Regulatory Decision Summary for Casgevy

The purpose of this New Drug Submission (NDS), filed by Vertex Pharmaceuticals (Canada) Incorporated and accepted under the Priority Review Pathway, was to seek marketing authorization for Casgevy, pursuant to section C.08.004 of the Food and Drugs Regulations. Casgevy is an ex vivo CRISPR/Cas9 genome edited autologous hematopoietic stem cell-based therapy proposed for the treatment of patients 12 years of age or older with either sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) or with transfusion-dependent β-thalassemia (TDT). After a review of the data included in the NDS, the indication proposed by the sponsor was accepted.

Casgevy is an autologous hematopoietic stem cell-based treatment composed of CD34-positive cells in which the erythroid specific enhancer region of the BCL11A gene has been disrupted using CRISPR/Cas9 technology. Ex vivo gene editing of these cells leads to reactivation of gamma-globin protein expression and increases in fetal hemoglobin (HbF) production in erythroid progenitor cells following infusion and engraftment of the cells into patients who have undergone myeloablative conditioning. Long-term production of HbF by Casgevy ameliorates the effects of the hemoglobinopathies (i.e., severe sickle cell disease and transfusion dependent beta-thalassemia) in patients who receive this therapy.

Study 121 is an ongoing multicentre single-arm study of Casgevy in patients with severe sickle cell disease (SCD) who were 12 to 35 years of age and had at least two severe vaso-occlusive crises (VOC) events during the two years prior to screening. The primary endpoint was the proportion of patients who did not experience any severe VOCs for at least 12 consecutive months any time within the first 24 months after Casgevy infusion (VF12). Study 111 is an ongoing multicentre single-arm study of Casgevy in patients with transfusion‑dependent β‑thalassemia (TDT) who were 12 to 35 years of age and had a history of requiring 100 mL/kg/year or 10 units/year of RBC transfusions in the two years prior to enrollment. The primary endpoint was the proportion of patients achieving red blood cell (RBC) transfusion independence for 12 consecutive months (TI12), defined as maintaining a weighted average Hb ≥ 9 g/dL without RBC transfusions for at least 12 consecutive months any time within the first 24 months after Casgevy infusion.

The vast majority of SCD and TDT patients studied achieved a clinically meaningful benefit with Casgevy treatment. Twenty-nine of the thirty SCD patients who comprised the primary efficacy set achieved a VF12 (no vaso-occlusive crises for a twelve-month consecutive period) and all thirty patients were free from hospitalization due to VOCs. Thirty-nine of the forty-two TDT patients achieved a TI12 (no RBC transfusions for twelve consecutive months). The three patients who did not achieve TI12 had reductions in annualized RBC transfusion volume requirements of 83.4%, 86.9% and 98.5%, and reductions in annualized transfusion frequency of 82.4%, 73.4% and 96.0%, respectively, compared to baseline requirements. The primary outcomes are supported by sustained increases in fetal hemoglobin in both SCD and TDT patients. Overall, the outcomes are significant improvements over currently available therapies.

The safety concerns are primarily related to the myeloablative busulfan chemotherapy. The most common adverse events were febrile neutropenia, headaches, and stomatitis. One serious adverse event (SAE) (grade 4) of hemophagocytic lymphohistiocytosis (HLH; also known as macrophage activation syndrome) was considered as possibly related to Casgevy, and not related to busulfan, in a patient with TDT, which could also be related to a severe engraftment syndrome event. The sponsor will continue to follow treated patients to monitor for potential rare side-effects of this gene therapy such as hematologic oncogenesis that could arise if editing occurs at a critical off-target site within the CD34⁺ cells. There is also the possibility of neutrophil engraftment failure, and in such cases a patient will require infusion of unmodified CD34⁺ cells and will not derive benefit from Casgevy.

The benefit-risk profile of Casgevy is considered positive and this therapy has the potential to provide unprecedented efficacy in people suffering from beta hemoglobinopathies such as SCD and TDT and for whom there are currently limited treatment options.

The minimum recommended dose of Casgevy is 3 × 10⁶ viable CD34⁺ cells/kg.

A Risk Management Plan (RMP) for Casgevy was reviewed and considered acceptable by Health Canada.

The chemistry and manufacturing information submitted for Casgevy demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and the implementation of revisions requested by Health Canada, the final labelling and Product Monograph were acceptable.

A Notice of Compliance was recommended.

For additional information about Casgevy, please refer to the Product Monograph approved by Health Canada and available through the Drug Product Database.