The loss of microvasculature that occurs in chronic kidney disease (CKD) reduces blood perfusion and therefore oxygen delivery to renal tissues, creating an increasingly hypoxic environment. This hypoxia, and the activation of hypoxia-inducible factor (HIF), may represent an early stage—and a potential initiating factor—in the fibrosis and inflammation that occur in CKD patients. Several companies (FibroGen, AstraZeneca, Astellas, Akebia, GlaxoSmithKline, and Bayer) are developing hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors. These small molecule agents are being investigated primarily for their effect on anemia associated with CKD. HIF-PH inhibitors have the potential to provide a safe, orally dosed alternative to erythropoietin-stimulating agents (ESAs), which are associated with an increased risk of CV events and must be given via injection. Although no agent in this drug class has yet completed a Phase III trial, early stage clinical trial data suggest that HIF-PH inhibitors could offer a number of advantages over ESAs, the mainstay therapy for anemia in dialysis and chronic kidney disease-nondialysis (CKD-ND) patients.

The most advanced agent in the HIF-PH inhibitor class is FibroGen/AstraZeneca/Astellas’ roxadustat, which is the subject of several long term Phase III trials targeting both CKD-ND and dialysis patients. FibroGen and AstraZeneca share marketing rights to roxadustat in the US, and Astellas has licensed rights in Europe and Japan. Phase II studies in CKD-ND patients and dialysis patients in the US and Europe have been completed.

Nephrologists interviewed by Decision Resources Group consistently express a strong need for alternative agents for treating renal anemia. These nephrologists view HIF-PH inhibitors to be efficacious in increasing hemoglobin levels from baseline, but they express concern about the lack of long-term safety data. In clinical trials of HIF-PH inhibitors to date, no signals or trends have been observed that suggest HIF-PH inhibitors increase cardiovascular (CV) risk. However, the CV risk associated with ESAs was not discovered until after the drugs had reached the market. Because of the lack of long-term safety data, interviewed nephrologists remain reserved about the safety profile of HIF-PH inhibitor agents, particularly given their previous experiences with ESAs. Although nephrologists are cautious in the absence of more comprehensive clinical trial data, they are largely enthusiastic about HIF-PH inhibitors’ potential. Nephrologists express interest in this drug class because it may offer a safer, more convenient alternative to ESAs, which dominate anemia treatment. ESAs’ high price and intravenous/subcutaneous administration mean that an alternative therapy for anemia with comparable efficacy would likely perform well. However nephrologists cautioned that a high price will likely limit access to these agents.

According to Decision Resources Group’s Current Treatment report1 on renal anemia, nephrologist interest in HIF-PH inhibitors to treat renal anemia has increased over the last year. In addition, nephrologists believe that significantly more of their dialysis patients are candidates for these agents compared with last year. Decision Resources Group’s Access & Reimbursement report2 on renal anemia suggests that assuming availability, nephrologists expect HIF-PH inhibitors to capture over one-third of their renal anemia patients. In addition, one in three nephrologists reported they would prescribe HIF-PH inhibitors over ESAs in their CKD-ND patients due to its less invasive route of administration.

In our Access & Reimbursement study2, payers reported that they employ a wide range of measures to control access to renal anemia therapies such as the premium-priced ESAs. Payers quoted prior authorization (PA) as the main control across ESAs. However, PA can be overcome as payers generally want to ensure that drugs are used according to the FDA label and are prescribed by specialists. Similar to the ESAs, assuming approval, PA is expected to be the most likely cost control measure implemented for HIF-PH inhibitors, followed by duration restrictions and step therapy. According to the surveyed payers, the rate of uptake for these agents will be broadly dependent on its formulary tiering, and the main market access challenge HIF-PH inhibitors will face is an anticipated high price compared with ESAs—and thus unfavorable tiering. However, two-thirds of payers indicate they would place HIF-PH inhibitors on tier 1 if priced at a 20% discount to ESAs.

Formulating a pricing strategy will be crucial to ensure market access, secure reimbursement, maximize uptake, and realize commercial potential for emerging HIF-PH inhibitors. Surveyed payers are receptive to drugs that can help reduce overall healthcare costs. Thus, emphasis should be placed on demonstrating cost effectiveness. In addition to cost, demonstrating efficacy benefits versus established renal anemia therapies such as ESAs and establishing CV safety will also be key for market uptake of novel HIF-PH inhibitors as these would positively affect prescription and formulary placement of this emerging drug class.

 

1 Decision Resources Group’s CurrentTreatment® Renal Anemia Q2 2016 (US) report, published in June 2016, provides a deep dive into, and longitudinal information on, the renal anemia market dynamics. It examines the management of dialysis and mid-to late-stage CKD 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? Also included in this content are sales and messaging efforts of key market players and coverage of late-stage products for the treatment of renal anemia.

2 Decision Resources Group’s Access & Reimbursement® Renal Anemia 2016 (US) report, published in May 2016, 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 managed care organization (MCO) pharmacy and medical directors. This research explores how payers and nephrologists interact and how reimbursement decisions impact the prescribing and uptake of specific therapies at the brand level.

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