans to trim its workforce by about 42% across “all areas of the company.” Akebia and Otsuka’s vadadustat does, however, have an endorsement in Japan, where it’s marketed by local partner Mitsubishi Tanabe Pharma under the Vafseo moniker.

For AZ and Fibrogen, additional studies would be needed for a potential roxadustat resubmission, the FDA said last summer. 

AZ and Fibrogen seem to have not counted out their drug’s chances in the U.S. yet. In November 2021, the partners said they’d scheduled a meeting with the FDA to hash out a potential path forward for roxadustat, which is approved in China, Japan and Europe as Evrenzo.

GSK, for its part, reaffirmed confidence in its med as the first potential oral option for patients with CKD-related anemia when it announced news of the FDA convening an AdComm. Anemia is an “important and frequent” complication of CKD, but it’s often “poorly diagnosed and undertreated” in patients with early-stage disease, such as those who aren’t on dialysis, GSK said in a release earlier this year. Of the more than 700 million CKD patients worldwide, GSK estimates some 14% suffer from anemia.