Summary characteristics of FDA-approved drugs for SCD
| . | Hydroxyurea . | L-glutamine . | Crizanlizumab . | Voxelotor . |
|---|---|---|---|---|
| Age (years) | ≥2 | ≥5 | ≥16 | ≥4 |
| Genotypes | HbSS, HbSβ0 thalassemia | All genotypes (only studied in HbSS, HbSβ0 thalassemia) | All genotypes | All genotypes (majority with HbSS, HbSβ0 thalassemia) |
| Mechanism of action | Multiple, but primarily by increasing HbF production | Uncertain, but thought to increase NAD redox potential; may decrease cell adhesion | Anti–P-selectin inhibitor (decreases adhesion of WBC, RBC to endothelium and possibly of platelets to WBC) | Decreases HbS polymerization by increasing Hb-oxygen affinity |
| Route of administration | Oral (capsules/tablets) | Oral (powder) | IV | Oral (tablets) |
| Clinical effects of therapy | Decreased frequency of VOC, decreased frequency of ACS, decreased hospitalization, decreased RBC transfusion requirement, decreased stroke risk | Decreased frequency of VOC, decreased frequency of ACS, decreased hospitalization | Decreased frequency of VOC in phase 2 SUSTAIN trial. Results of recent phase 3 STAND trial showed no benefit. | Increased Hb |
| Effect size for primary end point (NNT) | 44% decrease in VOC per year (median from 4.5 to 2.5); IRR, 0.56 | 25% decrease in VOC in 48 wk (median from 4 to 3); IRR, 0.75 | 45% decrease in crisis rate per year (median from 3 to 1.6); IRR, 0.55 | 7-fold increase in the Hb responders (7 to 51) at 24 wk, incidence proportion ratio = 7.3a |
| Common toxicities | Myelosuppression, skin hyperpigmentation, nail discoloration, teratogenicity, decreased sperm counts, nausea and vomiting | Constipation, nausea, headaches, abdominal pain | Nausea, arthralgia | Headache, diarrhea, nausea |
| Pharmacokinetics | Excreted via kidneys. Adjust dose for eGFR <60 mL/min/1.73 m2 | Use with caution with hepatic and renal impairment, but no recommended dose adjustment | No dosage adjustments in manufacturer labeling for renal and hepatic impairment (not tested in ESRD) | No dosage adjustment for renal impairment, but not yet studied in ESRD requiring dialysis. Dose reduction for severe liver disease (Child Pugh class C) |
| Cost | $ | $$$ | $$$$$ | $$$$$ |
| . | Hydroxyurea . | L-glutamine . | Crizanlizumab . | Voxelotor . |
|---|---|---|---|---|
| Age (years) | ≥2 | ≥5 | ≥16 | ≥4 |
| Genotypes | HbSS, HbSβ0 thalassemia | All genotypes (only studied in HbSS, HbSβ0 thalassemia) | All genotypes | All genotypes (majority with HbSS, HbSβ0 thalassemia) |
| Mechanism of action | Multiple, but primarily by increasing HbF production | Uncertain, but thought to increase NAD redox potential; may decrease cell adhesion | Anti–P-selectin inhibitor (decreases adhesion of WBC, RBC to endothelium and possibly of platelets to WBC) | Decreases HbS polymerization by increasing Hb-oxygen affinity |
| Route of administration | Oral (capsules/tablets) | Oral (powder) | IV | Oral (tablets) |
| Clinical effects of therapy | Decreased frequency of VOC, decreased frequency of ACS, decreased hospitalization, decreased RBC transfusion requirement, decreased stroke risk | Decreased frequency of VOC, decreased frequency of ACS, decreased hospitalization | Decreased frequency of VOC in phase 2 SUSTAIN trial. Results of recent phase 3 STAND trial showed no benefit. | Increased Hb |
| Effect size for primary end point (NNT) | 44% decrease in VOC per year (median from 4.5 to 2.5); IRR, 0.56 | 25% decrease in VOC in 48 wk (median from 4 to 3); IRR, 0.75 | 45% decrease in crisis rate per year (median from 3 to 1.6); IRR, 0.55 | 7-fold increase in the Hb responders (7 to 51) at 24 wk, incidence proportion ratio = 7.3a |
| Common toxicities | Myelosuppression, skin hyperpigmentation, nail discoloration, teratogenicity, decreased sperm counts, nausea and vomiting | Constipation, nausea, headaches, abdominal pain | Nausea, arthralgia | Headache, diarrhea, nausea |
| Pharmacokinetics | Excreted via kidneys. Adjust dose for eGFR <60 mL/min/1.73 m2 | Use with caution with hepatic and renal impairment, but no recommended dose adjustment | No dosage adjustments in manufacturer labeling for renal and hepatic impairment (not tested in ESRD) | No dosage adjustment for renal impairment, but not yet studied in ESRD requiring dialysis. Dose reduction for severe liver disease (Child Pugh class C) |
| Cost | $ | $$$ | $$$$$ | $$$$$ |
ACS, acute chest syndrome; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HbF, fetal hemoglobin; HbS, sickle hemoglobin; IV, intravenous; NAD, nicotinamide adenine dinucleotide; NNT, number needed to treat; VOC, vaso-occlusive crisis.
Patients treated with 1500 mg of voxelotor had 7.3 times the increased proportion of Hb responders (>1 g/dL increase from baseline at 24 weeks).
Data adapted from Rai and Ataga.62