Preliminary Pharmacodynamic Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a lifelong inherited disorder resulting in polymerization of sickle hemoglobin (HbS) that leads to red blood cell sickling/damage. SCD is characterized by chronic hemolytic anemia, vaso-occlusive crises, and cumulative organ damage. Voxelotor is a first-in-class HbS polymerization inhibitor approved in the US for the treatment of SCD in patients aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years as monotherapy or with hydroxyurea. GBT021601 is a next-generation HbS polymerization inhibitor with improved pharmacokinetic properties that increases hemoglobin (Hb)-oxygen affinity and stabilizes Hb in the oxygenated state to inhibit polymerization. GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden while improving clinical outcomes. Here we report preliminary pharmacodynamic (PD) data from an ongoing phase 2/3 study of orally administered GBT021601 (NCT05431088) in patients with SCD.

Methods:This is a 3-part, multicenter, phase 2/3 study: Part A is a randomized, open-label, 12-week, dose-finding study of GBT021601 in adult participants; Part B is a randomized, double-blind, placebo controlled 48-week study and will evaluate GBT021601 vs placebo in adult and adolescent participants; and Part C will evaluate open-label GBT021601 in pediatric participants. Herein, we present Week 6 and Week 12 data from Part A, which enrolled patients aged 18-65 years with SCD (HbSS or HbSB ⁰ genotype) and had Hb 5.5-10.5 g/dL at screening. Eligible patients were randomly assigned 1:1 to GBT021601 100 mg or 150 mg and received a loading dose twice daily for 4 days followed by once-daily maintenance doses through Week 12. The primary endpoint was change from baseline (BL) in Hb at Week 12. Clinical laboratory parameters, including RBC count, Hb, hematocrit (Hct), and mean corpuscular volume (MCV), were assessed. PD assessments included red blood cell (RBC) deformability (Oxygenscan, expressed as elongation index [EI]) as a function of partial pressure of oxygen [pO ₂]).

Results: At data cutoff (June 20, 2023), 28 of the 35 patients who received treatment in Part A of the study completed 12 weeks of treatment. The 100-mg group consisted of 17 patients, with a mean (range) age of 29.1 (18-49) years. The 150-mg group had 18 patients, with a mean (range) age of 30.2 (18-59) years. Most patients (32/35 [91.4%]) were homozygous for SCD (HbSS genotype). At BL, 16/35 patients (45.7%) were taking hydroxyurea. Patients treated with 100- and 150-mg doses of GBT021601 showed robust improvements from BL in several RBC parameters at 6 and 12 weeks ( Table). After 12 weeks of treatment, the mean (SD) increase in Hb from BL was 2.67 (1.52) g/dL for the 100-mg group (n=12) and 3.17 (1.82) g/dL for the 150-mg group (n=11). Additionally, the mean (SD) Hct gradually increased 7.87 (4.25) % in the 100-mg (n=12) and 9.61 (4.60) % in the 150-mg group (n=11), and RBC counts increased by 1.32 (0.79) 10 ¹²/L in the 100-mg group (n=12) and 1.53 (0.60) 10 ¹²/L, in the 150-mg group (n=11), thus approaching the normal range for these RBC parameters. At 12 weeks, mean (SD) MCV decreased from BL by 8.91 (6.49) fL in the 100-mg group (n=12) and 12.70 (9.05) fL in the 150-mg group (n=11). Ektacytometry results with GBT021601 showed marked improvement in RBC deformability with increases from BL in median EI _max at Week 6 (100 mg: 0.37 to 0.55 [n=7]; 150 mg: 0.42 to 0.55 [n=7]) and Week 12 (100 mg: 0.37 to 0.53 [n=6]; 150 mg: 0.42 to 0.50 [n=8]) and an increase in median EI _min from BL at Week 6 (100 mg: 0.09 to 0.42 [n=7]), which was indicative of improvement in RBC deformability. The median point of sickling during deoxygenation decreased from BL at Weeks 6 and 12 with dosing of GBT021601, indicating HbS polymerization was likely delayed ( Figure).

Conclusions: In patients with SCD, GBT021601 maintenance doses of 100 mg and 150 mg led to increased Hb, increased Hct, and improvements in RBC deformability by 6 weeks, which were maintained through to Week 12. Analyses of PD data show promising evidence of efficacy with near normalization of Hb and oxygenscan parameters consistent with the improved mechanism of the drug. PD data from Part A of this phase 2/3 study demonstrated blood parameters approaching normal ranges and support for the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD.