Evaluating the safety and efficacy of vadadustat for the treatment of anemia associated with chronic kidney disease

ABSTRACT

Introduction

The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application.

Areas covered

This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat.

Expert opinion

A phase 3, randomized, open-label, clinical trial (PRO₂TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO₂VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies.

KEYWORDS:

• Vadadustat
• HIF-PHI
• ESA
• PRO₂TECT
• INNO₂VATE

Article highlights

• A phase 3, randomized, open-label, clinical trial (PRO₂TECT) in non-dialysis-dependent patients demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa.

• Vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients.

• Vadadustat is not indicated for the treatment of renal anemia in patients with non-dialysis dependent in any country except Japan.

• In dialysis-dependent patients, a phase 3 clinical trial (INNO₂VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels.

• A post-hoc analysis of INNO₂VATE demonstrated safety and efficacy of vadadustat in dialysis-dependent patients.

Declaration of interest

T Tanaka received lecture fees from Mitsubishi Tanabe Pharma Corporation. M Nangaku received lecture fees, consulting fees, advisory fees and research funding from Mitsubishi Tanabe Pharma Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Akebia Therapeutics provided a scientific accuracy review at the request of the journal editor. A reviewer on this manuscript has disclosed that they are a Consultant and a member of the Speakers Bureau for daprodustat, a competitor of vadadustat. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was funded in part by the Grant- Grant-in-Aid for Scientific Research (C) 20K08604 by the Japan Society for the Promotion of Science (JSPS) KAKENHI, the Takeda Science Foundation, and The Naito Foundation.