Voxelotor, a First-in-Class Hemoglobin Oxygen Affinity Modulator

Transcription

1 Interim Results From a Cohort in a Phase 2a Study (GBT ) Evaluating Adolescents With Sickle Cell Disease Treated with Multiple Doses of Voxelotor (GBT440) Voxelotor, a First-in-Class Hemoglobin Oxygen Affinity Modulator Carolyn Hoppe, 1 Adle0e Ina2, 2 Clark Brown, 3 Winfred Wang, 4 Victor Gordeuk, 5 Robert Liem, 6 Gerald Woods, 7 Connie Piccone, 8 Erica Fong, 9 Ganesh Balaratnam, 9 Sandy Dixon, 9 Margaret Tonda, 9 Carla Washington, 9 Yifah Yaron, 9 Josh Lehrer 9 1 Children's Hospital Oakland, Oakland, CA; 2 Rafik Hariri Univ. Hosp., Tripoli, LBN; 3 Dept. of Pediatrics, Emory University, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA; 4 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN; 5 Medicine, University of Illinois Chicago, Chicago, IL; 6 Children's Hospital of Chicago, Chicago, IL; 7 Children's Mercy Hospital, Kansas City, Kansas City, MO; 8 Rainbow Babies and Children's Hospital, Cleveland, OH; 9 Global Blood Therapeu2cs, South San Francisco, CA

2 Consultant/advisory boards: Bio-Rad Laboratories Biovera7v Novar7s Cydan (Imara) Global Blood Therapeu7cs DISCLOSURES

3 VOXELOTOR CLINICAL HYPOTHESIS: INCREASE IN Hb O 2 AFFINITY INHIBITS HbS POLYMERIZATION HbSS RBC Oxy-SS RBC Oxy-HbS monomer Sickled RBC Deoxy-HbS polymer Hemolysis Vaso-occlusion Favorable Drug Proper7es 1:1 stoichiometry of voxelotor to Hb tetramer binding Preferen7al par77oning into RBCs (75:1) Once-daily dosing Voxelotor stabilizes Hb in high oxygen affinity state and inhibits Hb polymeriza2on à decreases RBC damage Improves blood flow Modifies course of SCD Reduces hemolysis and improves anemia Deoxy, deoxygenated; Hb, hemoglobin; HbS, sickle hemoglobin; O 2, oxygen; oxy, oxygenated; RBC, red blood cell; SCD, sickle cell disease, SS, sickle cell anemia.

4 STUDY OBJECTIVES Primary Assess efficacy of voxelotor 900 mg in pediatric pa7ents with SCD as measured by improvement in anemia Secondary Evaluate effect of voxelotor on clinical measures of hemolysis Evaluate effects of voxelotor on total symptom score (TSS) from PRO measurement Evaluate safety and tolerability of voxelotor following mul7ple doses Exploratory Evaluate effect of voxelotor on TCD measures of cerebral blood flow velocity Design Open-label, 24-week daily dosing in 900 mg cohort, followed by 1500 mg cohort PRO, pa7ent-reported outcome; SCD, sickle cell disease; TCD, transcranial Doppler ultrasound; TSS, total symptom score.

5 BASELINE CHARACTERISTICS (DATA AS OF NOVEMBER 6, 2017) Baseline Characteris2cs 900 mg N=24 All Treated Pa2ents to Date (safety popula2on) 900 mg N=12 16 Weeks of Treatment (efficacy popula2on) Male n (%) 14 (58) 6 (50) Age (years, median, range) 14 (12 17) 13 (12 17) Hb SS genotype, a n (%) 23 (96) 11 (92) Number of VOCs in prior year, n (%) >4 11 (46) 11 (46) 2 (8) 7 (59) 4 (33) 1 (8) Baseline Hb (g/dl, median, range) 8.9 ( ) 8.7 ( ) Current hydroxyurea use, n (%) 21 (88) 11 (92) Baseline HbF (%, median, range) 11.2 ( ) 10.7 ( ) Baseline TAMM for TCD (cm/sec, median, range) 120 (74 149) b 120 (89 143) Hb, hemoglobin; HbF, fetal hemoglobin; HbS, sickle hemoglobin; Sβ 0 thal; sickle beta zero thalassemia; SS, sickle cell anemia; TAMM, 7me-averaged mean of maximum velocity; TCD, transcranial Doppler ultrasound; VOC, vaso-occlusive crisis. a 1 pa7ent with Sβ 0 thal; b n=20.

6 55% OF SUBJECTS (6 OF 11 a ) ACHIEVED Hb RESPONSE >1 g/dl AT 16 WEEKS b Hb, hemoglobin; HU, hydroxyurea. a Data not available on 1 subject at 16 weeks. b Not on concurrent HU.

