FibroGen issued a statement seeking to provide "clarification" about certain data analyses concerning roxadustat, saying the oral HIF-PH inhibitor it is co-developing with AstraZeneca to treat anaemia in chronic kidney disease (CKD) may not have as encouraging a cardiovascular (CV) safety profile as previously thought in some patients. The disclosure, which comes ahead of an FDA advisory panel meeting now tentatively set for July 15, sent FibroGen shares tumbling more than 30% after hours on Tuesday.
The companies are seeking FDA approval of roxadustat, formerly FG-4592, to treat CKD-associated anaemia in both non-dialysis-dependent and dialysis-dependent patients. The filing, submitted in late 2019, was based on a Phase III programme that included more than 8000 study participants, with pooled analyses indicating roxadustat had a similar CV safety profile to placebo among non-dialysis-dependent patients, and had a comparable, or in some cases better, profile than epoetin alpha in patients on dialysis.
However, in the statement released Tuesday, FibroGen CEO Enrique Conterno explained that as the company was preparing for the upcoming advisory committee meeting, "we became aware that the primary cardiovascular safety analyses included post-hoc changes to the stratification factors." FibroGen also for the first time publicly released statistical analyses with the pre-specified stratification factors that had been agreed upon with the FDA, saying that while "the differences in the stratification factors were included in the [regulatory filing], we promptly decided to clarify this issue with the FDA and communicate with the scientific and investment communities."
The primary CV safety endpoint of the pooled analyses was time to first major adverse cardiovascular event (MACE), a composite of myocardial infarction, stroke and all-cause mortality, while secondary CV safety endpoints included time to first MACE+, which besides the MACE components also includes hospitalisation due to heart failure or unstable angina. FibroGen said that based on analyses using pre-specified stratification factors to calculate hazard ratios, "we cannot conclude that roxadustat reduces the risk of (or is superior to) MACE+ in dialysis, and MACE and MACE+ in incident dialysis compared to epoetin-alfa."
However, Conterno stressed "this does not impact our conclusion regarding the comparability, with respect to cardiovascular safety, of roxadustat to epoetin-alfa in dialysis-dependent patients and to placebo in non-dialysis dependent patients," nor has there been any "change in the underlying roxadustat data, or to the efficacy analyses from the Phase III programme." He said "we continue to have confidence in roxadustat's benefit-risk profile," although the company has launched an "internal review to ensure such issues do not occur in the future." For related analysis, read ViewPoints: FibroGen's fumble amplifies roxadustat doubts.
Commenting on the disclosure, Mizuho Securities analysts said that while the new data "still support the benefit/risk profile of [roxadustat], we were surprised by the news and believe this creates higher risk in the near term, and uncertainty around timelines to potential approval."
The oral HIF-PH inhibitor is currently approved in China, Chile and Japan, under the name Evrenzo, for the treatment of anaemia in CKD in non-dialysis dependent and dialysis-dependent adults. Meanwhile, Astellas filed an application for the drug in Europe, which was accepted by the European Medicines Agency for review in May last year.
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