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Sickled and normal
red blood cells
Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said. end hematology article

*Data in the abstract differ from the presentation.

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