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What Is So Exciting About HIF?

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Daprodustat (GSK1278863) is an oral HIF-PHI that is being developed for treatment of anemia associated with CKD in patients receiving or not receiving dialysis. In the hemodialysis study, the effects on hemoglobin coincided with expected elevations in endogenous erythropoietin but were markedly lower than those in the recombinant human erythropoietin control arm. Importantly, clinically significant elevations in plasma vascular endothelial growth factor (VEGF) concentrations, a potentially concerning off-target effect, were not seen.

Vadadustat, an oral agent also known as AKB-6548, is in development for the treatment of anemia in both nondialysis-dependent and dialysis-dependent CKD patients. In early clinical studies, vadadustat was well tolerated in healthy volunteers and patients with CKD, where it increased reticulocytes, plasma EPO, and Hb levels in a dose-dependent manner. Patients with ESA-resistant renal anemia, who account for 10 percent of ESA users, would be among the biggest beneficiaries of therapy with this class of drugs.

Trial reports demonstrate a notable additional benefit of HIF-PHIs: The drugs reduce or block the inflammatory response that keeps the body from using its own iron stores (e.g., reduction in hepcidin, an inflammatory inhibitor of iron uptake and utilization in the body). Furthermore, there have been no off-target effects reported to date. Although the early data is promising, larger longitudinal phase 3 studies already under way will yield further important therapeutic and safety data. Potential adverse events with these products could, however, include hypertension, acute pancreatitis, nausea, and diarrhea.

As with HIF proteins, HIF-PHIs vary in structure; therefore, they may have "off-target effects" with unintended consequences in the body beyond erythropoiesis. This is a source of potential concern. For example, HIFs can stimulate synthesis of VEGF, a protein that stimulates the growth of new blood vessels. Although the growth of new blood vessels is beneficial in appropriate circumstances, in the presence of malignancy (cancer), VEGF not only increases the blood supply to the tumor but can also potentially facilitate the spread of the malignancy. It is crucial that HIF-PHIs developed to treat anemia be specifically targeted for the individual substrate target, enabling the response (i.e., stimulating red blood cell production) to be singular.

HIF-PHIs represent a promising, novel therapeutic approach to the management of anemia. Roxadustat is anticipated to obtain FDA approval and be available for clinical use within the next 12 months; daprodustat and vadadostat are expected to follow suit in subsequent years. To the field of nephrology, the prospect of such a class of oral agents as HIF-PHIs is exciting, as it may provide expanded benefit in the management of anemia in patients with CKD both on dialysis and those not requiring dialysis (Figure 2).1,2,3,4,5 

FIGURE 2 | HIF mediates responses to hypoxic conditions

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Meet Our Experts

ROBERT J. KOSSMANN, MD, FACP, FASN
Executive Vice President, Chief Medical Officer, Fresenius Medical Care North America

Robert (Rob) Kossmann is executive vice president and chief medical officer for Fresenius Medical Care North America. From 2014 to 2019, he served as senior vice president and chief medical officer for Fresenius Medical Care's Renal Therapies Group, the company's medical equipment and renal pharmaceuticals division. Dr. Kossmann has been instrumental in helping guide the nephrology field through leadership roles, including formerly serving as president of the Renal Physicians Association (RPA); a founding member of RPA's Nephrology Coverage Advocacy Program (now Policy Advocacy Leadership program); a nephrology advisor to the American Medical Association's Relative Value Scale Update Committee; and founder of the New Mexico Renal Disease Collaborative Group. A practicing nephrologist for two decades, Dr. Kossmann trained in nephrology at the University of Washington in Seattle and holds his bachelor's and doctor of medicine degrees from Case Western Reserve University in Cleveland, Ohio.

DIXIE-ANN SAWIN, PhD, MS
Senior Director, Medical Information and Communications, Fresenius Medical Care Renal Therapies Group

With over 15 years of basic science research in neuroscience, genetics, molecular biology, and immunology, Dixie-Ann Sawin leads the Medical Information team for the Fresenius Medical Care Renal Therapies Group. She and her team are responsible for responding to all medical information queries from health care providers across the United States, providing medical and scientific expertise on promotional review committees as well as business and core development teams. Her team also supports pre- and post-market launch education, compiles regulatory and pharmacovigilance reports and publications for peer-reviewed journals, and develops educational content for the renal community through the Advanced Renal Education Program. She also serves as director for the Fresenius PharmD Fellowship and Internship Program.

References

  1. Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis 2016;67(6):912-24.
  2. Akizawa T, Tsubakihara Y, Nangaku M, et al. Effects of daprodustat, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor on anemia management in Japanese hemodialysis subjects. Am J Nephrol 2017;45(2):127-35.
  3. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int 2016;90(5):1115-22.
  4. Holdstock L, Meadowcroft AM, Maier R, et al. Four-week studies of oral hypoxia- inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016;27(4):1234-44.
  5. Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose- ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant 2015;30(10):1665-73.