New anemia drugs could change the steady state of kidney care
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During the last 3 decades, only one class of drugs – erythropoiesis-stimulating agents – has been available to treat anemia in patients with end-stage kidney disease. That has now changed.
Pharmaceutical company GlaxoSmithKline (GSK) has begun marketing Jesduvroq (daprodustat), a new hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for patients with ESKD. The anemia drug, approved by the FDA on Feb. 1, is the first alternative to erythropoiesis-stimulating agents (ESAs) since 1989, when Epogen (epoetin alfa, Amgen) was first approved by the agency.
“Over the last several decades, there has been little innovation in anemia of CKD. We are proud to have developed Jesduvroq as a new oral treatment where there is a patient desire for more options,” Tony Wood, president and chief scientific officer of GSK, said in a press release.
One of the main differences between the HIF-PHIs and the ESAs is the form of delivery: ESAs are injectable, while Jesduvroq and other HIF-PHIs come in a pill form.
“Potential benefits of HIF-PHIs, in addition to their oral route of administration (particularly for patients who are not treated with hemodialysis), include the theoretical advantage of reduced exposure to high peak serum EPO concentrations, as substantially lower peak serum EPO levels have been found in patients treated with HIF-PHIs, compared with the levels in those receiving epoetin injections,” Elaine Ku, MD, MAS, of the division of nephrology, University of California, San Francisco, and colleagues wrote in a report for a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on the potential for HIF-PHIs. “Due to their mechanism of action, HIF-PHIs may enhance enteric iron absorption and iron utilization (unlike ESAs) and may be more efficacious in correcting anemia despite chronic inflammation, although this remains an area of controversy,” the authors wrote.
Anemia and CKD
In clinical trials, GSK and other pharmaceutical companies developing HIF-PHIs had to show that the drug was superior to placebo and/or noninferior to ESAs with regards to efficacy and safety. GSK proved the case for patients with ESKD on dialysis but did not satisfy the FDA with regards to safety for patients with non-dialysis dependent CKD. Various estimates have placed that population at near 37 million patients, all who have some level of kidney disease but do not always have their anemia issues addressed.
The FDA turned down applications from drug companies FibroGen, Akebia Therapeutics and GSK to use HIF-PHIs in patients with non-dialysis dependent CKD because clinical trials showed a higher risk for major cardiovascular events (MACE) in study patients.
“It is ironic that patients with the greatest unmet need for an oral, convenient anemia therapy, namely those with [non-dialysis dependent CKD] NDD-CKD, are the populations in whom safety signals for HIF-PHIs are most apparent, including MACE (in the on-treatment analysis), thrombotic events, infections and seizures with roxadustat; MACE with vadadustat; and MACE (in the on-treatment analysis), esophageal and gastric erosions and cancer-related deaths or tumor recurrence with daprodustat,” Jay B. Wish, MD, wrote in an article in the American Journal of Nephrology about the limited potential of HIF-PHIs (see his interview with Healio | Nephrology News & Issues on page 24). “Despite demonstrated favorable effects on iron metabolism, including reductions in hepcidin, in NDD-CKD and ESKD on [patients on dialysis], HIF-PHIs have yet to prove in a randomized controlled trial they are more effective than ESAs in raising [hemoglobin] Hb levels in the challenging ESA hyporesponsive patients.”
Daniel W. Coyne, MD, a professor of medicine in the division of nephrology at Washington University in St. Louis, said the FDA has “serious safety concerns” about HIF-PHIs in the non-dialysis CKD population, “focused on increased thrombotic events, and possibly misuse of an oral drug,” he told Healio | Nephrology News & Issues. “Other countries’ regulators don’t appear to have these concerns. The FDA is either leading the pack or out of step. Only time may tell who is right.”
In a study lead by Glenn M. Chertow, MD, and colleagues looking at the use of the HIF-PHI vadadustat (Akebia Therapeutics) for patients with non-dialysis dependent CKD, the researchers found the higher risk “was due largely to an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes. We could not identify a reason for the excess in non-cardiovascular deaths,” they wrote. “Adverse events were evenly distributed between the vadadustat group and the darbepoetin alfa group.”
The FDA turned down the drug for both applications, but Akebia recently re-submitted its new drug application for the use of vadadustat to treat anemia in patients on dialysis. Steven K. Burke, MD, chief medical officer and senior vice president of research and development at the company, told Healio | Nephrology News & Issues that the FDA has accepted the application and has set a Prescription Drug User Fee Act date of March 27, 2024, for a final decision on the drug.
