Priority review granted for sickle cell, TDT gene therapy application

Health Canada expected to finish exa-cel's application within 180 days

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Health Canada has granted priority review to the application of the gene-editing therapy exagamglogene autotemcel (exa-cel) for patients ages 12 and older with sickle cell disease (SCD) having recurrent vaso-occlusive crises (VOCs) or transfusion-dependent beta thalassemia (TDT).

The agency is expected to complete the review of Vertex Pharmaceuticals‘ application within 180 days, or about six months, instead of the usual 300 days (about 10 months). Vertex co-developed exa-cel along with CRISPR Therapeutics.

The gene therapy has received conditional approval for the same patient groups in the U.K., and Europe. It’s also approved for similar indications in the U.S., Saudi Arabia, and Bahrain. Exa-cel is marketed as Casgevy where it’s approved.

“We are pleased that exa-cel has been accepted for priority review by Health Canada and look forward to bringing this therapy to eligible patients,” Michael Siauw, general manager at Vertex Pharmaceuticals (Canada), said in a company press release.

SCD and TDT are marked by the lack of functional hemoglobin, the protein in red blood cells that’s responsible for transporting oxygen in the body.

In SCD, mutations in the HBB gene result in a defective version of hemoglobin being produced, which causes red blood cells to take on a sickle-like shape, making it harder for them to circulate through blood vessels. The misshaped cells can obstruct blood vessels and restrict blood flow to tissues and organs, causing VOCs and other sickle cell symptoms and complications. In TDT, little to no hemoglobin is produced.

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Casgevy is a gene-editing therapy that increases fetal hemoglobin production. This version of hemoglobin is normally produced during fetal development and is more effective at transporting oxygen than its adult counterpart.

The therapy uses a patient’s hematopoietic stem cells, which are in the bone marrow and can give rise to all types of mature blood cells. The cells are then edited with the CRISPR gene editing tool to enable the production of fetal hemoglobin, which shuts down after birth. The modified cells are returned to the patient via a stem cell transplant, where they should multiply in bone marrow and give rise to new cells that can produce fetal hemoglobin.

The application for exa-cel’s approval in Canada is supported by data from the ongoing Phase 2/3 CLIMB-121 trial (NCT03745287), which included people with SCD, and the Phase 2/3 CLIMB-111 trial (NCT03655678) with TDT patients.

Data from CLIMB-121 presented late last year, showed exa-cel could prevent severe VOCs for at least a year in all but one of the evaluated SCD patients, all of whom were free of hospitalizations due to severe VOCs for at least 12 consecutive months. The therapy also led to sustained and clinically meaningful improvements in aspects of patients’ health-related quality of life, including physical, emotional, and general health.

Exa-cel was also associated with clinical benefits in TDT patients in CLIMB-111, including early and sustained increases in hemoglobin and fetal hemoglobin levels, transfusion independence, and improved quality of life.

Participants who complete either study may enter CLIMB-131 (NCT04208529), an extension study that’s collecting long-term safety data for people who received the gene therapy for up to 15 years following dosing.