Date: 2016-12-04
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 58th American Society of Hematology (ASH) Annual Meeting
Company: Global Blood Therapeutics (USA - CA)
Product: GBT440
Action
mechanism: hemoglobin modifier. GBT440 is being developed as an oral, once-daily therapy for patients with sickle cell disease. GBT440 works by increasing hemoglobin's affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, GBT believes GBT440 blocks polymerization and the resultant sickling of red blood cells (RBCs). With the potential to restore normal hemoglobin function and improve oxygen delivery, GBT440 may be capable of modifying the progression of sickle cell disease. The FDA has granted GBT440 both Fast Track and Orphan Drug designation for the treatment of patients with sickle cell disease in recognition of the critical need for new treatments.
Disease: sickle cell disease
Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases
Country: UK
Trial
details: GBT440-001 is a randomized, placebo-controlled, double-blind, single and multiple ascending dose study evaluating the safety, tolerability, PK and PD of GBT440 in both healthy subjects and patients with SCD. The study is being conducted in three parts: Part A (single dose administration), Part B (multiple dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients) and Part C (multiple dose administration, daily for 90 days in SCD patients). (NCT02285088)
Latest
news: * On December 4, 2016, Global Blood Therapeutics announced the presentation of results from its ongoing Phase 1/2 GBT440-001 study that further support the safety and efficacy profile of GBT440 as a potentially disease-modifying therapy for sickle cell disease. These data were presented at the 58th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego. Results showing how GBT440 is metabolized in healthy subjects were also presented. All 41 patients receiving GBT440 for up to six months have shown a profound and durable reduction in hemolysis as assessed by hemoglobin, reticulocytes and/or bilirubin. * On October 7, 2016, Global Blood Therapeutics announced that presentations of the GBT440-001 study data supporting the durability, safety and mechanism of action of GBT440 in sickle cell disease were presented in an oral session at the Academy for Sickle Cell and Thalassemia (ASCAT) 10th Anniversary Conference in London. These data were previously presented at the European Hematology Association's 21st Congress in June (see below). In the six patients treated with GBT440 700 mg/day for 90 days, results showed a durable reduction in hemolysisfrom baseline to day 90, as evidenced by a rapid and sustained reduction in bilirubin starting as early as day 4 and continuing through day 90 (median decrease of greater than 35% compared with an increase of approximately 20% with placebo). Data show a median 1.1 g/dL increase in hemoglobin concentration with GBT440 treatment compared with a 0.2 g/dL decrease with placebo. There is also amedian decrease of approximately 20% in reticulocyte count compared with an approximately 20% increase with placebo, suggesting that the observed increase in hemoglobin is due to a decrease in hemolysis. * On June 10, 2016, Global Blood Therapeutics announced new results from its ongoing Phase 1/2 GBT440-001 study in sickle cell disease (SCD) that further support the company's plans to develop GBT440 as a potential disease-modifying therapy for SCD. The data being presented at the European Hematology Association's (EHA) 21st Congress in Copenhagen include a poster presentation of 90-day data from a cohort of patients in the Phase 1/2 study who were taking 700 mg/day of GBT440 and 28-day results from three dosing cohorts of GBT440 (abstract #P371). Data on the pharmacokinetics (PK) and pharmacodynamics (PD) of GBT440 are being highlighted in a separate poster presentation (abstract #P370). As of June 2, 2016, eight SCD patients completed Part A of the study, 38 SCD patients completed Part B of the study, and 8 patients have either completed Part C of the study or are still being followed (700 mg cohort); the higher dose cohort in Part C (900 mg) is currently enrolling. Of the 46 SCD patients in Parts B and C, 16 patients have completed 700 mg/day dosing for 28 days and follow-up (12 on GBT440, 4 on placebo), 14 patients have completed 500 mg/day dosing for 28 days and follow-up (10 on GBT440, 4 on placebo), 8 patients have completed 1,000 mg/day dosing for 28 days and follow-up (6 on GBT440, 2 on placebo) and 8 patients have completed 700 mg/day dosing for 90 days (6 on GBT440, 2 on placebo). 