Landmark approval for Vertex's CRISPR drug 2 steps closer after trial wins, PDUFA date granted

Vertex and CRISPR Therapeutics’ dream of getting the first-ever CRISPR gene editing therapy approved now seems within reach as the candidate aced primary endpoints in a pair of phase 3 trials mere hours after the FDA penciled in a decision date for December.

Thursday, Vertex and its partner CRISPR made history by securing the first CRISPR gene editing filings to be accepted for review by the FDA. The regulator will assess the CRISPR-Cas9 therapy in two indications. For sickle cell disease (SCD), the FDA has granted priority review status and set an approval decision date of Dec. 8, while a standard review for transfusion-dependent beta thalassemia (TDT) will be concluded on March 30, 2024.

The candidate, exagamglogene autotemcel (exa-cel), is an ex vivo autologous cell therapy that involves using CRISPR-Cas9 to edit a patient’s own hematopoietic stem cells to produce high levels of fetal hemoglobin.

Backing up the FDA applications will be a pair of pivotal clinical wins the companies announced in the early hours of this morning. Of the 27 patients with TDT in the CLIMB-111 trial who were evaluable for an interim analysis, 24 (88.9%) achieved the primary endpoint of transfusion independence for at least 12 consecutive months.

An analysis of all 48 patients with TDT who have received exa-cel so far showed that mean total hemoglobin reduced by at least 11 g/dL after three months and at least 12 g/dL from six months, Vertex said.

The company also shared good news from an interim analysis of the CLIMB-121 trial in patients with SCD. Of the 17 evaluable patients, 16 (94.1%) achieved the primary endpoint of not experiencing a vaso-occlusive crisis for at least 12 consecutive months.

In addition, an analysis of all 35 patients with SCD who had received exa-cel by the time of the analysis showed that mean fetal hemoglobin was more than 30% of total hemoglobin by the third month and was then maintained at approximately 40% through to follow-up, Vertex noted.

The safety profile of exa-cel was generally consistent with standard of care treatment for SCD, which is myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant, Vertex added. While no SCD patients experienced any adverse events related to the therapy, two TDT patients experienced serious adverse events that were considered related, including one participant who experienced three: hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome and headache, as well as idiopathic pneumonia syndrome that was considered related to both exa-cel and the chemotherapy busulfan.

“The updated results from both the TDT and SCD trials are remarkable and bring the promise of an autologous CRISPR/Cas9 gene-edited cell therapy one-step closer to patients who are waiting,” said Vertex Chief Medical Officer Carmen Bozic, M.D., in today’s release.

Vertex has already painted a rosy picture of its planned launch of exa-cel, where it envisions a network of about 50 authorized treatments centers in the U.S. and 25 in Europe. In preparation for the launch, Vertex has established a supply chain, including building the required manufacturing capacity, executives revealed in February.

Things have been moving fast in Europe, where the European Medicines Agency validated the approval application for exa-cel back in January. Approval could end up being just the first challenge facing Vertex and CRISPR in Europe, however. Bluebird bio won conditional EMA approval for its autologous lentiviral gene therapy in beta thalassemia in 2019, only to quit the market two years later after concluding that “there is an element of the European system that’s frankly broken.”

Hoping not to repeat bluebird’s experience, Vertex said earlier this year that it’s busy talking to commercial and government payers and policymakers in the U.S. and Europe. The company aims to ensure that broad patient access and reimbursement deals are in place when exa-cel is approved.

Exa-cel is also different from the bluebird medicine in that rather than using viral vectors to deliver a functional HBB gene, it uses CRISPR to turn off the suppression of fetal hemoglobin and thus increase the amount of healthy hemoglobin in red blood cells.

With exa-cel racing to regulators, Vertex has doubled down on its gene therapy strategy, paying $100 million upfront to CRISPR in March to use the company’s gene editing tech to develop new hypoimmune cell therapies for Type 1 diabetes.