Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years

Abstract

Background: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. Procedure: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single-and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported.Results: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed.

Sickle Cell Disease in Children and Adolescents: A Review of the Historical, Clinical, and Public Health Perspective of Sub-Saharan Africa and Beyond

“…Participants in the 1500mg voxelotor arm had a significantly higher decrease in indirect bilirubin levels compared to those in the placebo arm, with a mean change of −29.1% and −3.2% respectively ( P < 0.001). Similar findings were demonstrated in the phase 2a HOPE KIDS-I trial ( NCT02850406 ) involving 45 children aged 4 to 11 years [ 177 ]. Just like L-glutamine and crizanlizumab, voxelotor has not yet been proven to prevent, delay, or improve organ-specific complications (e.g., renal disease, PAH), and improve quality of life or survival [ 45 ].…”

New therapeutics for children with sickle cell disease: A time for celebration, caution, or both?

“…Does any particular existing organ injury increase the risk of these treatments? In this context, the current study by Estepp and collaborators 2 provides safety data and hemoglobin (Hb) treatment responses that add to this discussion.…”

“…Getting the therapeutic balance right. The waterfall plot of Hb responses in the study by Estepp et al 2 . is shown with a superimposed visualization of the effect of loss of oxygen delivery capacity by voxelotor‐modified Hb.…”

“…In the current study, estimated Hb occupancy by voxelotor was 26.2%, including 76% of children with >20% occupancy. 2 The overall or net leftward shift in p50 (the pressure at which Hb is 50% saturated) was small, but because that value represents an average across all circulating erythrocytes, the functional effect may instead be substantial.…”

“…However, by modulating oxygen affinity, the trade-off is oxygen delivery F I G U R E 1 Getting the therapeutic balance right. The waterfall plot of Hb responses in the study by Estepp et al 2 is shown with a superimposed visualization of the effect of loss of oxygen delivery capacity by voxelotor-modified Hb. The height of each blue bar is the reported increment or decrement in total Hb in the manuscript.…”