Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease

Abstract

Voxelotor, a sickle hemoglobin polymerization inhibitor, was approved by the U.S. Food and Drug Administration to treat sickle cell disease (SCD) in November 2019. This article reviews published data about voxelotor treatment of SCD based on a search of MEDLINE, Embase, and International Pharmaceutical Abstracts. In a phase I/II trial, voxelotor demonstrated a dose‐dependent pharmacokinetic and pharmacodynamic response and was well tolerated in healthy volunteers and patients with SCD. In a multi‐center, randomized, double‐blind, phase III trial (HOPE trial), a significantly higher percentage of patients randomized to voxelotor had increased hemoglobin (> 1 g/dl from baseline) compared to placebo. A greater reduction of hemolytic markers was also observed in the voxelotor‐treated group, whereas the incidence of adverse effects was comparable. Three case series or reports also demonstrated the efficacy and safety of voxelotor use in a limited number of SCD patients in the real‐world situation, although one patient with SCD, severe anemia, and a history of autoantibody‐mediated hemolysis failed to respond to voxelotor. An ongoing trial (HOPE‐KIDS) is designed to establish the use of voxelotor in younger pediatric patients with SCD. There is a theoretical concern that voxelotor may impair oxygen delivery, due to modification of the oxygen affinity of hemoglobin, which needs to be further evaluated. As a first‐in‐class hemoglobin modulator, voxelotor offers a new treatment option targeting the root cause of SCD.

Outcomes of Kidney Transplant Recipients with Sickle Cell Disease: An Analysis of the 2000–2019 UNOS/OPTN Database

“…Thus, future studies are needed to assess the impact of hydroxyurea, EBT, and perioperative management on outcomes of kidney transplant recipients with SCD. Furthermore, there are now new medications recently made available that are expected to be of significant benefit among SCD patients [ 36 , 37 , 38 , 39 ], which require future studies in kidney transplant recipients.…”

A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design

“…Recently this strategy was extended to targeting N-terminal amines 18 , through approval of Voxelotor to treat sickle cell disease. 19,20 Herein we will discuss an alternative design strategy harnessing a ligandable interaction to orchestrate a selective privileged thiol-electrophile interaction. Privileged thiol-electrophile interactions are referred to as such because reactions between such matched thiol/electrophile pairs are intrinsically rapid.…”

Incorporation of novel therapies for the management of sickle cell disease: A pharmacist's perspective

“…Currently, there is an ongoing study investigating voxelotor use in pediatrics (HOPE-kids). 65 Patients and providers may potentially lean towards this therapy because of its once daily oral dosage form. However, pharmacists need to educate both providers and patients that voxelotor has not been proven to reduce VOC rates and may even increase them.…”