FDA Questions Safety of Roxadustat Ahead of AdComm Review



FibroGen and AstraZeneca have been pushing for a better heart safety profile for their likely top-of-the-shelf anemia med roxadustat compared with traditional erythropoietin drugs. However in the eyes of the FDA, that is still up for deliberation.


For treating chronic kidney disease-related anemia, roxadustat’s efficacy isn’t an issue, the FDA disclosed in a briefing document for an upcoming AdComm meeting. The main issue that worth debating is the drug’s safety, staffers disclosed.


The results of Thursday’s meeting could offer FDA reviewers key insights into how best to explain roxadustat’s heart safety profile in the build-up to the agency’s choice of a label that could ultimately make or break the med’s blockbuster potential.


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


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


Yet, the data showed an imbalance in MACE that slightly favored the control arm in the two subgroups. The FDA attempted to interpret the seemingly greater imbalance in the nondialysis-dependent trials to higher dropout rates for placebo.


Epogen and Procrit are considered to pose adverse cardiovascular threats and as a result not approved to treat less serious kidney disease patients who don’t require dialysis. AZ and FibroGen’s roxa is the first in the series of drugs called HIF-PHIs, which induce the production of red blood cells by imitating a low oxygen environment.


In pursuing the candidate, the companies have opined the drug, with its innovative mechanism of action, could avoid the heart problem by Epogen/Procrit and could as a much be suitable for more anemia patients.


Industry analysts have previously put blockbuster peak sales likelihood for the drug on the assumption that it could snatch market share from the existing standard-of-care erythropoiesis stimulating agents and accommodate nondialysis patients.


But those wishes suffered a loss in late 2020 when the FDA delayed its decision with a request for more data analyses. Then the firms launched the surprising FDA AdComm criteria in March.


The most severe setback was in April, when FibroGen affirmed that it had altered criteria used to analyze heart safety data for roxadustat. The changes made the final data look more favorable for the drug, and the company has yet to disclose the culprit in the data doctoring.

Now the FDA staff’s targeting of the blood clots issue represents yet another hit to roxa’s blockbuster case. But there’s a silver lining.


As the FDA remarked in its exploratory analyses, higher rates of hemoglobin were discovered to be linked to increased rates of thromboembolic events. FibroGen is of the view that the information shows a means to minimize safety risks by reducing roxa’s starting dose. The FDA appears open to the idea, noting that the theory “seems plausible, but it is unproven.”

Besides the heart problem, the FDA also confirmed a strange signal of severe infections. Staffers also noted sepsis as a serious concern.


Ultimately, there are “too many risks and scenarios that preclude an obvious win” for roxa, Jeffries expert Michael Yee remarked in a note to investors. In their separate notes to investors, both SVB Leerink analyst Geoffrey Porges and Jeffries analyst Peter Welford disclosed that the FDA briefing document indicates 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 by the regulatory bodies in China and Japan under the brand name Evrenzo. After the delay in December, the FDA has yet to disclose a new decision date for roxa.