Erythropoiesis-stimulating agents (ESAs) in combination with iron supplementation have been the mainstay of treatment of anemia in chronic kidney disease (CKD) for the past 30 years. While treatment for patients with anemia of CKD with ESAs is highly efficacious, results of clinical trials have shown an association between the use of ESAs with a high hemoglobin target and increased risk of cardiovascular events. The resulting safety concerns have raised interest in development of an alternative therapeutic strategy.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as novel treatments for anemia in CKD. The mechanism of action of HIF-PHIs is stimulation of endogenous erythropoietin production via HIF activation and induction of erythropoiesis. Mai Sughara, MD, and colleagues provided an overview of the future of the agents in Pharmacology & Therapeutics [doi.org/10.1016/j.pharmthera.2022.108272].
To date, at least six small-molecule HIF-PHIs have been developed. Results of phase 3 clinical trials have demonstrated that the effect of HIF-PHIs is noninferior to ESAs. The new agents may offer several advantages over conventional treatment, including an oral route of administration and the ability to raise hemoglobin levels in patients with chronic inflammation.
While many of the phase 3 trials demonstrated that HIF-PHIs were noninferior to placebo or ESAs regarding cardiovascular safety, one of the compounds failed to meet the prespecified noninferiority criterion in non-dialysis-dependent CKD patients. In some studies, another a HIF-PHI appeared to be associated with potential risks for thromboembolic events.
The regulatory agencies of some countries, including Japan and the European Union, concluded that roxadustat, one of the HIF-PHIs in development, had a favorable benefit-risk profile. The US FDA opted not to approve roxadustat due to safety concerns.
“To establish the optimal anemia management for CKD, further studies are needed to evaluate important aspects of HIF-PHIs, such as long-term safety , appropriate hemoglobin target, and the types of patients who would gain benefits from these new drugs,” the researchers said.