Characteristics of pivotal clinical trials of OD for SCD in the United States and the EU
| Drug . | Indirect inhibition of HbS polymerization . | Targeting adhesion . | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Senicapoc . | Voxelotor . | Velopoxamer . | Rivipansel . | Sevuparin . | Prasugrel . | L-Glutamine . | Crizanlizumab . | ||
| OD | FDA | FDA-EMA | EMA | FDA-EMA | FDA-EMA | FDA | FDA-EMA | FDA-EMA | |
| Marketing authorization | Not approved | United States-EU | Not approved | Not approved | Not approved | Not approved | United States | United States-EU∗ | |
| Study | ASSERT-(NCT00102791) Ataga et al,19 Brit J Haematol 2011 | HOPE-(NCT03036813) Vichinsky et al,20 N Engl J Med 2019 | EPIC-(NCT01737814) Casella et al.21 JAMA 2021 | RESET-(NCT02187003) Dampier et al.22 Blood 2023 | NCT02515838 Biemond et al.23 Lancet Haematol 2021 | DOVE-(NCT01794000) Heeney et al.24 N Engl J Med 2016 | NCT01179217 Niihara et al.25 N Engl J Med 2018 | SUSTAIN-(NCT01895361) Ataga et al,26 N Engl J Med 2017 | STAND-(NCT03814746) |
| Mechanism of action | Gardos channel inhibitor | Binds directly to HbS so increasing HbS oxygen affinity | Blocks cell-to-cell interactions | E-selectin antagonist | P- and L-selectins inhibitor, thrombospondin, fibronectin, and von Willebrand factor | Inhibits ADP-mediated platelet activation and aggregation | Regulates oxidative stress by normalizing the altered NAD redox system | P-selectin inhibitor | |
| Study aim | Prevention of VOC | Hemoglobin response and markers of hemolysis | Treatment of VOC | Treatment of VOC | Treatment of VOC | Prevention of VOC | Prevention of VOC | Prevention of VOC | |
| Study design and arms | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 297 (A) 145 senicapoc 20 mg bid for 4 d followed 10 mg QD (B) 144 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 274 (A) 90 voxelotor 1500 mg QD (B) 92 voxelotor 900 mg QD (C) 92 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 388 (A) 194 poloxamer 188 (1-h loading 100 mg/kg; 12-48 h at 30 mg/kg per hour) (B) 194 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 345 (A) 173 rivipansel (>12 y: 1680 mg followed by 840 mg every 12 h; 6-11 y: 40 mg/kg (max 1680 mg) followed by f 20 mg/kg (max of 840 mg) every 12 h. (B) 172 placebo | Phase 2, multicentre, randomized, double-blinded, placebo-controlled N = 144 (A) 68 Sevuparin 3 mg/kg loading dose followed by 18 mg/kg per day continuous infusion (B) 76 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 341 (A) 171 Prasugrel 0.08 mg/kg then adjusted to 0.04-0.12 mg/kg (max 10 mg) (B) 170 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 230 (A) 152 L- glutamine 0.3 g/kg (B) 78 placebo | Phase 2, multicenter, randomized, double-blind, placebo-controlled N = 198 (A) 67 Crizanlizumab 5 mg/kg (B) 66 crizanlizumab 2.5 mg/kg (C) 65 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 252 (A) 83 Crizanlizumab 7.5 mg/kg (B) 84 crizanlizumab 5 mg/kg (C) 55 placebo |
| Eligibility criteria | Age: 16-65 y Hb level: from 4 to 11 g/dL at screening | Age: 12-65 y Hb level: from 5.5 to 10.5 g/dL at screening | Age: 4-65 y | Age: ≥6 y | Age: 12-50 y | Age: 2-17 y | Age: 5-58 y | Age: 16-65 y | Age: ≥12 y |
