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A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease

Jo Howard, Claire Jane Hemmaway, Paul Telfer, D. Mark Layton, John Porter, Moji Awogbade, Timothy Mant, Daniel D. Gretler, Kobina Dufu, Athiwat Hutchaleelaha, Mira Patel, Vincent Siu, Sandra Dixon, Noel Landsman, Margaret Tonda and Joshua Lehrer-Graiwer

Article Figures & Data

Figures

  • Figure 1.

    Study flowchart for the SCD cohort of the GBT440-001 study.

  • Figure 2.

    Time-dependent change in hemoglobin from baseline to day ≥90.

  • Figure 3.

    Hb change from baseline to last observation (≥90 days): responder analysis for ≥1 g/dL. *Day 15 presented due to a protocol-specified dose reduction on day 17 (because of a 2.7 g/dL increase in Hb). †Day 150 presented because this is the last time point collected for Hb while the patient was receiving study drug. ‡Concurrent hydroxyurea. §Documented nonadherence with study drug regimen.

  • Figure 4.

    Sickled red cells. Change from (A) baseline (Wright-Giemsa stain) to (B) day 90 (Wright-Giemsa stain) in SCD patients. (C) Percentage of sickled red cells. Relative change from baseline, median, and 25th and 75th percentile; baseline irreversibly sickled cell (ISC) counts ranged from 3.1% to 17.2%. †Represents 5 of 6 subjects at day 90 (D90).

  • Figure 5.

    A summary of the p20 and p50 values observed in SCD patients after 28 days of dosing. (A) p20 values; (B) p50 values. *Sidak multiple comparisons tests were used to measure statistical significance. ns, not significant.

  • Figure 6.

    Linear correlation. Linear correlation observed between the percentage of Hb modification (derived from OECs) and the percentage of Hb occupancy (derived from voxelotor RBC concentrations) in time-matched samples from SCD patients.

Tables

  • Table 1.

    Patient demographics and baseline characteristics

    Voxelotor/placebo, mg/dMultiple dose for 28 dMultiple dose for 90 d
    Placebo5007001000Placebo700900
    N1010126466
    Median age (range), y38 (21-53)29 (20-48)29 (20-56)40 (25-47)28 (18-48)41 (29-53)37 (25-42)
    Male sex, n (%)6 (60)8 (80)4 (33)2 (33)3 (75)4 (67)3 (50)
    Median BMI (range), kg/m223.5 (19.6-30.5)21.4 (17.2-27.5)23.0 (17.8-34.4)22.4 (20.2-26.1)18.8 (17.2-28.4)26.9 (21.9-35.3)22.8 (20.0-27.3)
    Median baseline Hb (range), g/dL8.1 (7.2-10.0)7.9 (7.0-9.7)9.1 (7.5-9.8)8.2 (7.5-8.4)7.9 (7.2-9.3)8.3 (7.1-9.7)9.0 (7.6-9.7)
    Hospitalizations due to painful crisis in the previous 12 mo, median (range)1 (0-7)0 (0-1)1 (0-7)1 (0-4)1 (0-2)0 (0-2)0 (0-1)
    Patients with 0 events in previous 12 mo, n5753245
    Blood transfusions in previous 12 mo, median (range)0 (0-1)0 (0)0 (0-4)0 (0-5)0 (0)0 (0)0 (0-1)
    Current use of HU, n (%)3 (30)1 (10)3 (25)2 (33)1 (25)0 (0)2 (33)
    • BMI, body mass index; HU, hydroxyurea.

  • Table 2.

    Change in hemolysis measures from baseline to day 28

    Change from baseline to day 28Multiple dose for 28 d
    Voxelotor/placebo, mg/dPlacebo5007001000
    N1010126
    Hb, median (25th, 75th percentile), g/dL−0.1 (−0.4, 0.4)0.4 (0.1, 0.7)0.7 (0.5, 1.0)0 (−0.4, 0.3)
    Unconjugated bilirubin, median (25th, 75th percentile), % change−3.6 (−25.9, 6.7)−30.6 (−48.9, −15.4)−42.6 (−44.4, −23.8)−56.3 (−57.8, −47.1)
    Percentage of reticulocytes, median (25th, 75th percentile), % change9.0 (−1.7, 13.7)−31.2 (−48.9, −20.8)−37.0 (−52.6, −4.5)−49.9 (−64.3, −34.4)
    LDH, median (25th, 75th percentile), % change−6.6 (−16.8, −2.9)−19.9 (−39.0, 6.2)−12.0 (−30.2, −5.7)−12.4 (−20.2, −12.1)
    Sickled red cells, median (25th, 75th percentile), % change12.9 (−13.6, 12.9)−56.4 (−70.2, −26.2)−45.9 (−93.0, −6.0)−45.7 (−57.9, 5.9)
  • Table 3.

