Table 3.

Summary of findings from included studies of voxelotor (Oxbryta).

Source (Country)	Outcome Measured	Study Design	Age, Years	Group, n	Summary of Findings
Clinical Efficacy
Vichinsky 2019, international	Primary: hemoglobin response	Phase 3 RCT (HOPE trial)	12–64, median 24	274	-51% in 1500 mg had response vs. 7% in placebo (p < 0.001) -At week 24, significant reduction in baseline indirect bilirubin and reticulocyte count -Mean change in hemoglobin: 1.1 g/dL in 1500 vs. 0.6 in 900 vs. −0.1 in placebo (p < 0.001) -Markers of hemolysis: indirect bilirubin −29.1% vs. −3.2% (p < 0.001), reticulocytes −19.9% vs. +4.5% (p < 0.001) -Annual incidence of VOE: 2.77 vs. 2.76 vs. 3.19 -Similar adverse events across all groups: at least grade 3 in 26% in 1500, 23% in 900, 26% in placebo -Most common: headache (26%), diarrhea (20%), nausea (17%) in 1500 mg group -No substantial differences in the percentages of participants who had sickle-cell disease-related adverse events among the 3 groups
Howard 2019, international	Measurements of hemolysis	Post hoc of HOPE trial	12–64, median 24	274	-Patients with hemoglobin change >1 g/dL had greatest reduction in markers of hemolysis (reticulocyte count, indirect bilirubin, LDH) -Patients with hemoglobin change >1 g/dL had greater effect with 1500 vs. 900 mg
Howard 2021, international	Changes from baseline hemoglobin, safety	72-week follow-up of HOPE	12–64, median 24	274	-89% receiving 1500 mg had hemoglobin increased of 1 g/dL or greater over 72 w vs. 25% of placebo (p < 0.001) -Mean change 1.0 g/dL vs. 0 (p < 0.001) -Improvements in hemolysis: indirect bilirubin, reticulocyte count, LDH -Lower number of VOEs but not statistically significant
Minniti 2021, international	Leg ulcers	Post hoc of HOPE	12–64, median 24	274	-Nearly all patients (>90%) receiving voxelotor (1500 and 900 mg) had their leg ulcers improve or resolve by week 72 -Resolution of leg ulcers was associated with increased Hb levels
Vichinsky 2020, international	Hemoglobin response and VOE incidence	72-week follow-up of HOPE	12–64, median 24	274	-60 study participants achieved average Hb levels ≥10 g/dL and 10 achieved average Hb ≥12 g/dL -Incidence rate of VOCs was lowest in patients who achieved the highest Hb levels (≥12 g/dL) compared with those who achieved lower Hb levels and those receiving placebo
Achebe 2021, international	Hemoglobin response, markers of hemolysis	Long-term open-label extension of HOPE, 1500 mg	Median 25	178	-Patients who received placebo during HOPE: mean change in Hb 1.3 g/dL; if had already received voxelotor: 900 mg, 0.7 g/dL, if 1500 mg, 0.2 g/dL -Hemolysis: −39.5% indirect bilirubin in previous placebo recipients, −28.6% reticulocyte percentage; stable for those who received voxelotor during HOPE: −2.0% and 1.1% indirect bilirubin, −14.6% and −21.0% reticulocytes for voxelotor 900 mg and 1500 mg -83.7% experiences non-SCD related AE, most grade 1 or 2 -6.2% had AE leading to discontinuation
Estepp 2021, USA	Increase in hemoglobin, side effects	Open-label, multicenter, multiple-dose trial (HOPE KIDS 1)	4–11, median 7	45	-84% on baseline HU -At week 24, mean change in hemoglobin was +1 g/dL -47.1% achieved hemoglobin response -Decreases in markers of hemolysis: −28.6% indirect bilirubin, −2.6% LDH, −3.3% reticulocytes -48.9% had side effects: diarrhea 11%, 11% vomiting, 11% rash -9% discontinued due to side effects
Brown 2018, USA	Increase in hemoglobin	Phase 2a study of 900 mg/day in adolescents	12–17, median 14	25	-92% on baseline HU -42% had increase of hemoglobin >1 g/dL -Mean reduction 32% reticulocytes, 38% indirect bilirubin -No serious adverse events, no one terminated use -Most common side effects: nausea 12%, vomiting 8%, headache 8%, rash 8%
