FibroGen's roxadustat was dreaming of being the first-in-class hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) for treatment of chronic kidney disease (CKD)-related anemia. FibroGen submitted its new drug application to the US Food and Drug Administration (FDA) in December 2019 and suggested roxadustat safety was comparable to placebo and comparable or superior to erythropoiesis-stimulating agents (ESAs) in its global trials.
The dream became a nightmare at the July 15, 2021, FDA Advisory Committee meeting, where a panel of 14 experts overwhelmingly advised against approval of roxadustat for use in anemic non-dialysis or dialysis patients. The FDA is not required to follow the panel's advice.
An April 6, 2021, FibroGen press release presaged trouble at the FDA. The company disclosed that the roxadustat safety data touted since 2019 were wrong, and roxadustat was not superior in any population. Additionally, primary hazard ratios and 95% confidence intervals for major adverse cardiovascular events were moved perilously higher.
Data at the FDA Advisory Committee meeting showed that roxadustat was clearly efficacious for treating anemia, but roxadustat had numerous safety signals including increased thromboses, seizures, major infections, and even higher mortality. Perhaps recognizing that the safety issues were a major problem, FibroGen preemptively proposed that the roxadustat label should recommend a lower hemoglobin target of 10–11 g/dL and a lower roxadustat starting dose than employed in any of the phase 3 trials. The expert panel rejected that those changes would ensure greater safety and opposed approving roxadustat, with votes of 1-13 for non-dialysis CKD and 2-12 for dialysis-dependent CKD.
The next HIF-PHI up for consideration for FDA approval is Otsuka and Akebia's vadadustat, which had significantly higher major adverse cardiovascular events compared to ESAs in the non-dialysis CKD population.