| ≥2 acute VOCs in the previous year requiring a medical facility visit and treatment with oral or parenteral opioids or other analgesics, or ACS, hepatic/splenic sequestration, priapism, stroke and death | 1-10 moderate/severe acute VOCs or ACS in the previous year, requiring oral or parenteral opioids or other analgesics prescribed by a health care professional in a medical setting or by telephone at home | Acute VOCs treated in a medical setting with parenteral opioids | Acute VOCs treated in a medical setting with parenteral opioids | Acute VOCs to be treated/or treated with parenteral opioid analgesia and need for hospitalization at least 48 h. | ≥2 acute VOCs in the previous year, requiring therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care provider in a medical setting or at home or ACS. | ≥ 2 acute VOCs during the previous year treated with a parenteral opioid in a medical setting or ACS, priapism, and splenic sequestration; patients on HU at a stable dose for at least 3 mo. | 2-10 VOCs the previous year requiring medical facility visit and treatment with oral or parenteral opioids, or parenteral nonsteroidal anti-inflammatory drugs; patients on HU at a stable dose for at least 3 mo. | ≥2 VOCs in the previous year leading to health care visit and treated with oral or parenteral opioids, or parenteral non-steroidal anti-inflammatory drugs, including ACS, priapism and hepatic or splenic sequestration. | |
| Primary Outcome Measure | VOCs rate (time frame: 52 wk) | Number of participants with increase in Hb >1 g/dL from baseline to week 24 | Reduction of the duration of VOCs at hospital (time frame: expected average of 4 d) | Time to readiness-for-discharge (time frame: assessments will be every 4 h for the duration of hospitalization, expected average of 5 d) | Time to resolution of VOCs (time frame: from hospitalization until discharge) | Number of VOCs per participant per y (time frame: randomization through 24 mo) | The number of occurrences of protocol-defined VOCs (time frame: 48 wk) | Rate of VOCs leading to health care visit (time frame: 1 y) | Rate of VOCs leading to health care visit (time frame: 1 y) |
| Primary end point | VOCs rate: (A) 0.38 (0.03); (B) 0.31 (0.04), P = .054 | Hb response at week 24: (A) 51% (95% CI, 41-61)∗; (B) 33% (95% CI, 23-42); (C) 7% (95% CI, 1-12) | Reduction of the duration of VOCs: 81.8 vs 77.8 h (P = .09) | Time to readiness-for-discharge: (A) 87.9 (65.7-100.2) vs (B) 93.5 (74.7-109.7) h; diff: −5.7 (P = .79) | Time to VOCs resolution: (A) 100.4 h (95% CI, 85.5-116.8) vs (B) 86.4 hours (70.6-95.1). HR, 0.89 (0.6-1.3; P = .55) | VOCs rate: (A) 2.30 events P-YRS, (B) 2.77 events P-YRS; rate ratio, 0.83; (95% CI, 0.66 to 1.05) (P = .12) | VOCs rate: median, (A) 3 vs (B) 4 (P = .005) | Annual VOCs rate: median, (A) 1.63 vs (B) 2.01 vs (C) 2.98 (P = .01) | Annual VOCs rate: median, (A) 2.04 vs (B) 2.49 vs (C) 2.30 (P = ns) |
| Secondary end points | Change from baseline in Hb g/dL (SE): (A) 5.9 (1)∗; (B) −1.0 (1.0), P = <.001 % indirect bilirubin: (A) −16.6 (2.1)∗; (B) −0.3 (1.7), P < .001 % reticulocytes: (A) −2.46 (0.42)∗; (B) 0.79 (0.30), P < .001 erythrocyte count: (A) 0.23 (0.04)∗; (B) −0.02 (0.04), P < .001 LDH: (A) −58.7 (10.6)∗; (B) 13.2 (12.4), P < .001 FACIT-Fatigue score: (A) 1.3; (B) 2, P = ns | Change from baseline in Hb g/dL (95% CI): (A) 1.1 (0.9-1.4)∗; (B) 0.6 (0.3-0.8); (C) −0.1 (−0.3 to 0.2) % indirect bilirubin: (A) −29.1 (−35.9 to −22.2)∗; (B) −20.3 (−27.1 to −13.6); (C) 3.2 (−10.1 to 3.8) % reticulocytes: (A) −19.9 (−29.0 to −10.9)∗; (B) −1.3 (−10.3 to 7.7); (C) 4.5 (−4.4 to 13.6) Absolute reticulocytes count: (A) −8.0 (−18.1 to 2.1); (B) 5.1 (−4.9 to 15.2); (C) 3.1 (−7.0 to 13.2) LDH: (A) −4.5 (−11.9 to 2.8); (B) 1.4 (−5.9 to 8.7); (C) 3.4 (−4.0 