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Committee members raised safety concerns about FibroGen/AstraZeneca’s oral therapy roxadustat.
The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted on Thursday July 15, 2021, against recommending approval for roxadustat for anemia in patients with chronic kidney disease (CKD). The committee voted 12-2 against approval in patients who are on dialysis and 13-1 against approval in patients who not on dialysis.
Safety issues were the biggest concern raised committee members. “I think we all felt challenged by the unmet need for alternatives in this population, but the safety concerns outweigh the desire to help meet the unmet need,” said committee member Julia B. Lewis, M.D., speaking specifically about patients who are on dialysis. “Those who voted 'no' are concerned about the adverse safety signal.” Lewis is professor of medicine at Vanderbilt University School of Medicine in Nashville.
"While we are disappointed with today's outcome, we believe the scientific evidence supports roxadustat approval in the United States and will work with the FDA as it completes its review of the New Drug Application for roxadustat," Enrique Conterno, chief executive officer of FibroGen said in a statement.
Roxadustat is hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) to market to treat anemia in patients with CKD. HIF-PHI drugs aim to restore production of the hormone erythropoietin and improve iron regulation; currently, the condition is treated by injections of epoetin alpha and darbepoetin alpha.
This application has had a rocky journey. Fibrogen submitted the New Drug Application for roxadustat tablets in December 2019 for the treatment of anemia associated with CKD in both dialysis-dependent and non-dialysis-dependent patients. The PDUFA date was March 20, 2021, which was already an extension from the original PDUFA date of December 20, 2020. This time agency officials asked for an advisory committee to review the NDA.
According to documents from the FDA ahead of the meeting, agency officials believed the data showed roxadustat demonstrated efficacy. The concern, agency official said, was the hemoglobin overcorrection especially in non-dialysis-dependent patients. Although data submitted demonstrated it was effectiveness in increasing hemoglobin levels, roxadustat tends to overshoot targets in patients who are non-dialysis-dependent.
For example, in study 610, which compared roxadustat and dabepoetin alfa, hemoglobin increased more rapidly in patients treated with roxadustat. In study 613 comparing roxadustat and erythropoiesis-stimulating agents (ESAs) hemoglobin was once again higher.
Regulatory officials indicated the relation to risk is uncertain.
Fibrogen officials presented an overview of the roxadustat, saying it corrects and maintains hemoglobin across a spectrum of patients by mimicking natural response to low oxygen. Cardiac safety was comparable to placebo in non-dialysis-dependent patients and comparable to epoetin alfa in dialysis-dependent patients.
Regarding safety, at the request of the FDA, the company conducted two large studies and did a meta-analysis of cardiac safety. Major adverse cardiac events (MACE), a composite endpoint of all-cause mortality, stroke, and myocardial infarction, was the primary safety endpoint, as well as MACE+, which evaluated MACE plus hospitalization for heart failure or unstable angina.
Fibrogen presented data for these two studies, but also included an analysis of study 613, and the three studies showed cardiac risk was comparable to placebo among non-dialysis patients. Among dialysis-dependent patients, roxadustat was comparable to epoetin alfa.
The inclusion of stratification factors not previously reported was another sticking point for regulators. FibroGen included this data in addition to data from stratification factors previoulsy reported at the American Society of Nephrology conference in November 2019.
Company officials said this didn’t change the underlying roxadustat data or to the efficacy analyses from the phase 3 program. “It is important to emphasize that 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. We continue to have confidence in roxadustat’s benefit risk profile,” Enrique Conterno, chief executive officer of FibroGen, said in a statement in April.
FibroGen officials said more than 8,000 patients from six pivotal studies were treated with roxadustat. These include studies of both dialysis-dependent and non-dialysis dependent patients. The pre-specified primary efficacy endpoints were met in each individual study. Regarding safety, roxadustat was comparable to Epogen/Procrit in dialysis-dependent patients and comparable to placebo among non-dialysis patients.
Roxadustat has been approved for dialysis-dependent and non-dialysis-dependent patients with chronic kidney disease in China since 2018 and 2019, respectively, and in Japan since 2019 and 2020, respectively.