7 HEMOLYSIS MEASURES AT 16 WEEKS Parameter Hemoglobin (g/dl) Re7culocytes (%) Unconjugated bilirubin (%) Change From Baseline Median (25th, 75th percen2le) N=11 a 1.1 (0.2, 1.6) 10.5 ( 42.3, 6.2) 39.8 b ( 67.9, 10.0) a 16-week data not available for 1 subject. b n=10.

8 DAILY SCD SYMPTOMS ASSESSED USING TSS Daily SCD symptoms recorded using PRO instrument TSS = sum of 9 ques7ons with each ques7on having score range from 0 (no symptoms) to 3 (severe symptoms) Poten7al TSS range from 0 (no SCD symptoms) to 27 (severe) for any given day, rescaled to 100-point scale PRO Conceptual Framework Body ache Worst pain Time with pain Time with pain while trying to sleep Energy level Time with 2redness Time feeling physically weak Time with trouble breathing Time with trouble concentra2ng PRO, pa7ent-reported outcome; SCD, sickle cell disease; TSS, total symptom score.

9 REDUCED TSS AT WEEK 16 (N=12) Mean TSS (0 100) 10 of 12 subjects showed reduc7on in TSS from baseline to week 16 There was a 94% median reduc7on in TSS from baseline 5 of 12 subjects had a mean TSS of 0 at week 16 1 subject had a mean TSS of 0 at baseline and at week 16 (no change) TSS, total symptom score. Weeks Each dot represents mean daily TSS averaged over preceding study period (2-week screening and weeks of treatment)

10 SAFETY AND TOLERABILITY Voxelotor 900 mg was well tolerated up to 24 weeks of dosing Drug-related AEs related to voxelotor were grade 1 or 2 (except one grade 3 rash*) There were no drug-related SAEs There were no study drug discon7nua7ons due to AEs Drug-related AEs occurring in 2 pa2ents Adverse Event Voxelotor 900 mg N=24 Number (%) Nausea 3 (12.5) Headache 2 (8.3) Rash 2 (8.3) AEs, adverse events; SAEs, serious adverse events. 10 *Did not recur with con7nued dosing.

11 NORMAL TCD VELOCITY AT BASELINE PRECLUDES ASSESSMENT OF TREATMENT EFFECT All pa7ents normal at baseline a with TCD <170 cm/sec 200 Condi7onal TCD Range 150 TCD Velocity 100 TCD, transcranial Doppler ultrasound. a 7 of 12 pa7ents had numerical decrease at week Weeks

12 SUMMARY 55% (6 of 11 pa7ents) achieved >1 g/dl response at 16 weeks and a median Hb change of 1.1 g/dl Reduc7on in clinical measures of hemolysis in adolescents were consistent with results in adults There was improvement in SCD TSS at 16 weeks (10 of 12 pa7ents) There were no drug-related SAEs or drug-related discon7nua7ons due to adverse events PK profile of adolescents was similar to adults (data not shown) Hb, hemoglobin; PK, pharmacokine7c; SAEs, serious adverse events; SCD, sickle cell disease; TSS, total symptom score.

13 CONCLUSIONS Voxelotor 900 mg for 16 weeks in adolescents with SCD, the majority on HU, demonstrated consistent and sustained efficacy on Hb levels and measures of hemolysis The 1500 mg dose is currently being evaluated in this ongoing study Improvement in TSS in mildly symptoma7c pa7ents suggests that the PRO is sensi7ve to treatment effect and supports use in the ongoing HOPE phase 3 study Results provide a reassuring safety and tolerability profile consistent with results in adults Future studies assessing the effect of voxelotor on TCD velocity should enrich for pa7ents with condi7onal/abnormal TCD at baseline Interim results support ongoing clinical evalua2on of voxelotor as a poten2al disease-modifying therapy for adults and children with SCD Hb, hemoglobin; HOPE; Hemoglobin Oxygen Affinity Modula7on to Inhibit HbS Polymeriza7on; HU, hydroxyurea; PRO, pa7ent-reported outcome; SCD, sickle cell disease; TCD, transcranial Doppler ultrasound; TSS, total symptom score.

14 ACKNOWLEDGMENTS The authors wish to thank all the pa7ents with sickle cell disease, families, caregivers, research nurses, study coordinators, and support staff who contributed to this study Medical wri7ng and editorial assistance was provided by ApotheCom (San Francisco, CA) and was supported by Global Blood Therapeu7cs, Inc This study was supported by Global Blood Therapeu7cs