to 10.9) VOCs per person-year: (A) 2.77 (1.15-3.57); (B) 2.76 (2.15-3.53); (C) 3.19 (2.50-4.07) | ACS n/total (%): 32/194 (16.5%) vs 22/194 (11.3%) Re-hospitalization for VOC within 14 d of initial discharge n/total (%): 16/192 (8.3%) vs 13/190 (6.8%) | Median time to discharge: 86.8 (71.3-98.7) vs 90.7 (72.1-108.6) h, P = .72 Median time to discontinuation of IV opioids: 67.2 (53.3 - 80.5) vs 68.5 (53.8-85) h, P = .86 | Mean change in pain severity: (A) −35.3 mm (SD, 19.7) vs (B) −34.1 mm (SD, 18.8) (P = .726) Median time to a 30% pain reduction: (A) 24.1 hours (95% CI, 16.0-39.9) vs (B) 20.1 h (95% CI, 16.0-24.2) (P = ns) | ACS rate: (A) 0.11 vs (B) 0.12 events per person-y; Rate ratio: 0.96; 95% CI, 0.48-1.93; P = .92 Hospitalization for VOCs rate: (A) 1.06 vs (B) 1.13 events per person-y; rate ratio, 0.94; 95% CI, 0.65-1.37; P = .76) | Hospitalizations: median, 2 vs 3 (P = .005) ED visits for sickle cell–related pain: median, 1 vs 1 (P = .9) | Time to 1st and 2nd VOC: median, (A) 4.07 vs (B) 2.20 vs (C) 1.38 months (P = .001), and (A) 10.32 vs (B) 9.20 vs (C) 5.09 months (P = .02) Annual rate of uncomplicated VOCs: median, (A) 1.08 vs (B) 2 vs (C) 2.91 (P = .02) Annual rate of Hx d: median, (A) 4.00 vs (B) 6.87 vs (C) 6.87 (P = .45) Annual rate of ACS (median rate per year, 0.00) | Rate of all VOCs leading to health care visit and treated at home: median, (A) 3.22 vs (B) 4.70 vs (C) 3.87 (P = ns) |
| Drug . | Indirect inhibition of HbS polymerization . | Targeting adhesion . | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Senicapoc . | Voxelotor . | Velopoxamer . | Rivipansel . | Sevuparin . | Prasugrel . | L-Glutamine . | Crizanlizumab . | ||
| OD | FDA | FDA-EMA | EMA | FDA-EMA | FDA-EMA | FDA | FDA-EMA | FDA-EMA | |
| Marketing authorization | Not approved | United States-EU | Not approved | Not approved | Not approved | Not approved | United States | United States-EU∗ | |
| Study | ASSERT-(NCT00102791) Ataga et al,19 Brit J Haematol 2011 | HOPE-(NCT03036813) Vichinsky et al,20 N Engl J Med 2019 | EPIC-(NCT01737814) Casella et al.21 JAMA 2021 | RESET-(NCT02187003) Dampier et al.22 Blood 2023 | NCT02515838 Biemond et al.23 Lancet Haematol 2021 | DOVE-(NCT01794000) Heeney et al.24 N Engl J Med 2016 | NCT01179217 Niihara et al.25 N Engl J Med 2018 | SUSTAIN-(NCT01895361) Ataga et al,26 N Engl J Med 2017 | STAND-(NCT03814746) |
| Mechanism of action | Gardos channel inhibitor | Binds directly to HbS so increasing HbS oxygen affinity | Blocks cell-to-cell interactions | E-selectin antagonist | P- and L-selectins inhibitor, thrombospondin, fibronectin, and von Willebrand factor | Inhibits ADP-mediated platelet activation and aggregation | Regulates oxidative stress by normalizing the altered NAD redox system | P-selectin inhibitor | |
| Study aim | Prevention of VOC | Hemoglobin response and markers of hemolysis | Treatment of VOC | Treatment of VOC | Treatment of VOC | Prevention of VOC | Prevention of VOC | Prevention of VOC | |