    Change in hemolysis measures from baseline to 90 days or more

    Change from baseline to end of treatmentDosing duration ≥90 dP* for pooled voxelotor vs placebo
    Voxelotor/placebo, mg/d700900700/900Placebo
    N67§134
    Hb, median (25th, 75th percentile), g/dL1.1 (0.6, 1.3)0.8 (0.5, 1.3)1.0 (0.6, 1.3)−0.1 (−0.2, 0.1)<.05
    Unconjugated bilirubin, median (25th, 75th percentile), % change−37.2 (−43.4, −23.7)−42.9 (−58.4, −30.5)−39.7 (−49.9, −28.8)14.8 (1.8, 18.5)<.05
    Percentage of reticulocytes, median (25th, 75th percentile), % change−21.0 (−32.9, −18.1)−18.9 (−35.4, −6.2)−18.9 (−32.9, −15.0)8.9 (2.5, 25.5)<.05
    LDH, median (25th, 75th percentile), % change0.8 (−14.7, 1.1)−47.7 (−63.4, −12.5)−12.9 (−47.7, 0.9)0.5 (−0.7, 7.2)NS
    Dense RBC, median (25th, 75th percentile), % change−35.5|| (−63.1, 18.1)−21.0 (−60.5, 11.3)−31.4# (−62.5, 11.3)3.8** (−21.3, 4.3)NS
    Sickled red cell, median (25th, 75th percentile), % change−72.6 (−79.0, −60.6)−79.2 (−91.3, −57.7)−74.0†† (−88.6, −57.0)6.9 (3.9, 10.3)<.05
    • NS, not significant.

    • * Wilcoxon rank-sum test.

    • Ninety days of dosing.

    • Ninety days to 6 months of dosing (2 patients had 90 days of dosing, 1 patient had 118 days of dosing, and 4 patients had 6 months of dosing).

    • § Includes 1 patient who received placebo in GBT440-001 and voxelotor 900 mg for 6 months in GBT440-024.

    • || n = 4.

    • n = 6.

    • # n = 10.

    • ** n = 3.

    • †† n = 12.

  • Table 4.

    TEAEs occurring in 10% or more of patients

    Voxelotor/placebo, mg/dPooled placebo
    5007007009001000All
    Days28289090 d to 6 mo2828-90
    N101267*641*14
    Headache, n (%)4 (40)5 (42)1 (17)2 (29)4 (67)16 (39)8 (57)
    Back pain, n (%)2 (20)3 (25)02 (29)2 (33)9 (22)2 (14)
    Pain, n (%)1 (10)4 (33)02 (29)1 (17)8 (20)4 (29)
    Pain in extremity, n (%)1 (10)1 (8)1 (17)2 (29)05 (12)0
    Diarrhea, n (%)02 (17)02 (14)2 (33)6 (15)0
    Cough, n (%)02 (17)2 (33)01 (17)5 (12)0
    Rash, n (%)001 (17)1 (14)3 (50)5 (12)1 (7)
    Sickle cell anemia with crisis,§ n (%)2 (20)2 (17)2 (33)2 (29)1 (17)9 (22)1 (7)
    • * Includes 1 patient who received placebo in GBT440-001 and transitioned to voxelotor 900 mg in the extension study.

    • Grade 1; all resolved with continued dosing.

    • Two patients had treatment-related rashes (preferred terms of rash and rash papular): 1 in the voxelotor 1000-mg group and 1 in the voxelotor 900-mg group. Other TEAEs of rash were not consistent with drug rashes.

    • § Also referred to as VOC. Events occurred off-treatment (during posttreatment follow-up; n = 9) or after a dose hold/dose reduction (voxelotor 900-mg group; n = 1).

  • Table 5.