Brown 2019, USA	Increase in hemoglobin	Phase 2a study of 1500 mg/day in adolescents	12–17, median 14	15	-100% on baseline HU -55% had increase of hemoglobin >1 g/dL, median increase of 1.1 -Markers of hemolysis: −5.8% reticulocytes, −36.9% indirect bilirubin, −23.1% LDH -Most side effects were grade 1 or 2, one grade 3 (rash), no one discontinued
Muschick 2021, USA	Increase in hemoglobin	Single-center retrospective review	12–21	17	-100% on baseline HU -Hemoglobin improved mean 1.49 g/dL -Reticulocyte percentage decreased 4.14%, total bilirubin by 1.71 mg/dL -All reported subjective clinical improvement (increased energy, decreased pain) -Side effects: mild diarrhea, nausea, necessitating supportive care
Phan 2021, USA	Exercise capacity	Pilot study	12–20	9	-Mean rise in hemoglobin +1.3 g/dL, decrease reticulocyte count −2.4%, bilirubin −0.4 mg/dL -Changes in peak VO2 ranged from −10% to 10%, not statistically significant -7 of 9 with subjective positive change on lifestyle questionnaire
Zaidi 2020, USA	Effect on anemia	Retrospective review in Symphony Health system	Mean 35.7	1275	-n = 52 had hemoglobin measurements following initiation of voxelotor -Mean increase in Hb from baseline was 1.1–1.3 g/dL -55% achieved increase of >1 g/dL of hemoglobin 1 year -Decrease in transfusion rates (p < 0.05) -Decrease in VOC rates (p = 0.258)
Side Effects and Prescribing Data
Ware 2020, international	Concomitant use of HU	Post hoc of HOPE	12–64, median 24	274	-65% of patients receiving HU at study enrollment -Similar percentages of participants reported treatment-emergent adverse events in those receiving HU and those not -Voxelotor led to increase in hemoglobin levels but not MCV, %HbF, and ANC, consistent with stable HU exposure throughout the study
Betancourt 2020, USA	Real-world experience, barriers to use, health outcomes	Single-center retrospective review	21–70, mean 41	54	-52% also taking HU at start of voxelotor -After 2–4 weeks, 63% had increase of hemoglobin of >1 g/dL -65% able to access drug, mean time to obtain drug 45 days -Barriers: prior authorization or appeal 9%, incomplete follow-up 7%, missing documentation 6%, and high patient co-pay 6% -Side effects: GI 23%, dermatologic 17%, increase in pain 11% -29% required dose modification from side effect, 23% terminated medication
Shah 2020, USA	Prescribing, side effects, clinical efficacy	Multicenter retrospective review	Mean 33	60	-80% on HU, 20% on chronic transfusions, 10% on Epo-stimulating agents, average hemoglobin 7.4 g/dL -52% were prescribed but did not start taking or did not follow-up for labs -15% required dose adjustment to 1000 mg due to side effects -Average hemoglobin at 1 month 8.6 g/dL, at 3 months 8 g/dL -52% increased by 1 g/dL at 1 month and 44% increased by 1 g/dL at 3 months -Increased report of more energy, quality of life -5% discontinued due to pregnancy, transaminitis, GI symptoms
Andemariam 2021, USA	Prescribing, side effects, clinical efficacy	Multicenter retrospective post-marketing review	Mean 34.3	300, 49 at time of data analysis	-Rationale for prescription: reduction of anemia (73.5%), reduction in frequency of VOEs (46.9%), reduction in pain (69.4%), reduction in the need for blood transfusion (16.3%) -Average 1.6 g/dL increase of hemoglobin from baseline -50% had >1 g/dL improvement -Improvement in hemolytic markers: −4.9% reticulocyte percentage, −1.9 mg/dL indirect bilirubin -38.8% reported at least one adverse event, most common diarrhea, headache, rash, most mild