FDA panel does not recommend approval of roxadustat for anemia
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After more than 7 hours of discussion, the Cardiovascular and Renal Drugs Advisory Committee of the FDA voted against approval of roxadustat for the treatment of anemia due to chronic kidney disease for patients not on dialysis and on dialysis.
Citing safety concerns, committee members voted 13-1 against roxadustat (FibroGen Inc.), an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PI) inhibitor, for patients with non-dialysis dependent chronic kidney disease (NDD-CKD). The panel also voted 12-2 against approval of the drug in patients on dialysis.
“The safety signal is a concern to the panel,” Julia B. Lewis, MD, chair of the committee and professor of medicine, division of nephrology at Vanderbilt Medical Center, said. “We are empathetic to the patients’ voice, but not at the expense of an unknown safety profile.”
She voted against approval for both indications.
Risk of thrombosis
Committee members heard presentations from FibroGen representatives detailing results of five clinical trials testing performance and safety of the drug against placebo and other erythropoiesis stimulating agents, as well as testimony from patients and nephrologists showing support.
FibroGen executives said trial results showed a higher portion of NDD-CKD patients and DD-CKD patients experienced vascular access thrombosis compared with controls. The advisory panel was receptive to a plan proposed by FibroGen for a new 1-year clinical trial of 10,000 patients to determine if a lower dose of the drug, which would also deliver lower hematocrits, could reduce or eliminate the higher risk of thrombosis.
The panel also discussed the potential value of an oral anemia drug like roxadustat for patients with NDD-CKD and patients who dialyze at home or had a functioning kidney transplant. Likewise, panel members expressed optimism that the HIF-PI inhibitor could be effective in the treatment of anemia in patients on dialysis who have been hyporesistant to other anemia drugs.
“It’s okay to get in through the side door, even if it is only 10% of the population,” Ravi I. Thadhani, MD, MPH, panel member and professor of medicine and dean for academic programs at Massachusetts General Brigham in Boston, said.
Drug approval
FibroGen and its partner AstraZeneca submitted its new drug application to the FDA for roxadustat in December 2019, and the agency announced it had accepted the NDA in February 2020. Days before approval of the drug was expected in December of that year, the FDA called for an advisory meeting to review additional data.
FibroGen also recently announced it had found inaccuracies in its own analysis of the trial results.
“... We became aware that the primary cardiovascular safety analyses included post-hoc changes to the stratification factors,” Enrique Conterno, CEO of FibroGen, said in a press release. “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 (DD) patients and to placebo in non-dialysis dependent (NDD) patients.”
Based on the analysis, however, “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,” Conterno said in the release.
The Institute for Clinical and Economic Review also released a report stating there was insufficient data to show that the HIF-PH inhibitor provided a health benefit over currently available anemia drugs, such as Aranesp (Amgen Inc.).
“If roxadustat gains regulatory approval, the manufacturer should price the drug in alignment with its demonstrated value, which at the current time is highly uncertain given the lack of clarity about overall mortality and cardiovascular outcomes,” according to the report. “In this setting, with significant uncertainty of this magnitude, the manufacturer should set the price lower than treatments with more established evidence and wait until further evidence addresses the uncertainties before seeking a higher price.”
References:
https://icer.org/assessment/anemia-in-chronic-kidney-disease-2021/
Perspective
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As a practicing nephrologist, I was disappointed that the July 15 adverse decision by the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) will further delay the availability of an orally administered agent for the treatment of anemia in CKD.
There is no question there is an unmet need for such an agent, as was so passionately articulated by the patients and physicians who spoke during the public comment portion of the meeting. This is particularly true in the nondialysis-dependent (NDD) anemic patient population for whom travel to clinics to receive erythropoiesis-stimulating agents (ESAs) and IV iron therapy can be particularly burdensome.
Nonetheless, the CRDAC appropriately takes its duty to protect this population seriously and carefully scrutinized the safety data for roxadustat in the NDD and dialysis-dependent (DD) clinical trials.
The discussion by the CRDAC regarding roxadustat clearly sets a precedent for the review of other hypoxia inducible factor (HIF) stabilizer drugs in the U.S. approval pipeline, namely vadadustat (Akebia Therapeutics, Inc.) and daprodustat (GlaxoSmithKline). Top-line major adverse cardiac events (MACE) safety data for vadadustat in global phase 3 trials failed to demonstrate noninferiority to ESAs in the NDD population. Top-line MACE safety data for daprodustat in global clinical trials announced this week showed noninferiority to ESA in NDD and DD populations, but it is clear from the roxadustat proceedings the FDA will examine all safety data, some of which may not be presented at professional meetings or in publications.
Many comments by the FDA and roxadustat CRDAC members reflect a perception that ESAs are dangerous drugs and that any alternative therapy for CKD anemia had better not be less safe than ESAs. If we knew in 1989 what we know now about the safety of ESAs, there’s the possibility that ESAs might not have been approved.
There is also concern that off-target effects of HIF stabilization may lead to unacceptable adverse events and that the approval of these agents should be very cautious. This needs to be balanced against a significant unmet need for a patient-accessible oral therapy for anemia in the NDD and home dialysis populations.
Nephrologists and our patients eagerly await the approval of a relatively safe (acknowledging that no drug is completely safe) oral option for treatment of CKD anemia.
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