    Peak exercise oxygen uptake, ventilatory threshold, and erythropoietin with voxelotor treatment

    Voxelotor/placeboPlacebo700 mg/d900 mg/dVoxelotor-treated pooledP* for pooled voxelotor vs placebo
    N46612
    Peak exercise oxygen uptake VO2 max, mL/min/kg
     Median baseline (range)23.3 (15.7-23.8)16.7 (8.2-19.6)21.2 (17.1-23.4)18.9 (8.2-23.4)
     Median change at day 91 (range)−2.4 (−7.5 to 0.3)1.0 (−6.6 to 2.1)−1.9 (−5.0 to −0.4)−0.4 (−6.6 to 2.1)NS
    Ventilatory threshold oxygen uptake, mL/min/kg
     Median baseline (range)11.9 (11.7-12.7)9.4 (6.4-12.4)12.8 (11.5-16.3)12.0 (6.4-16.3)
     Median change at day 91 (range)−1.4 (−5.5 to 2.3)1.6 (−0.1 to 4.7)−1.4 (−1.8 to 1.4)0.6 (−1.8 to 4.7)NS
    Erythropoietin
     Median baseline mU/mL (IQR 25%:75%)112.2 (46.5, 183.0)91.2 (77.6, 125.0)113.5 (42.4, 150.0)104.4 (68.6, 137.5)
     % Median change to day 90 (IQR 25%:75%)−43.5 (−79.3, 19.7)0.4 (−32.9, 27.6)−7.2 (−11.5, −4.7)−5.2 (−22.2, 14.8)NS
    Vital signs: heart rate at rest
     Median baseline, beats per minute (range)83 (75-93)81 (65-101)87 (71-99)81 (65-101)
     Median change to day 91 (range)17 (17)11 (6-38)3 (0-5)6 (0-38)NC
    Vital signs: heart rate at peak exercise
     Median baseline, beats per minute (range)162 (160-162)150 (116-173)171 (146-184)164 (116-184)
     Median change to day 91 (range)−12 (−28 to 4)−2 (−20 to 16)1 (−7 to 8)−2 (−20 to 16)NC
    • CPET (peak exercise and ventilatory threshold) not available in all patients. CPET data available for n = 3 (placebo), n = 5 (900 mg), n = 11 (voxelotor-treated pooled).

    • IQR, interquartile range; NC, not calculated; NS, not significant.

    • * Two-sample Student t test.

  • Table 6.

    Mean (plus or minus SD) PK and PD parameters in SCD patients

    Dosing duration 28 d*Dosing duration ≥90 d
    Voxelotor/placebo, mg/dPlacebo5007001000700900
    RBC PK parameters
     Cmax, μg/mL271 ± 102329 ± 129483 ± 239242 ± 99.7336 ± 61.8
     AUC0-24, h × μg/mL5050 ± 13207560 ± 221010 100 ± 47905200 ± 23007250 ± 1430
    Plasma PK parameters
     Cmax, μg/mL3.6 ± 0.85.2 ± 1.98.1 ± 2.84.9 ± 2.06.3 ± 1.9
     AUC0-24, h × μg/mL60 ± 12.995.7 ± 28.2151 ± 49.783.1 ± 38.8128 ± 27.1
    PD parameters (obtained from whole blood)
     p50, mm Hg34.3 ± 3.330.9 ± 2.129.6 ± 2.628.0 ± 3.2NDND
     p20, mm Hg18.4 ± 1.615.1 ± 1.813.9 ± 3.110.0 ± 3.2NDND
     % Hb Mod, %−1.4 ± 4.410.6 ± 7.214.7 ± 9.627.0 ± 11.612.7 ± 4.419.8 ± 4.5
    • —, not applicable; AUC0-24 indicates area under the concentration-time curve from time 0 to 24 hours; Cmax, maximum blood or plasma concentration; % Hb Mod, percentage hemoglobin modification; ND, not determined; p20 and p50, partial pressure of O2 at which Hb is 20% or 50% saturated with O2; SD, standard deviation.

    • * Parameters on day 28 (at 6 hours postdose for PD).

    • Parameters on day 90 (at 6 hours postdose for PD).

    • Percentage Hb occupancy derived from voxelotor RBC concentrations at 6 hours postdose on day 90.