Initial Results from a Cohort in a Phase 2a Study (GBT440-007) Evaluating Adolescents with Sickle Cell Disease Treated with Multiple Doses of GBT440, a HbS Polymerization Inhibitor

Background: Sickle cell disease (SCD) is a genetic disorder in which deoxygenation produces polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing significant end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis) and other clinical complications that are under-recognized, under-treated, and associated with early death.

GBT440 is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, thereby inhibiting hemoglobin polymerization. GBT440-007 is a Phase 2a study designed to assess the safety, pharmacokinetics (PK) and efficacy of GBT440 in pediatric SCD patients (HbSS or HbSβ⁰ thalassemia). This abstract reports the first evaluation of multiple doses of GBT440 in adolescents (12 to 17 years) with SCD.

Methods: This ongoing study is being conducted in 2 parts, Part A: single dose of GBT440 at 600 mg in pediatric patients (6 to 11 years) and adolescents (12 to 17 years) and Part B: multiple doses of GBT440 at 2 dose levels, 900 mg/d and 1500 mg/d for 24 weeks in adolescents (approximately 12 patients at each dose). Part A PK data in adolescents was previously reported. The primary objective of Part B is to assess the effect of GBT440 on anemia. Secondary objectives include effect on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial Doppler ultrasound (TCD), daily SCD symptoms using a patient-reported outcome (PRO) measure and safety. The PRO Sickle Cell Disease Severity Measure (SCDSM) was developed following FDA guidance as a clinical outcomes assessment.

Results: Enrollment in Part B of the 900 mg cohort is complete. As of 21July2017, 13 patients (7 females) have received GBT440 for up to 12 weeks. The median age was 13 years (range 12 to 17 years) and median weight 52 kg (range 30 to 96 kg); 92% were on hydroxyurea (HU); 38% had 2 or more painful crises (range 2 to 8) in the year prior to enrollment.

Data for measures of hemolysis and TCD are available for 4 patients who received GBT440 for 12 weeks; all were receiving HU at study entry. Three of the 4 patients achieved hemoglobin (Hb) response of > 1 g/dl increase (Figure 1); one patient had a smaller Hb increase with documented non-adherence with study medication and associated lower GBT440 exposures. Clinical measures of hemolysis improved concordantly; median reduction in reticulocytes and indirect bilirubin were 34% and 27% respectively, consistent with previously reported results of GBT440 in adults with SCD. Preliminary data following multiple doses of GBT440 suggest that the PK in adolescents were similar to those observed in adults with SCD. Baseline TCD velocity ranged from 89 to 150 cm/s in 13 patients. One patient at 12 weeks had a decline in TCD velocity from baseline of 22 cm/s, and 3 patients showed small reductions. Empirical distribution functions of the SCDSM questionnaires indicate total symptom scores (TSS) trended lower post dose in comparison to screening (Figure 2).

All treatment-related adverse events (AEs) were Grade 1 or 2 and there were no treatment- related serious adverse events or no drug discontinuations due to AEs. The most common treatment emergent AEs were Grade 1 nausea and diarrhea reported in 2 patients.

Data for all 13 patients treated with GBT440 for a minimum of 12 weeks will be presented at the conference.

Conclusions: Based on preliminary results, treatment with GBT440 at 900 mg has been well tolerated in all 13 adolescents. Data from 4 adolescents at 12 weeks show a marked improvement in Hb and reduction in clinical measures of hemolysis. Importantly, hematologic improvements are seen in patients already maximally managed with hydroxyurea. TCD and PRO data suggest that TCD velocity (i.e. risk of stroke) and clinical symptoms may improve with GBT440 treatment. Overall, these results are consistent with in vivo inhibition of HbS polymerization by GBT440 and support the ongoing clinical evaluation of GBT440 as a potential disease-modifying therapy for SCD in an ongoing pivotal Phase 3 study.

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