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Cutting out sickle-cell disease and beta-thalassemia with CRISPR-Cas9

The US FDA has accepted Vertex and CRISPR Therapeutics’ BLA for exagamglogene autotemcel (exa-cel), a first-in-modality CRISPR-Cas9 therapy. This gene-editing regimen will be assessed for sickle-cell disease (SCD), with a priority review status, and for transfusion-dependent beta-thalassemia (TBT).

SCD and TBT are beta-hemoglobinopathies caused by mutations in the beta-subunit of hemoglobin, resulting in the production of abnormal hemoglobin with reduced oxygen-carrying function.

Exa-cel is an ex vivo autologous cell therapy where a patient’s own stem cells are edited to produce high levels of fetal hemoglobin (HbF). HbF occurs naturally during fetal development but is silenced after birth. HbF produced by reactivation of the corresponding genes by exa-cel can compensate for the defective adult hemoglobin occurring in SCD and TBT.

The BLA applications for exa-cel are backed by promising results from two pivotal trials. Of the 27 evaluable patients with TBT in the CLIMB-111 trial, 24 (88.9%) achieved the primary end point of transfusion independence for at least 12 consecutive months. Similarly, 16 (94.1%) of the 17 patients with SCD in the CLIMB-121 trial achieved the primary endpoint of freedom from vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was consistent with the standard-of-care treatment for SCD.

With a regulatory decision date set for December 2023 and March 2024 for the SCD and TBT indications, respectively, if approved, exa-cel will be the first CRISPR-Cas9 regimen to become available, after a mere decade of the landmark 2012 publication on harnessing this gene-editing system.

Written by Zaraa Malvat


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