Dazzled by early positive results in a pair of Phase I/II trials, Vertex Pharmaceuticals said today it will pay CRISPR Therapeutics $900 million upfront to lead the global development, manufacturing, and commercialization of CTX001, the CRISPR-Cas9 gene-edited therapy co-developed by the companies for a pair of blood disorders, sickle-cell disease (SCD) and beta thalassemia.

The companies’ revised agreement raises the stakes for their multi-billion collaboration that began with a potentially $2.5 billion-plus collaboration launched in 2015, with an additional up-to-$1.175 billion agreed upon by the companies four years later.

Under the revised agreement Vertex has agreed to pay 60% of program costs for CTX001 and will receive 60% of profits from future sales of the gene-edited therapy—up from the companies’ previous 50-50 split, when Vertex initially agreed to pay $105 million upfront ($75 million cash plus $30 million in equity) for its 50% stake, and CRISPR Therapeutics agreed to lead commercialization of any product developed by the companies.

CRISPR Therapeutics has agreed to bear the remaining 40% of costs in return for 40% of profits.

Vertex also plans to pay CRISPR Therapeutics a potential additional $200 million milestone payment tied to achieving the first regulatory approval of CTX001—from the FDA or European Commission, according to a regulatory filing.

“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,” Vertex executive chairman Jeffrey Leiden, MD, PhD, said in a statement.

In January, researchers from CRISPR Therapeutics, Vertex, and their clinical partners published data in The New England Journal of Medicine (NEJM) from the Phase I/II trials showing continued positive results for the first two patients who had been treated with CTX001 and followed for at least a year. One of the patients was treated with CTX001 for TDT in the CLIMB-111 trial (NCT03655678), while the other was treated for SCD in the CLIMB-121 (NCT03745287).

After a year of follow-up care, both patients showed high frequencies of allelic editing across all subpopulations of CD34+ cells, including long-term hematopoietic stem cells (HPSCs). In edited CD34+ HSPCs, fetal hemoglobin levels increased to a mean of 29.0±10.8%, versus 10.5±5.2% in unedited control cells.

“The clinical course of both patients supports our conclusion that CTX001 mimics the phenotype of hereditary persistence of fetal hemoglobin levels,” the researchers observed.

Since the study was submitted for publication, the researchers administered CTX001 to another eight patients (six with TDT and two with SCD), and obtained more than three months of follow-up data: “Initial efficacy data from these additional patients are broadly consistent with the findings in the two patients described here.”

The 10 patients studied showed a consistent and sustained positive response to treatment, according to data presented in December from the CLIMB trials at the annual American Society of Hematology (ASH) Meeting and Exposition. All seven patients with TDT—including three who have either a severe or b0/b0 genotype—were transfusion independent at the last follow-up in the TDT trial, while all three patients with SCD were free of vaso-occlusive crises (VOCs) from infusion with the therapy through last follow-up.

“New operating model”

“We are on track to complete enrollment in both clinical trials this year,” added CRISPR Therapeutics CEO Samarth Kulkarni, PhD. “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.”

More than 30 patients have been treated in the CLIMB trials. Leiden told The Boston Globe that Vertex plans to submit results from the trials, with data from 40 to 50 patients, when it applies for approvals of CTX001 within the next two years.

A month after Vertex and CRISPR Therapeutics published positive clinical results from their trials in the NEJM, bluebird bio temporarily and voluntarily suspended two clinical trials  assessing its LentiGlobin gene therapy for SCD (bb1111), after acknowledging that two participants in the earlier-phase study developed blood cancers—one of acute myeloid leukemia (AML), the other of myelodysplastic syndrome (MDS).

After an analysis, however, bluebird said March 10 that its BB305 lentiviral vector (LVV) was very unlikely to have played a role in the AML case: “We have shared with the FDA that we believe these results support lifting the clinical holds on our β-thalassemia and sickle cell disease programs,” stated Philip Gregory, chief scientific officer, bluebird bio, at the time.

In a statement released today, bluebird said it has also conducted additional review of the MDS case, with its treating investigator having “concluded this is not a case of MDS and has revised the diagnosis to transfusion-dependent anemia”—a finding the company said has been reported to regulatory agencies and study investigators.

“The company continues to work with the treating investigator to determine the potential cause of this patient’s anemia,” bluebird added.

In Europe, bluebird obtained the first approval for a gene therapy indicated for TDT, Zynteglo® (betibeglogene autotemcel), in 2019—but suspended sales of the treatment as a result of the AML and MDS cases, since it is manufactured using the same BB305 lentiviral vector used in LentiGlobin gene therapy for SCD.

In a separate statement, bluebird said today it was withdrawing Zynteglo from Germany after it failed to reach agreement with German regulators on a price for the gene therapy.

Through the revised agreement, Vertex and CRISPR Therapeutics aim to position themselves to be first to market with a gene-based treatment for TDT and SCD.

“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,” Leiden added.