AstraZeneca, FibroGen's roxadustat hit with tough safety questions in FDA review ahead of key expert meeting

FibroGen and AstraZeneca have been touting a better heart safety profile for their potentially first-in-class anemia drug roxadustat compared with traditional erythropoietin drugs. But in the eyes of the FDA, that’s still up for debate. 

For treating anemia caused by chronic kidney disease, roxadustat’s efficacy isn’t in question, the FDA said in a briefing document (PDF) for an upcoming advisory committee meeting. The “principal issue” that worth discussing is the drug’s safety, staffers said.

The outcome of Thursday’s meeting could give FDA drug reviewers valuable insight into how best to interpret roxadustat’s heart safety profile in the lead-up to the agency’s decision on a label that could ultimately make or break the drug’s blockbuster potential.

In their review ahead of the meeting, FDA staffers flagged concerning evidence of blood clotting—not only when compared with placebo in nondialysis-dependent patients but also when compared against Amgen and Johnson & Johnson’s Epogen/Procrit, “which is itself known to pose these risks,” in dialysis-dependent patients.

The staffers pooled their safety analysis from six phase 3 trials, three each in non-dialysis- and dialysis-dependent patients. On a composite of major adverse cardiac events (MACE), roxa was comparable to Epogen/Procrit in dialysis-dependent patients and comparable to placebo among non-dialysis patients. The marker includes death, heart attack and stroke.

RELATED: FDA slaps AstraZeneca, Fibrogen with last-minute roxadustat AdComm, cuing another delay for anemia drug

Still, the data pointed to an imbalance in MACE that slightly favored the control arm in both subgroups. The FDA tried to explain the seemingly greater imbalance in the nondialysis-dependent trials to higher dropout rates for placebo.

Epogen and Procrit are known to pose serious cardiovascular threats and are therefore not used much to treat less severe kidney disease patients who don’t require dialysis. AZ and FibroGen's roxa is the first in a class of drugs called HIF-PHIs, which induce the production of red blood cells by mimicking a low oxygen environment.

In pursuing the candidate, the companies have argued the med, with its novel mechanism of action, could avoid the heart problem by Epogen/Procrit and could therefore be suitable for more anemia patients.

Industry watchers have previously pegged blockbuster peak sales potential for the drug on the assumption that it could steal market share from the current standard-of-care erythropoiesis stimulating agents and expand into nondialysis patients.

RELATED: FibroGen admits to messing with roxadustat safety data, upending hopes for the AZ-partnered anemia drug

But those hopes took a hit in late 2020 when the FDA delayed its decision with a request for more data analyses. Then the companies unveiled the surprising FDA advisory committee requirement in March.

The most serious setback came in April, when FibroGen acknowledged that it had changed criteria used to analyze heart safety data for roxadustat. The data alternations made the final data appear more favorable for the drug, and the company has yet to outline the culprit in the data doctoring.

Now the FDA staff's targeting of the blood clots problem represents yet another blow to roxa’s blockbuster case. There’s however a silver lining.

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

As the FDA noted in its exploratory analyses, higher rates of hemoglobin were found to be associated with higher rates of thromboembolic events. FibroGen suggests that the information points to a way to reduce safety risks by lowering roxa’s starting dose. The FDA seems open to the idea, saying the theory “seems plausible, but is unproven.”

In addition to the heart problem, the FDA also noted an unexpected signal of serious infections. Staffers also pointed to sepsis as “an obvious concern.”

Overall, there are “too many risks and scenarios that preclude an obvious win” for roxa, Jefferies analyst Michael Yee wrote in a note to investors Tuesday. In their separate notes to investors, both Jefferies analyst Peter Welford and SVB Leerink analyst Geoffrey Porges said the FDA briefing document suggests the agency will likely slap a black box warning for roxa for the risk of thromboembolic events if it approves the drug.

Roxa has been approved in China and Japan under the brand name Evrenzo. After the delay in December, the FDA has yet to set a new decision date for roxa.

Editor's Note: The story has been updated with additional projections from Jefferies' Peter Welford and SVB Leerink's Geoffrey Porges.