FDA review committee recommends daprodustat for patients on dialysis
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Weighing the potential benefits for two different kidney patient populations, a review board for the FDA voted 13-3 to approve use of the anemia drug daprodustat for patients with dialysis-dependent chronic kidney disease.
Citing greater risks of adverse events, the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), which reviews select new drug applications for the FDA, also voted 11-5 to not approve use of the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) for patients with nondialysis-dependent (NDD)-CKD.
The committee’s vote is a recommendation to the FDA; the agency has until Feb. 1, 2023, to decide whether to approve use of the drug in either patient groups.
If that occurs, it would be the first orally available treatment for anemia in patients with kidney disease in the United States and the first HIF-PHI — roxadustat, developed by FibroGen and AstraZeneca. The FDA has declined to approve two other HIF-PHIs — roxadustat, developed by FibroGen, and vadadustat, developed by Akebia Therapeutics.
Patient fatigue
During the committee hearing, aired on YouTube and attracting more than 600 viewers throughout the day, members reviewed data presented by GSK on the ASCEND D and ASCEND-ND trials that compared the drug with placebo and the anemia drug darbepoetin alfa (Aranesp, Amgen Inc.). GSK and its investigators, led by Harvard Medical School nephrologist Ajay K. Singh, MBBS, FRCP, MBA, said the oral form of the drug would be more convenient for patients with NDD-CKD and for those on home dialysis. “Fatigue is the major issue that CKD patients complain about,” Singh said during his presentation before the committee.
Kirsten Johansen, MD, a professor of medicine at the University of Minnesota, told the committee that patients with NDD-CKD have a low quality of life because they experience fatigue. “The injection is the only option for anemia treatment, and it can be painful,” Johansen said. “Even when we have an effective treatment, the method of delivery is inconvenient.”
“I understand what it is like to go through this,” Paul T. Conway, a committee member and chair of policy and global affairs for the American Association of Kidney Patients, said. “[Anemia] is a kick in the pants. As the numbers show, this is a condition that is not being treated. It does not offer choice,” Conway, a kidney transplant recipient, said.
With an oral medication, “you can avoid going into a medical center. It’s time out of work, it’s your caregivers time out of work,” he said.
Drug safety
But committee members raised questions about safety issues that surfaced during the clinical trials, including a higher incidence of heart failure, gastrointestinal bleeding and AKI. Those adverse events, however, were elevated in the NDD-CKD group compared with the DD-CKD group.
“Heart failure is a serious event,” Milton Packer, MD, a cardiologist and committee member, said during the hearing. Trial data showed that the risk of heart complications was primarily in patients who already had experienced heart failure, the committee said.
Members, however, said they approved the drug for DD-CKD because trial results showed a lower risk of such events in that patient group and nephrologists and kidney care staff could monitor patients more effectively in the dialysis clinic vs. patients with NDD-CKD.
“These patients are highly monitored and highly watched” in the dialysis clinic, Leslie S. Cho, MD, a committee member, said after the vote.
“I believe the benefits outweigh the risk; I think the risks can be managed,” Ravi I. Thadhani, MD, MPH, a committee member who voted to approve use of the drug in patients with DD-CKD, said. “I think this is the kind of drug that can change the way we practice.”
“I think the choice [of anemia treatment] makes patients stronger,” Conway said after the vote, suggesting patients on in-center dialysis may want to choose an oral form of anemia treatment. “It helps patients on dialysis by providing more choices.”
Christopher Corsico, senior vice president of development for GSK, said in a statement to Healio: “Today’s robust discussion was an important step in the review of daprodustat. We are pleased the committee recognized the potential for daprodustat to help certain patients who are living with anemia of CKD given limited treatment options.”
He added, “We look forward to continuing to work with the U.S. FDA as they complete their review of our new drug application.”
References:
Meeting of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-contact-information-october-26-2022-meeting-cardiovascular-and-renal-drugs-advisory. Accessed Oct. 26, 2022.
