HIF-PH Inhibitors: A New Hope for Renal Anemia?

Contributors : Jihan Khan, Ph.D. : Principal Business Insights Analyst

Publish date: 17 Aug, 2018

The renal anemia market does not have a wide variety of drug classes available for improving and maintaining patients’ hemoglobin (Hb) levels. However, a new class of drugs is on the horizon.

Overview of Renal Anemia Management

Chronic kidney disease (CKD) can lead to reduced levels of erythropoietin, a cytokine that stimulate red blood cell (RBC) production. Consequently, patients with CKD can develop renal anemia. The disease is currently managed using oral or intravenous iron supplements and erythropoiesis-stimulating agents (ESAs), which are heavily prescribed. Nephrologists commonly initiate renal anemia treatment with supplemental iron prior to ESAs because subphysiological iron levels limit the efficacy of ESAs. The severity of CKD dictates the choice of renal anemia therapy. Chronic kidney disease-nondialysis (CKD-ND) patients with renal anemia are initially treated with oral iron therapies. Intravenous (IV) iron therapies are typically prescribed in the second-line, and ESAs are prescribed as third-line therapy when CKD worsens. Dialysis patients are usually put on IV iron therapy, followed by ESAs if IV iron fails to achieve and maintain target Hb levels.

Concerns around ESAs

ESAs are generally extremely efficacious, but there is evidence that a subset of patients does not respond to treatment even at high doses.1 In addition, several studies have shown that use of ESAs may lead to higher rates of cerebrovascular and cardiovascular (CV) events and mortality.2 In addition to these safety concerns, interviewed nephrologists frequently lament the need for more convenient and cost-effective therapies. ESAs are administered either intravenously or subcutaneously, and these are not ideal options for patients with CKD who do not require dialysis. There is also a tough reimbursement environment for ESAs as the high prices of these agents often provoke access restrictions, such as prior authorization (PA), which present a challenge to prescribers. PA requirements typically decrease as patients progress to requiring dialysis, but cost controls in dialysis centers also raise uncertainty for ESAs. Physicians frequently report pressure from their dialysis chains to use less ESA, to use more iron at the expense of ESAs, and to use lower ESA doses.

HIF-PH inhibitors: a new hope?

Due to these safety, delivery, and affordability concerns, interviewed nephrologists consistently express a strong need for alternative treatment options. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors are a novel drug class in development for treating renal anemia. The HIF system moderates the body’s response to hypoxia, inducing angiogenesis and a shift toward anaerobic metabolism. While oxygen levels are normal, HIF-PH rapidly metabolizes HIF, but when oxygen levels are reduced, HIF-PH activity is curbed and HIF stimulates EPO production, increased iron uptake, and maturation of RBCs.3 Consequently, inhibition of HIF-PH could provide an alternative treatment for anemia and may protect against damage related to ischemia-reperfusion injury.

Several companies are developing HIF-PH inhibitors for the treatment of renal anemia in both dialysis and CKD-ND patients. Although no agent in this drug class has yet to complete a Phase III trial, available clinical trial data suggest that HIF-PH inhibitors offer a number of advantages over ESAs, the mainstay therapy for renal anemia in dialysis and CKD-ND patients.

HIF-PH inhibitors are small-molecule agents rather than complex biologics, and they are administered orally. Although HIF-PH inhibitors are not expected to be significantly more efficacious than ESAs in increasing Hb levels, they are expected to have considerable uptake, particularly in ESA hyporesponders and in the CKD-ND population. The prospects for addressing safety are also promising. To date, the HIF-PH inhibitor class has not posed any serious safety concerns. However, it is important to note that the CV risk associated with ESAs was not discovered until after the drugs had reached the market. Some nephrologists expressed concerns about the lack of understanding or familiarity with HIF-PH inhibitors and the expected high price tags may produce roadblocks for uptake.

Overall, nephrologists view these HIF-PH inhibitors with excitement but conveyed concerns regarding long-term safety due to the absence of more-comprehensive clinical trial data, pricing, and, access. A favorable reimbursement environment for these agents is going to be critical for uptake given the long-standing history of ESAs and imminent availability of biosimilar ESAs.

References:

  1. Solak Y, et al. Novel Masters of Erythropoiesis: Hypoxia Inducible Factors and Recent Advances in Anemia of Renal Disease. Blood Purification. 2016;42(2):160-7.
  2. Biggar P and Kim GH. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. Kidney Research and Clinical Practice. 2017 Sep;36(3):209-223.
  3. Gupta N and Wish JB. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD. American Journal of Kidney Disease. 2017 Jun;69(6):815-826.

DRG products associated with this blog:

Renal Anemia | Current Treatment: Physician Insights | US provides a deep dive and longitudinal information on the renal anemia market dynamics. It examines the management of dialysis and mid-to late-stage chronic kidney disease patients from the perspective of 100 nephrologists. How is renal anemia being treated in the US today, and what are the factors behind those treatment decisions?

Renal Anemia | Access & Reimbursement | US examines the market access factors that influence success of therapies for the treatment of renal anemia. This content is based on primary research data with 100 US nephrologists and 30 MCO pharmacy and medical directors. This research explores how payers and physicians interact and how reimbursement decisions impact the prescribing and uptake of specific therapies at the brand level.

Renal Anemia | Disease Landscape & Forecast | G7  includes a summary of disease etiology, pathophysiology, and drug targets; annualized epidemiological projections, including estimates of diagnosis and/or drug-treatment; a deep examination of current therapies and medical practice; a review of top unmet needs; a thorough pipeline assessment, including launch timing, positioning, and peak sales of key late-phase drugs; a topline review of pertinent market access themes; and an epidemiology- based, bottom-up market forecast with supporting tables, figures, and methods.

 

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