“Their initial concern was about a case of drug-induced liver injury from 2014; we have never seen a case like that since,” Burke said. “We had treated thousands of patients in the U.S. and had not seen that, plus the tens of thousands of cases in Japan” of patients who were treated with vadadustat.
Burke said the process for seeking drug approval in the United States vs. other countries does differ.
In Japan, few patients with kidney disease experience cardiovascular events, so none of the HIF-PHI manufacturers had to do MACE trials for approval, Burke said. But he said he was “not aware of any reports or problems” among patients on dialysis in Japan using vadadustat.
Even though HIF-PHI drugs have been approved for use in the non-dialysis dependent CKD population in other countries, it remains unclear if that will occur in the United States, said Coyne.
“I think the overriding issue in NDD-CKD is the FDA doesn’t think anemia treatment is indicated for most patients,” Coyne said. “They state unequivocally in the review [by the Cardio and Renal Drug Advisory Committee] for GSK’s daprodustat that the only benefit is reduced transfusions. Unlike dialysis patients, untreated NDD-CKD patients do not get many transfusions.”
Burke said more research may eventually lead to U.S. approval to treat non-dialysis dependent CKD. “We have learned a lot in this process and in our trials,” Burke said. “Remember that the ESAs have had more experience in treating anemia – since the late 1980s. The [companies] have learned over time how to administer those drugs while maximizing efficacy and minimizing safety issues.
“I think we are still in the early stages of how to dose HIF-PHIs. I have not given up on finding the right dosing for our NDD-CKD patients. It is just going to take some time.”
Soon after the FDA approved Epogen for treating anemia, Amgen signed an agreement with Johnson & Johnson, which had helped to fund Amgen’s research and development for Epogen. That allowed Johnson & Johnson to sell Epogen, renamed as Procrit, to physician practices with patients who were patients with CKD not on dialysis and were anemic from cancer or early stages of kidney disease.
But approving HIF-PHIs for patients not on dialysis has been more challenging, Anatole Besarab, MD, previously executive director of clinical research and development at FibroGen, told Healio | Nephrology News & Issues. “I think the answer is different,” Besarab said. “With ESAs, peak levels and EPO-area under curve can be very high (1,000 mU/mL) and the rapid fall in EPO levels can induce neocytolysis which reduces efficiency,” Besarab said. “[Subcutaneous] SC administration produces lower peak levels (log order) and the decrease in EPO levels is more gradual, leading to persistence of levels for most of the interdialytic period. This minimizes neocytolysis.
“The HIF-PHIs produce even lower peak levels of about 40 [mU/mL] to 120 mU/mL depending on the ‘dustat’ and the dose which also can be maintained longer,” Besarab said.
Safety issues
Coyne points to specific safety issues with daprodustat in the non-dialysis patient population, particularly increased thrombotic events cited by the Cardio and Renal Drug Advisory Committee. “Although none of those event types are significantly higher with daprodustat, they all lean toward favoring the ESA, darbepoetin” for patients with non-dialysis dependent CKD. These concerns – higher CV mortality, heart failure and thrombotic events in the U.S. cohort compared to ESAs in the NDD-CKD patients – also came up with the other HIF-PHI drugs at the FDA.”
For patients on dialysis, HIF-PHIs do have a place in anemia management, Burke said. “I think it’s important to have a choice. Basically, all the ESAs are the same. Patients should have options on treating anemia.”
- References:
- Akebia receives FDA acceptance of resubmission to NDA of vadadustat for the treatment of anemia due to chronic kidney disease. https://ir.akebia.com/news-releases/news-release-details/akebia-receives-fda-acceptance-resubmission-nda-vadadustat. Published Oct. 25, 2023. Accessed Oct. 25, 2023.
- Chertow G, et al. NEJM. 2021:doi:10.1056/NEJMoa2035938.
- Jesduvroq (daprodustat) approved by US FDA for anemia of chronic kidney disease in adults on dialysis. https://www.gsk.com/en-gb/media/press-releases/jesduvroq-daprodustat-approved-by-us-fda-for-anaemia-of-chronic-kidney-disease-in-adults-on-dialysis/#:~:text=GSK%20plc%20(LSE%2FNYSE%3A,have%20been%20receiving%20dialysis%20for. Published Feb. 1, 2023. Accessed Oct. 24, 2023.
- Ku E, et al. Kid Int.2023;doi:10.1016/j.kint.2023.05.009.
- Wish J. Am Jrnl Neph. 2022;doi:10.1159/000523946.
- For more information:
- Anatole Besarab, MD, can be reached at besaraba1943@outlook.com.
- Steven K. Burke, MD, can be reached at sburke@akebia.com.
- Daniel W. Coyne, MD, can be reached at dcoyne@wustl.edu.
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