Anemia of CKD: Emerging Treatments

Key Takeaways

• There is an unmet need for oral therapy in anemia of CKD due to logistical barriers with current treatment.
• HIF-PHIs are oral agents under investigation in the United States for the treatment of anemia of CKD.
• HIF-PHIs are distinct molecules that have different pharmacokinetic properties, dosing intervals, and specificity for prolyl hydroxylase enzymes.

The logistical barriers to the effective treatment of anemia of chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) due to their parenteral administration have created an unmet need for an oral therapy that is more accessible to patients, especially those with nondialysis CKD and those undergoing dialysis at home.

Here’s my take on a promising new class of agents in development, their distinct advantages and disadvantages, and their potential place in therapy, if approved.

The Search for Oral Treatment in Anemia of CKD
The Nobel Prize–winning discovery of the oxygen-sensing pathway has elucidated the role of hypoxia-inducible factors (HIFs) as the central regulator of erythropoiesis in response to oxygen delivery to the kidney tissue. HIF has 2 subunits: an alpha subunit that is rapidly degraded after the oxygen-dependent activation of HIF prolyl hydroxylase, and a beta subunit that is continuously present. The alpha + beta HIF heterodimer acts in the nucleus of the cell to promote the transcription of a variety of genes that augment erythropoiesis, including erythropoietin (EPO) and iron transport proteins, as well as indirectly decreasing the production of hepcidin. A new class of drugs, HIF-prolyl hydroxylase inhibitors (HIF-PHIs) inhibit the prolyl hydroxylase enzymes, which lead to the degradation of HIF-alpha, thereby simulating a hypoxic environment in the cell even when oxygen is present. This leads to increased transcription of EPO and iron transport proteins, producing a more coordinated erythropoietic response than pharmacologic doses of ESAs alone. HIF-PHIs are small molecules that are orally administered, and this may help overcome some of the logistical barriers to ESA treatment for patients who must come to an infusion center or physician’s office to receive the ESA injections.

HIF Agents Under Investigation
There are 3 HIF-PHIs undergoing development in the United States: roxadustat, vadadustat, and daprodustat. Each are distinct molecules with different pharmacokinetic properties, dosing intervals, and specificity for prolyl hydroxylase enzymes. Roxadustat is the first-in-class HIF-PHI that has been approved in China, Japan, Chile, South Korea, and the European Union. It has been shown to be as equally effective as ESAs in increasing hemoglobin levels, but it was rejected by the FDA in August 2021 after the completion of global phase III studies involving approximately 4000 nondialysis and 4000 dialysis patients with CKD. In nondialysis patients, roxadustat demonstrated a significantly increased incidence of deep vein thrombosis (DVT), pulmonary emboli, seizures, and infection compared with placebo. In dialysis patients, roxadustat demonstrated incidence of DVT and vascular access thrombosis vs ESA. 

Vadadustat has been approved in Japan but was rejected by the FDA in March 2022. It demonstrated similar efficacy to ESA in raising hemoglobin levels in approximately 4000 dialysis and 3500 nondialysis patients with CKD and anemia. In the dialysis patients, there was no increased incidence of major adverse cardiovascular events compared with placebo, but there was concern by the FDA regarding thrombosis and liver enzyme abnormalities. In the nondialysis patients, vadadustat did not demonstrate noninferiority for major adverse cardiovascular events vs ESA, and there was also concern regarding thrombosis and liver enzyme abnormalities.

Daprodusat has also been approved in Japan. Global phase III studies examined 4000 nondialysis patients and 3000 dialysis patients for cardiovascular safety and other adverse effects vs ESA. There were also smaller studies of incident dialysis patients vs ESA, 3 times weekly administration in hemodialysis patients vs ESA, and a quality-of-life study in nondialysis patients vs placebo. The FDA has not made its decision regarding daprodustat approval, but the FDA cardiorenal drug advisory committee met in October 2022, and the majority vote was in favor of daprodustat approval for dialysis patients but not in favor of daprodustat approval for nondialysis patients. The efficacy and safety of daprodustat were noninferior to ESA in dialysis patients. The primary prespecified intention-to-treat analysis of cardiovascular safety in nondialysis patients demonstrated noninferiority to ESA, but the secondary supportive on-treatment analysis did not demonstrate noninferiority to ESA for cardiovascular safety. It is not clear what the final decision will be regarding FDA approval of daprodustat at this time.

Summary
In summary, HIF-PHIs are an attractive oral alternative to ESAs in patients who have difficulty coming to a clinic or infusion center regularly for injections. This includes patients with anemia associated with nondialysis CKD and an expanding home dialysis population. HIF-PHIs have been approved in many countries including the European Union, but none is yet approved by the FDA. They have potential beneficial effects on iron metabolism, which may decrease oral iron requirements. As with any new therapy, the balance of benefit to risk of HIF-PHIs will need to be individualized for each patient.