| Study design and arms | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 297 (A) 145 senicapoc 20 mg bid for 4 d followed 10 mg QD (B) 144 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 274 (A) 90 voxelotor 1500 mg QD (B) 92 voxelotor 900 mg QD (C) 92 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 388 (A) 194 poloxamer 188 (1-h loading 100 mg/kg; 12-48 h at 30 mg/kg per hour) (B) 194 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 345 (A) 173 rivipansel (>12 y: 1680 mg followed by 840 mg every 12 h; 6-11 y: 40 mg/kg (max 1680 mg) followed by f 20 mg/kg (max of 840 mg) every 12 h. (B) 172 placebo | Phase 2, multicentre, randomized, double-blinded, placebo-controlled N = 144 (A) 68 Sevuparin 3 mg/kg loading dose followed by 18 mg/kg per day continuous infusion (B) 76 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 341 (A) 171 Prasugrel 0.08 mg/kg then adjusted to 0.04-0.12 mg/kg (max 10 mg) (B) 170 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 230 (A) 152 L- glutamine 0.3 g/kg (B) 78 placebo | Phase 2, multicenter, randomized, double-blind, placebo-controlled N = 198 (A) 67 Crizanlizumab 5 mg/kg (B) 66 crizanlizumab 2.5 mg/kg (C) 65 placebo | Phase 3, multicenter, randomized, double-blind, placebo-controlled N = 252 (A) 83 Crizanlizumab 7.5 mg/kg (B) 84 crizanlizumab 5 mg/kg (C) 55 placebo |
| Eligibility criteria | Age: 16-65 y Hb level: from 4 to 11 g/dL at screening | Age: 12-65 y Hb level: from 5.5 to 10.5 g/dL at screening | Age: 4-65 y | Age: ≥6 y | Age: 12-50 y | Age: 2-17 y | Age: 5-58 y | Age: 16-65 y | Age: ≥12 y |
| ≥2 acute VOCs in the previous year requiring a medical facility visit and treatment with oral or parenteral opioids or other analgesics, or ACS, hepatic/splenic sequestration, priapism, stroke and death | 1-10 moderate/severe acute VOCs or ACS in the previous year, requiring oral or parenteral opioids or other analgesics prescribed by a health care professional in a medical setting or by telephone at home | Acute VOCs treated in a medical setting with parenteral opioids | Acute VOCs treated in a medical setting with parenteral opioids | Acute VOCs to be treated/or treated with parenteral opioid analgesia and need for hospitalization at least 48 h. | ≥2 acute VOCs in the previous year, requiring therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care provider in a medical setting or at home or ACS. | ≥ 2 acute VOCs during the previous year treated with a parenteral opioid in a medical setting or ACS, priapism, and splenic sequestration; patients on HU at a stable dose for at least 3 mo. | 2-10 VOCs the previous year requiring medical facility visit and treatment with oral or parenteral opioids, or parenteral nonsteroidal anti-inflammatory drugs; patients on HU at a stable dose for at least 3 mo. | ≥2 VOCs in the previous year leading to health care visit and treated with oral or parenteral opioids, or parenteral non-steroidal anti-inflammatory drugs, including ACS, priapism and hepatic or splenic sequestration. | |
| Primary Outcome Measure | VOCs rate (time frame: 52 wk) | Number of participants with increase in Hb >1 g/dL from baseline to week 24 | Reduction of the duration of VOCs at hospital (time frame: expected average of 4 d) | Time to readiness-for-discharge (time frame: assessments will be every 4 h for the duration of hospitalization, expected average of 5 d) | Time to resolution of VOCs (time frame: from hospitalization until discharge) | Number of VOCs per participant per y (time frame: randomization through 24 mo) | The number of occurrences of protocol-defined VOCs (time frame: 48 wk) | Rate of VOCs leading to health care visit (time frame: 1 y) | Rate of VOCs leading to health care visit (time frame: 1 y) |