90-Day Results in GBT440-001 700 mg/day: The new 90-day results with GBT440 700 mg/day (n=6) showed: A durable reduction in hemolysis from baseline to day 90, as evidenced by a rapid and sustained reduction in bilirubin starting as early as day 4 and continuing through day 90 (median decrease of greater than 35% compared with an increase of approximately 20% with placebo). 28-Day Results in GBT440-001 from Three Dosing Cohorts: The complete 28-day results from three dosing cohorts of GBT440 (500 mg [n=10]), 700 mg [n=12] and 1,000 mg administered as 500 mg BID [n=5]) showed: The therapeutic target between 10-30% Hb modification was achieved at GBT440 doses ?500 mg. GBT440 demonstrates linear, dose-proportional pharmacokinetics with a half-life of 2.8 and 1.6 days in healthy subjects and SCD patients, respectively. While SCD subjects are right-shifted at baseline, a dose proportional left shift in the P50 to the normal range (26-29 mm Hg) in the oxygen equilibrium curve was observed. Collectively, these data confirm the mechanism of action and pharmacodynamic effect of GBT440 and support once daily dosing. GBT440-001 Overall Safety Summary: Across the GBT440 clinical development program, GBT440 has now been dosed in 177 adults, including 99 subjects in multiple dosing cohorts up to 90 days. It has been shown to be well tolerated with no drug-related serious adverse events. There has been no evidence of tissue hypoxia in healthy subjects up to approximately 40% Hb modification or in SCD subjects up to approximately 30% Hb modification.
All patients taking GBT440 showed profound and durable reductions in irreversibly sickled cells compared with those taking placebo.
Results from Part C (dosing for at least 90 days) demonstrate that among the 13 GBT440-treated patients:
Patients treated with GBT440 for at least 90 days demonstrated a clinically significant increase in hemoglobin (greater than 1 g/dL increase) compared with 14 placebo patients (46 percent vs. 0 percent; p=0.006).
Patients treated with GBT440 had a sustained reduction in irreversibly sickled cells compared with placebo treated patients (-76.6 percent vs. +9.7 percent; p<0.001).
GBT440 was well tolerated up to six months of dosing. The most common treatment-related adverse events were Grade 1/2 headache and gastrointestinal disorders, and occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events. No sickle cell crises events occurred in study participants while on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).
Results of a study evaluating the pharmacokinetics, metabolism and excretion of GBT440 given orally to healthy subjects showed that the drug was completely excreted from the body, with a half-life of approximately three days. This is much shorter than the lifespan of a red blood cell (about 120 days) of a healthy subject, suggesting that the binding of GBT440 to hemoglobin is a reversible process. The data also suggest that the pharmacokinetics of GBT440 are unlikely to be affected in patients with renal disorders.
GBT440 was well tolerated over 90 days of dosing. The most common adverse event was headache, seen in both the placebo and GBT440 arms. There have been no drug-related serious adverse events.
Complete 28-day results from three dosing cohorts of GBT440 (500 mg [n=10]), 700 mg [n=12] and 1,000 mg administered as 500 mg BID [n=5]) showed a consistent beneficial effect was seen in at least one key parameter: hemolysis, reticulocytosis or sickle cell counts. The therapeutic target between 10-30% Hb modification was achieved at GBT440 doses ?500 mg.
A median 1.1g/dL increase in hemoglobin concentration was observed with GBT440 treatment compared with 0.2 g/dL decrease with placebo.
A median decrease of approximately 20% in reticulocyte count compared with an approximately 20% increase with placebo, suggesting that the observed increase in hemoglobin is due to a decrease in hemolysis (red blood cell destruction).
After initial variability of hemoglobin and reticulocytes during the first 3-6 weeks (likely due to bone marrow adjusting to dramatic reduction in hemolysis), hemoglobin and reticulocyte counts show steady improvement through day 60 to 90.
A sustained reduction in irreversibly sickled cells, with a median decrease of approximately 70% within 90 days compared to an increase of approximately 15% with placebo.
GBT440 was well tolerated over 90 days of dosing. The most common adverse event was headache, seen in both the placebo and GBT440 arms. There have been no drug-related serious adverse events.
A consistent beneficial effect was seen in at least one key parameter: hemolysis, reticulocytosis or sickle cell counts.
GBT440 Pharmacokinetic (PK) and Pharmacodynamic (PD) Data
