Unique drug targets fundamental mechanism of sickle cell disease

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 [689]

Preliminary results from a new trial of the investigational drug voxelotor (previously GBT440) suggest the drug is safe and effective in older children and adolescents with sickle cell disease (SCD). Voxelotor has previously been tested only in adults. Designed to prevent the abnormal curving, or “sickling,” of red blood cells with defective hemoglobin, the drug aims to reduce the frequent pain, inflammation, and long-term tissue damage associated with the accumulation of sickled cells in blood vessels.

The results suggest voxelotor can offer benefits above and beyond those of hydroxyurea, a chemotherapy drug that has long been considered the standard of care for SCD.

“What sets this drug apart is that it was designed specifically for sickle cell disease,” said lead study author Carolyn C. Hoppe, MD, associate hematologist at UCSF Benioff Children’s Hospital Oakland. “This is one of the first drugs that intentionally targets the fundamental mechanism of sickle cell disease — the polymerization, or clumping together of sickle cell hemoglobin. This prevents cells from sickling early on, eliminating all the downstream consequences of sickling.”

People with SCD have a genetic mutation in hemoglobin, the protein in red blood cells responsible for binding oxygen. This causes red blood cells to become rigid and misshapen, building up in blood vessels and impeding the delivery of oxygen to tissues. Administered orally, voxelotor binds to the defective hemoglobin, preventing the red cells from forming the characteristic sickled shape and thereby reducing the risk of life-threatening sickle cell crises.

This trial is being conducted in 24 teens (ages 12 to 17) with SCD. A preliminary analysis of results from the first 12 patients treated for 16 weeks reveals that voxelotor increased hemoglobin, reduced anemia, and helped participants’ red blood cells live longer. These results mirror the findings from previous trials conducted in adults. In addition, the researchers noted evidence of reductions in pain and possibly the risk of stroke. The treatment was not associated with any serious adverse effects.

Because most of the study participants also took hydroxyurea before and during the voxelotor trial, the improvements seen in the trial suggest the two drugs could provide additive effects. The researchers are continuing to assess outcomes in the enrolled patients and to experiment with different dosing regimens.

This study was supported by Global Blood Therapeutics, Inc.

Carolyn C. Hoppe, MD, UCSF Benioff Children’s Hospital Oakland, will present this study during an oral presentation on Monday,December 11, at 2:45 p.m. EST in Room B308 of the Georgia World Congress Center.