Systematic review of voxelotor: a first-in-class sickle hemoglobin polymerization inhibitor for management of sickle cell disease
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 (> 1g/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.
A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease
The New England journal of medicine. 2019
BACKGROUND Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sbeta(0)-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).
Carbonyl iron supplementation for female blood donor
Blood. 1996;88((10):):89b.. Abstract No. 3085.
Prevention of iron deficiency with carbonyl iron in female blood donors
The effectiveness of elemental, nontoxic carbonyl iron in replacing iron lost at blood donation was examined. In a randomized double-blind design, 99 women, aged 18 to 40, were given placebo or low-dose carbonyl iron (100 mg orally) at bedtime for 56 days after phlebotomy. Compliance was equivalent for the two regimens. Mild side effects were slightly greater with carbonyl iron. At Day 56, estimated net iron absorption from therapy or diet, or both, was sufficient to replace iron in 85 percent of those receiving carbonyl iron but in only 29 percent of those taking placebo (p less than 0.001). The rates of deferral from repeat donation were 8 percent in the carbonyl iron group and 36 percent in the placebo group (p less than 0.01), and the positive predictive value of routine screening in identifying participants without iron deficiency was 83 versus 13 percent (p less than 0.01). It can be concluded that short-term carbonyl iron supplementation in female blood donors can replace the iron lost at phlebotomy, protect the women against iron deficiency, and enhance their ability to give blood.
High-dose carbonyl iron for iron deficiency anemia: a randomized double-blind trial
American Journal of Clinical Nutrition. 1987;46((6):):1029-34.
To determine if high doses of oral iron could shorten the duration of therapy necessary to treat Fe deficiency anemia, high-dose Fe 600 mg three times per day (given as nontoxic carbonyl Fe) was compared with standard ferrous sulfate 60 mg Fe++ three times per day in a randomized, double-blind, 3-wk trial involving 36 female blood donors with mild Fe deficiency anemia. In animal studies, both forms of Fe have similar bioavailability when administered in equal amounts. High-dose carbonyl Fe was well tolerated with gastrointestinal side effects similar those observed with standard FeSO4 therapy. The 10-fold larger amount of Fe resulted in a mean 1.5-fold increase in estimated Fe absorption. Both regimens corrected anemia but neither replenished storage Fe. These results suggest that the principal advantage to the use of carbonyl Fe would derive from its safety rather than from the large doses that can be given.
Carbonyl iron for short-term supplementation in female blood donors
A randomized, double-blind trial of iron replacement after repeated blood donation was conducted in 75 menstruating women; 51 completed the study. Volunteers were assigned randomly to one of three treatment groups: 1) carbonyl iron (nontoxic elemental iron powder), 600 mg; 2) ferrous sulfate, 300 mg (60 mg Fe++); or 3) placebo, each given three times daily for 1 week immediately after blood donation. Blood samples obtained initially and 56 days later were tested for hemoglobin, mean corpuscular volume (MCV), free erythrocyte protoporphyrin, serum ferritin, serum iron, total iron binding capacity (TIBC), and percent saturation of TIBC. The prevalence of gastrointestinal side effects was similar in both groups taking iron. At the end of the study there was no laboratory evidence of change in iron status in women who received carbonyl iron (n = 15). In those treated with ferrous sulfate (n = 17) the mean TIBC increased (p less than 0.001), and in the placebo group (n = 19) there were decreases in mean MCV (p less than 0.01), serum ferritin (p less than 0.001), and percent saturation (p = 0.027) with an increase in mean TIBC (p = 0.004). Carbonyl iron seems to be effective for short-term iron replacement in repeat blood donors and may have the advantage of decreased or absent risk of poisoning if accidentally ingested by children.