Four years after Regeneron Pharmaceuticals and Intellia Therapeutics began working together to research the use of CRISPR/Cas9 to treat liver diseases, the partners are expanding their pact to bleeding disorders.
The deal announced Monday covers the development of potential treatments for hemophilia, which stems from genetic mutations that lead to insufficient levels of blood clotting proteins. The revised alliance covers the joint development of potential treatments for both hemophilia A and B. Regeneron also gains rights to discover and develop potential therapies addressing an additional five liver targets, bringing the total liver targets covered by the agreement to 15. The pact, which was set to end in 2022, now extends two more years.
Regeneron (NASDAQ: [[ticker:REGN]]) is paying Intellia (NASDAQ: [[ticker:NTLA]]) $70 million in cash up front to expand the agreement. Tarrytown, NY-based Regeneron has also agreed to make a $30 million equity investment in its partner at $32.42 per share—an 85.1 percent premium to Friday’s closing price. Shares of Cambridge, MA-based Intellia opened at $19.97, up 14 percent from Friday’s close.
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The amended agreement follows preclinical research that the companies say demonstrated the first use of the CRISPR technology to insert a gene from another organism into the liver of monkeys. This gene led to normal or higher levels of Factor IX, the blood clotting factor that is missing or defective in hemophilia B patients. The companies say these early results suggest that this approach may provide a way to get patients to produce this protein, leading to a potential cure for hemophilia B. The approach could also apply to hemophilia A, which is caused by mutations to the gene that produces Factor VIII.
By adding hemophilia to their agreement, Regeneron and Intellia join a handful of other companies aiming to tinker with genes as a way of addressing the bleeding disorder. BioMarin Pharmaceutical (NASDAQ: [[ticker:BMRN]]) is awaiting an FDA decision for valoctocogene roxaparvovec, a gene therapy that the biotech developed to treat hemophilia A. Pfizer (NYSE: [[ticker:PFE]]) is heading into Phase 3 testing with a hemophilia A gene therapy it took over from partner Sangamo Therapeutics (NASDAQ: [[ticker:SGMO]]).
Gene therapy involves delivering a functional gene to a cell via an engineered virus. Although the viruses are modified so they can’t cause disease, their use still brings the risk of dangerous side effects. Intellia notes in its annual report that early gene therapy clinical trials sparked cases of leukemia and death. By editing the defective genes instead of replacing them, Intellia aims to an alternative.
“We believe that our CRISPR/Cas9-based technology addresses the limitations of current replacement and gene therapy approaches, and importantly, may provide a durable, potentially life-long solution to these genetic diseases,” Intellia CEO and President John Leonard said in a prepared statement.
The initial agreement with Regeneron paid Intellia $75 million up front. Intellia is taking the lead on the most advanced liver program covered by the partnership with Regeneron, a potential treatment for transthyretin amyloidosis, a rare inherited disorder in which a genetic mutation leads to a buildup of amyloid protein in tissues and organs. Intellia said in its annual report that it plans to submit an application to begin a clinical trial for NTLA-2001 in the middle of this year.
If NTLA-2001 is successful, it would provide an alternative to a transthyretin amyloidosis treatment commercialized by Alnylam Pharmaceuticals (NASDAQ: [[ticker:ALNY]]). Two years ago, Alnylam won FDA approval for patisiran (Onpattro), a drug the employs RNA interference (RNAi)—the delivery of genetic instructions to stop a gene from producing a disease-causing protein. It was the first RNAi drug approved by the agency.
Under the amended pact with Regeneron, Intellia retains the right to develop therapies for certain disease targets other than transthyretin amyloidosis. The Cambridge company may also choose additional liver targets for its own research, which may also be covered by the co-development and co-promotion terms of the agreement with Regeneron.
The original agreement called for Regeneron and Intellia to split equally the development costs of the liver drugs, and the promotion costs if any of them reach the market. In December, Regeneron informed Intellia it would exercise its right to reduce its share of the development costs and potential profits of the transthyretin amyloidosis program to 25 percent, according to Intellia securities filings.
The hemophilia part of the revised agreement calls for the companies to collaborate in the R&D of CRISPR-based hemophilia therapies. Regeneron will take the lead on clinical development of these therapies and, if approved, commercialization, according to an Intellia filing. Worldwide development costs and profits of any future products will be split: 35 percent to Intellia and 65 percent to Regeneron.
The original agreement granted Regeneron the right to independently develop gene-editing products that do their work in vivo—inside the patient. Regeneron will pay milestones and royalties to Intellia for the products it develops independently. Regeneraon also receives a non-exclusive license to Intellia intellectual property for developing and commercializing up to 10 products made by ex vivo CRISPR gene editing, in which the therapy is created outside of the body.
Image: iStock/vchal