Perspective
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Although the final decision regarding approval of daprodustat for treatment of anemia in patients with kidney disease is yet to come, it seems unlikely that the FDA will disagree with the Cardiovascular and Renal Drugs Advisory Committee.
The committee, consisting of cardiologists, nephrologists, statisticians and consumer/patient representatives, voted no on approval of the HIF-PHI daprodustat for patients with NDD-CKD and voted yes on approval of daprodustat for patients with DD-CKD.
The main reasons against the approval for patients with NDD-CKD were the increased risk for hospitalization for heart failure, gastrointestinal (GI) bleeding and AKI when compared with erythropoiesis-stimulating agents (ESAs).
The hospitalizations for heart failure occurred primarily among patients with a previous history of heart failure, and the sponsor, GSK, proposed a risk mitigation strategy in such patients to restrict use of the agent and/or provide more intensive monitoring. Despite a higher incidence of GI bleeding among NDD-CKD patients treated with daprodustat vs. ESAs, there was no higher incidence of transfusion, and despite a higher incidence of AKI, there was no increased rate of CKD progression nor initiation of dialysis vs. ESAs.
Blood transfusions
GSK emphasized the unmet need for a more accessible anemia treatment among patients with NDD-CKD given data that blood transfusions exceed ESA use in this population, particularly among historically underrepresented and economically disadvantaged patients who may have difficulty traveling to a clinic to receive ESA injections. Nonetheless, most of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) members did not think the risks outweighed the benefit of more accessible anemia treatment.
In DD-CKD patients, the unmet need is not as compelling, but the expanding percentage of patients on home dialysis provides a basis for preferring the use of an oral anemia agent to ESAs. The safety signals of heart failure and GI bleeding were not as strong as in the NDD-CKD patients treated with daprodustat, so the risk/benefit ratio was thought to be favorable.
An interesting finding was that the incidence of vascular access thrombosis (VAT) was 20% lower among patients treated with daprodustat vs. ESAs; this reached statistical significance and could provide a rationale for using daprodustat in in-center hemodialysis patients with a high risk of VAT.
Cardiovascular risk
Several members of the CRDAC noted that the increased cardiovascular safety signals among NDD vs. DD-CKD patients is a pattern that also occurred with HIF-PHIs roxadustat (FibroGen and AstraZeneca) and vadadustat (Akebia Therapeutics). The reason for this is not understood, as a cardiovascular safety signal would be expected to occur with greater frequency in the population with a higher rate of background cardiovascular events, such as patients with DD-CKD. Several members of the CRDAC questioned whether these findings are a “class effect,” but GSK staff maintained that daprodustat has different pharmacokinetics and target specificity from other agents in the HIF-PHI class and should be judged on its individual results.
Roxadustat failed FDA approval due to issues with seizures, infections and thromboembolic disease (including VAT in patients on dialysis) that were not seen with daprodustat. Vadadustat failed FDA approval due to drug-induced liver injury (also not seen with daprodustat) and thromboembolic disease, as well as failure to achieve prespecified outcomes for major adverse cardiovascular events in the intention-to-treat analysis for NDD-CKD patients, which daprodustat did achieve. These differences in safety outcomes seem to reinforce the non-interchangeability of these agents.
The persistence of a lack of oral alternative to ESAs for the treatment of anemia in the NDD-CKD population reinforces the importance of using existing therapies in a manner that accounts for patient choice and lifestyle, barriers to care, symptoms and transfusion risk. Early detection of anemia with regular screening of patients with stage 3 or greater CKD; treatment of reversible factors, such as iron deficiency; use of longer-acting ESAs if available and assisting patients to overcome logistical barriers to ESA treatment can improve anemia management, decrease transfusions and often decrease symptoms.
Given the fact that daprodustat appears, for the most part, no less safe than ESAs in DD-CKD patients and that it might decrease VAT, its use as an alternative to ESAs when ESAs are not working makes sense. That is the nice thing about having choices.
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