| Summary, etc. |
<span style="font-size: 10pt;"><span style="color: #4a4a4a; font-family: Lato, &quot;Helvetica Neue&quot;, Helvetica, Arial, sans-serif; text-decoration-color: initial;">Background: Sickle cell disease (SCD) is caused by polymerization of Hemoglobin S (HbS), resulting in hemolysis and vaso-occlusion. No therapy achieving pancellular, direct inhibition of HbS polymerization is available. GBT440 is a novel small molecule which increases hemoglobin oxygen affinity and inhibits HbS polymerization and prevents sickling in vitro. Aims: This study explored safety, pharmacokinetics (PK) and pharmacodynamics (PD) of GBT440 in healthy volunteers (HV) and subjects with SCD and anti-hemolytic and anti-sickling effects in SCD subjects. Methods: This randomized, placebo-controlled, double-blind, phase I/II study enrolled HV and HbSS and HbSB0 SCD subjects. GBT440 was dose orally. The study was conducted in three parts: Part A, single ascending doses, Part B multiple ascending doses for 28 days and Part C 90-day dosing (ongoing). The primary endpoint was safety. Secondary endpoints included PK, PD and hematologic response. Results: As of 22 February 2016, 30 SCD subjects had completed Part B (10 at 500 mg; 12 at 700 mg; 8 received placebo [pbo]). The 1000 mg (28 days) and 700 mg (90 days) cohorts in Parts B and C, respectively, were still under evaluation; 60% were male, 40% were female; 20% were on hydroxyurea (HU); 80% had 0-1 painful crisis in the prior year (range 0-7); median age was 32 yrs. GBT440 was well tolerated; there were no drug-related severe or serious adverse events and the most common AEs were headache and pain. PK exposures increased dose-proportionally; mean GBT440 blood half-life after a single dose was 1.6 days in SCD subjects and RBC: Plasma ratio was 75:1. GBT440- treated subjects demonstrated increased hemoglobin oxygen affinity (p50 moved towards the normal range) and a sustained decrease in unconjugated bilirubin, a marker of hemolysis, during the treatment period, with return to baseline by day 43 (Table 1, Figure 1). Other markers of hemolysis, hemoglobin level, sickle cell counts, and erythropoietin levels improved concordantly, as did the inflammatory marker P-Selectin (Table 1, change to day 28). At the EHA conference, additional results, including hemolysis markers and exploratory markers of RBC function, will be presented from Part B 1000 mg and Part C 700 mg cohorts. Summary/Conclusions: GBT440 was well tolerated with dose-proportional PK and increases in hemoglobin oxygen affinity. GBT440 resulted in a marked and sustained reduction in clinical markers of hemolysis, an increase in hemoglobin, and decreases in erythropoietin, circulating sickle cells, and the inflammatory marker P-Selectin. These results are consistent with inhibition of HbS polymerization leading to decreased RBC damage, improved RBC lifespan, improvement in inflammation and tissue oxygen delivery, and support further investigation of GBT440 as a potential disease-modifying therapy for SCD.</span>&nbsp;</span> |