| Primary end point | VOCs rate: (A) 0.38 (0.03); (B) 0.31 (0.04), P = .054 | Hb response at week 24: (A) 51% (95% CI, 41-61)∗; (B) 33% (95% CI, 23-42); (C) 7% (95% CI, 1-12) | Reduction of the duration of VOCs: 81.8 vs 77.8 h (P = .09) | Time to readiness-for-discharge: (A) 87.9 (65.7-100.2) vs (B) 93.5 (74.7-109.7) h; diff: −5.7 (P = .79) | Time to VOCs resolution: (A) 100.4 h (95% CI, 85.5-116.8) vs (B) 86.4 hours (70.6-95.1). HR, 0.89 (0.6-1.3; P = .55) | VOCs rate: (A) 2.30 events P-YRS, (B) 2.77 events P-YRS; rate ratio, 0.83; (95% CI, 0.66 to 1.05) (P = .12) | VOCs rate: median, (A) 3 vs (B) 4 (P = .005) | Annual VOCs rate: median, (A) 1.63 vs (B) 2.01 vs (C) 2.98 (P = .01) | Annual VOCs rate: median, (A) 2.04 vs (B) 2.49 vs (C) 2.30 (P = ns) |
| Secondary end points | Change from baseline in Hb g/dL (SE): (A) 5.9 (1)∗; (B) −1.0 (1.0), P = <.001 % indirect bilirubin: (A) −16.6 (2.1)∗; (B) −0.3 (1.7), P < .001 % reticulocytes: (A) −2.46 (0.42)∗; (B) 0.79 (0.30), P < .001 erythrocyte count: (A) 0.23 (0.04)∗; (B) −0.02 (0.04), P < .001 LDH: (A) −58.7 (10.6)∗; (B) 13.2 (12.4), P < .001 FACIT-Fatigue score: (A) 1.3; (B) 2, P = ns | Change from baseline in Hb g/dL (95% CI): (A) 1.1 (0.9-1.4)∗; (B) 0.6 (0.3-0.8); (C) −0.1 (−0.3 to 0.2) % indirect bilirubin: (A) −29.1 (−35.9 to −22.2)∗; (B) −20.3 (−27.1 to −13.6); (C) 3.2 (−10.1 to 3.8) % reticulocytes: (A) −19.9 (−29.0 to −10.9)∗; (B) −1.3 (−10.3 to 7.7); (C) 4.5 (−4.4 to 13.6) Absolute reticulocytes count: (A) −8.0 (−18.1 to 2.1); (B) 5.1 (−4.9 to 15.2); (C) 3.1 (−7.0 to 13.2) LDH: (A) −4.5 (−11.9 to 2.8); (B) 1.4 (−5.9 to 8.7); (C) 3.4 (−4.0 to 10.9) VOCs per person-year: (A) 2.77 (1.15-3.57); (B) 2.76 (2.15-3.53); (C) 3.19 (2.50-4.07) | ACS n/total (%): 32/194 (16.5%) vs 22/194 (11.3%) Re-hospitalization for VOC within 14 d of initial discharge n/total (%): 16/192 (8.3%) vs 13/190 (6.8%) | Median time to discharge: 86.8 (71.3-98.7) vs 90.7 (72.1-108.6) h, P = .72 Median time to discontinuation of IV opioids: 67.2 (53.3 - 80.5) vs 68.5 (53.8-85) h, P = .86 | Mean change in pain severity: (A) −35.3 mm (SD, 19.7) vs (B) −34.1 mm (SD, 18.8) (P = .726) Median time to a 30% pain reduction: (A) 24.1 hours (95% CI, 16.0-39.9) vs (B) 20.1 h (95% CI, 16.0-24.2) (P = ns) | ACS rate: (A) 0.11 vs (B) 0.12 events per person-y; Rate ratio: 0.96; 95% CI, 0.48-1.93; P = .92 Hospitalization for VOCs rate: (A) 1.06 vs (B) 1.13 events per person-y; rate ratio, 0.94; 95% CI, 0.65-1.37; P = .76) | Hospitalizations: median, 2 vs 3 (P = .005) ED visits for sickle cell–related pain: median, 1 vs 1 (P = .9) | Time to 1st and 2nd VOC: median, (A) 4.07 vs (B) 2.20 vs (C) 1.38 months (P = .001), and (A) 10.32 vs (B) 9.20 vs (C) 5.09 months (P = .02) Annual rate of uncomplicated VOCs: median, (A) 1.08 vs (B) 2 vs (C) 2.91 (P = .02) Annual rate of Hx d: median, (A) 4.00 vs (B) 6.87 vs (C) 6.87 (P = .45) Annual rate of ACS (median rate per year, 0.00) | Rate of all VOCs leading to health care visit and treated at home: median, (A) 3.22 vs (B) 4.70 vs (C) 3.87 (P = ns) |
The table compares the study designs, the inclusion criteria, and the outcomes of the clinical trials regarding the ODs that obtained the marketing authorization either in the United States or in the EU for the treatment of SCD with those that failed in the latest phase of drug development due to a lack of efficacy.
ACS, acute chest syndrome; ADP, adenosine diphosphate; bid, twice daily; CI, confidence interval; HU, hydroxyurea; Hx d, hospitalized (days); NAD, nicotinamide adenine dinucleotide; P-YRS, person-years; SD, standard deviation; SE, standard error; QD, daily.
Conditionally approved in the EU upon the results from the Phase 2 SUSTAIN trial but withdrawn upon results from the Phase 3 STAND trial.