HIF Stabilizers: Will They Have a Place?

Hypoxia-inducible factor prolyl-hydroxylase inhibitors (commonly known as HIF stabilizers or PHIs) belong to a new class of orally administered drugs to treat anemia in patients with CKD.

Hypoxia-inducible factor (HIF) is present in nearly all tissues and constitutes the body’s natural mechanism to adapt to hypoxic conditions. HIF is a heterodimer consisting of an alpha and beta subunit. The alpha subunit is rapidly degraded by a proline hydroxylase (PH) enzyme in the presence of oxygen, thereby preventing the heterodimerization with the beta subunit and its transcriptional effects on over 4000 genes, depending on the tissue.

Activation of these genes leads to increased red blood cell (RBC) production through increased synthesis of erythropoietin and the erythropoietin receptor, as well as increased synthesis of a variety of iron handling proteins including transferrin, transferrin receptor, duodenal cytochrome B, divalent metal transporter-1, and ceruloplasmin. The net effect is a more “complete” stimulation of erythropoiesis than can be achieved by erythropoiesis stimulating agents (ESAs) alone, which do not affect iron metabolism. However, HIF stabilizers also stimulate a variety of genes not affecting erythropoiesis including those that affect angiogenesis, glucose metabolism, extracellular matrix production, and cellular proliferation.

The HIF stabilizers under development have attempted to achieve specificity for erythropoiesis by targeting specific PH enzymes and with pharmacokinetics that allow for periods between doses during which there is no PH inhibition so that the effect of these agents on non-targeted genes can be minimized. There are three HIF stabilizers currently under development in the US: roxadustat, vadadustat and daprodustat.

Roxadustat has a half-life of 12–13 hours and has been shown to be effective in raising hemoglobin (Hb) levels when administered three times weekly; vadadustat and daprodustat have half-lives of around 4 hours and are administered daily. Multiple phase 2 studies have been published with all three agents demonstrating comparable efficacy in maintaining Hb levels within target range when dialysis patients are switched from ESAs and in raising Hb levels to target range in ESA-naïve dialysis and non–dialysis-dependent (NDD)-CKD patients. Because of their beneficial effects on iron metabolism, which lead to an increase in oral iron absorption, increased release of stored iron from macrophages, and increased transport of iron to the erythroid marrow, HIF stabilizers have been shown to be equally effective with oral or intravenous iron in the short term (although it is unlikely this can be sustained over the long term in hemodialysis [HD] patients given their ongoing iron losses).

The use of HIF stabilizers has been shown to decrease hepcidin levels, although this is thought to be mediated by increased erythroferrone released by RBC precursors in the setting of accelerated erythropoiesis, not a direct effect of the HIF stabilizers. Nonetheless, HIF stabilizer therapy has demonstrated comparable responsiveness in raising Hb levels among patients with normal or high C-reactive protein (CRP) levels, the latter being a surrogate for the inflammatory conditions that typically lead to “ESA resistance.” Chinese phase 3 studies of roxadustat (presented at Kidney Week 2018) demonstrated efficacy superiority to placebo in NDD-CKD patients and non-inferiority to ESA in ESKD patients. However, these studies were not adequately powered for major adverse cardiovascular event (MACE) outcomes (<1000 patients, 6 months duration). Roxadustat has been approved for use in China by Chinese regulatory authorities.

The phase 3 studies of roxadustat in the US and Europe have been completed. Top-line efficacy data have been released by the sponsor (not yet published) and revealed: superiority to placebo in NDD-CKD patients (n=922, mean f/u 1.7 years); superiority to ESA in the US and non-inferiority to ESA in Europe in ESA-naïve incident ESKD patients (n=1043, mean f/u 1.8 years); and superiority to ESA in prevalent ESKD patients converted from ESA (n=741, mean f/u 1.9 years). It is thought that the superiority to ESA stems from the HIF stabilizers’ improved efficacy in the subset of inflamed ESA-resistant patients. The top-line safety data from the roxadustat phase 3 US and European studies have not yet been released, and may not be until late 2019. Phase 3 studies of vadadustat and daprodustat are still underway, and will likely be completed in 2020 and 2021, respectively.

Prior to the release of long-term (3-year) safety data, it is difficult to predict what the role of HIF stabilizers will be in the treatment of anemia in patients with CKD. Even with 3-year MACE data, there may still be reservations regarding the widespread adoption of these agents because it may take more than 3 years to determine their non-MACE effects such as angiogenesis (tumor growth, diabetic retinopathy), altered glucose metabolism, rate of renal function decline in NDD-CKD patients, and pulmonary hypertension. There are several possible 3-year safety scenarios, each of which will likely have a different effect on the short-term adoption of these new agents. If the HIF stabilizers demonstrate superior safety (MACE outcomes being of greatest interest) to ESAs in dialysis patients, it is likely the uptake of the HIF stabilizers will be robust, although there may be some providers who wish to take more of a “wait and see” attitude regarding longer-term safety issues. If the HIF stabilizers demonstrate non-inferior safety to ESAs in dialysis patients, it is likely the HIF stabilizers will be preferred to ESAs in inflamed “ESA resistant” patients to decrease transfusion risk and costs.

Given the failing record of interventional trials of all sorts in dialysis patients to demonstrate superior outcomes in one arm, it is felt by many to be unlikely that HIF stabilizers will demonstrate safety superiority in this population. In some phase 3 trials in NDD-CKD patients, HIF stabilizers are being compared to placebo. If the safety of a HIF stabilizer is non-inferior to placebo in such trials does that mean that the HIF stabilizer is safer than ESA even if the head-to-head trials with ESA did not demonstrate the safety superiority of the former? If the safety of a HIF stabilizer is non-inferior to placebo does that mean the FDA would not require a black box warning as it does for ESAs? Even if that were the case, would there be enough reservations regarding the long-term non-MACE safety issues of HIF stabilizers that their adoption might be sluggish? The appeal of an oral anemia therapy in non-HD patients is undeniable, even without longer-term safety data. A reasonable approach in the non-HD population would be to discuss the risks and benefits of ESAs vs. HIF stabilizers so the patient can make an informed decision balancing convenience with possible unknown risk. The same risk vs. benefit discussion applies to the HD population where the motivation to abandon the parenterally administered ESA class of drugs with 30 years clinical experience is less compelling except if the patient is ESA-resistant.

The answer to the question posed in the title of this article, “Will HIF stabilizers have a place?” is “It depends.” It depends on their safety in phase 3 clinical trials. It depends on how much clinicians are satisfied by the MACE outcomes of these agents in phase 3 clinical trials or remain concerned regarding possible angiogenesis, tumor growth, abnormal glucose metabolism, accelerated decline of kidney function, and pulmonary hypertension that are not addressed in phase 3 trials to their satisfaction. It depends on costs, payment policies, formularies, prior authorizations, and dialysis organization protocols. Unless there is a safety signal in phase 3 trials, it is likely HIF stabilizers will initially be favored in patients unable to reach target Hb levels on high doses of ESAs (“ESA resistant”) and in non-HD patients who favor an oral drug over an injection. Further uptake is likely once concerns regarding safety over longer than the 3 years in the phase 3 trials are satisfied.

Figure 1.

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May 2019 (Vol. 11, Number 5)

References

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3. Locatelli F, et al. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol 2017; 45:187–199.