CRISPR, Vertex Amend Collaboration for CTX001 in SCD, TDT

Jeffrey Leiden, MD, PhD

Vertex Pharmaceuticals will take the lead on worldwide development, manufacturing, and commercializing of CTX001, which is a CRISPR/Cas9-based gene editing therapy in development as a potentially curative therapy for sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).

The amended agreement was announced by Vertex and CRISPR Therapeutics. In the new terms of the agreement, CRISPR will received $900 million in upfront payments with the potential for $200 million, if CTX001 is approved by regulatory authorities. Additionally, if marketed, the companies plan to split revenue, with 60% to Vertex and 40% to CRISPR.

Based on preliminary findings for CTX001, the FDA has granted the gene editing therapy Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations for both TDT and SCD. In early findings from 7 patients with at least 3 months of follow-up, treatment with CTX001 resulted in increased fetal hemoglobin (HbF) production and total Hb overall, according to findings presented at the 2021 Transplantation & Cellular Therapy (TCT) Meetings Digital Experience.

“Our increased investment in our partnership with CRISPR is based on the compelling clinical profile of CTX001, which shows its potential to be a durable cure for patients with SCD and TDT, and the rapid progress that we and our partners at CRISPR have made toward registration and commercialization," Jeffrey Leiden, MD, PhD, executive chairman of Vertex, said in a statement. "We see a significant commercial opportunity for CTX001, and we believe we will be able to further enhance that opportunity by fully leveraging the breadth of Vertex’s capabilities – including our established and proven R&D and commercialization expertise in serious diseases – to bring CTX001 to more patients around the world, more quickly.”

CTX001 is a first-in-human, CRISPR-Cas9-modified autologous hematopoietic stem and progenitor cell (HSPC) therapy. For the therapy, CRISPR-Cas9 is used to edit the erythroid enhancer region of BCL11A in HSPCs, which is a key transcription factor associated with HbF suppression in red blood cells.

“Working with Vertex, we have made tremendous progress with CTX001, the first CRISPR/Cas9-based therapy to demonstrate proof of concept in the clinic and together we have broken new ground in the treatment of genetic diseases," Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, said in a statement. "We have now dosed more than 30 patients with CTX001, with longest follow-up beyond two years, and we are on track to complete enrollment in both clinical trials this year."

In the presented TCT 2021 data, investigators shared efficacy and safety results from all consecutive patients infused with CTX0001 and with ≥3 months of follow-up. The 7 reported patients included 5 patients with TDT with follow-up through months 15, 6, 4, 4, and 3, plus a pair of patients with SCD with follow-up through months 12 and 3. Among patients with TDT treated with CDX001, mean neutrophil engraftment was on day 32 (range, 27-36), and median platelet engraftment was on day 37 (range, 34-52).

Among the 2 patients with SCD, neutrophil engraftment was experienced with CTX001 on day 30 and 22, and platelet engraftment was on day 30 and 33, respectively. All observed patients in the follow-up reported increased in Hb and HbF over time. Patients with TDT received their last transfusion within 2 months after CTX001 infusion, with the first patient remaining transfusion free over 15 months.

Both patients with SCD reported no vaso-occlusive crises since their CTX001 infusion. The first patient has remained free of such events for over 1 year. Investigators observed a safety profile with CTX001 consistent with busulfan myeloablation, which was given as a preconditioning regimen. One patient with TDT reported 4 serious adverse events potentially related to CTX0001, including headache, HLH, ARDS, and IPS. All serious events were clinically resolved or improving at the time of assessment, however.

“Given the transformative results and momentum that we have generated with this program, we are adopting a new operating model to enable a globally coordinated launch of CTX001, leveraging Vertex’s best-in-class global capabilities and leadership in development, manufacturing, and commercialization to enable this medicine to reach all patients that can benefit from it as quickly as possible," said Kulkarni. "We remain deeply committed to the Sickle Cell and Thalassemia patient communities and look forward to continued success in our partnership with Vertex.”