Positive Phase 2/3 Results Suggest Potential for GBT021601 As Future Treatment for Sickle Cell


These findings presented at ASH show promise for future studies on GBT02601 as a potential alternative to voxelotor for sickle cell disease.

Santosh L. Saraf, MD

Credit: UI Health

Santosh L. Saraf, MD

Credit: UI Health

GBT021601 loading and daily doses for 12 weeks are well-tolerated among adults with sickle cell disease (SCD), according to findings presented at the 2023 American Society of Hematology meeting, with the data indicating that there should be ongoing clinical development of GBT021601 as a future treatment for those with SCD.1

These new findings were considered invaluable, given that SCD is an inherited and lifelong disorder which is characterized by the polymerization of sickle hemoglobin (HbS), known to result in vaso-occlusive crises (VOCs), chronic hemolytic anemia, and end-organ damage.

This new research into treatment options for SCD was led by Santosh L. Saraf, MD, from the Division of Hematology/Oncology at the University of Illinois Chicago.

Voxelotor is a pioneering HbS polymerization inhibitor that was given approval in the US for SCD treatment in individuals who are aged ≥4 years, as well as in Europe for hemolytic anemia from SCD in individuals aged ≥12 years. In this new research presented at ASH, the investigators looked into an alternative for SCD.

“GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden and improve clinical outcomes,” Saraf and colleagues wrote. “Here we report preliminary safety, efficacy, and pharmacodynamic (PD) data from an ongoing phase 2/3 study of orally administered GBT021601 (NCT05431088) in patients with SCD.

The research team began phase 2/3 study, which they constructed into 3 distinct parts: Part A had a 12-week randomized, open-label trial for adult patients with the aim being to find the optimal dose of GBT021601, whereas Part B was the team’s placebo-controlled study on both adults and adolescents.

Part C involved an open-label study looking at pediatric participants. The investigators’ report covers Week 12 data drawn from that of Part A, where adults with SCD (HbSS/HbSβ0 genotype) and Hb 5.5-10.5 g/dL were given random assignment to either 100 mg of GBT021601 or 150 mg.

Elevated VCAM-1 levels during participants’ VOCs are linked with greater risk of VOC. The investigators also assessed GBT021601's impact on adherent cells through the implementation of a microfluidic device coated with VCAM-1.

The research team’s overall primary endpoint was a change in Hb at the 12-week mark. They determined their secondary endpoints to be alterations in subjects’ hemolysis markers, Hb response, safety signals, PK, and PD.

The investigators reported that, as of the June 2023 data cutoff, there were 35 subjects who had completed treatment in Part A of the study. Among those in the 100-mg arm (48.6%), the team noted that there was a mean age 29.1 years.

For those in the 150-mg arm (51.4%), the investigators noted a mean age 30.2 years, and most were shown to have the HbSS genotype. Following 12 weeks of study, the research team found that mean Hb increases from the point of baseline were 2.67 g/dL for those in the 100-mg cohort and 3.17 g/dL for those in the 150-mg cohort.

The team’s flow adhesion data showed a reduction in adherent cells. Additionally, they found that the safety data at the cutoff point showed GBT021601 was well-tolerated among the participants.

For 27 of the subjects with ≥1 VOC at the point of baseline, on-study annualized VOC rate was shown to be 1.16, with treatment-emergent adverse events among 62.9% mostly being unrelated to their treatment. TEAEs for 22.9% were shown to include diarrhea, suspected seizure, abdominal discomfort, headaches, sickle cell anemia with crisis, nausea, upper abdominal pain, and urticaria.

The investigators noted a single case of unrelated TEAE had been shown to lead to study discontinuation (sepsis), and one death unrelated to the drug was found to have been the result of a cerebrovascular event in a participant with a prior related health history, occurring after new onset high fever and no change from baseline Hb 8.0 g/dL.

“Despite large increases in mean Hb levels, pain episodes did not increase and there was a reduction of adherent cells in a flow adhesion assay with VCAM-1, a potential biomarker for VOC risk,” they wrote. “Data from Part A of this phase 2/3 study support the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD.”


  1. Saraf S, Abdullahi S, Akinsete A. Preliminary Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease. Presented at: ASH Annual Meeting and Exposition. San Diego, CA. December 9-12, 2023.
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