Alexion Pharmaceuticals Inc. has negotiated an exclusive license to develop and commercialize up to four preclinical RNAi molecules for complement-mediated diseases using Dicerna Pharmaceuticals Inc.'s liver-focused gene-silencing platform, GalXC. Dicerna will receive $22 million up front and an equity investment of $15 million for the first two candidates and stands to receive $20 million more if Alexion exercises an option to advance preclinical GalXC RNAi molecules for two additional targets within the complement pathway.

Under terms of the deal, Dicerna is also eligible for additional development and sales milestones totaling up to $580 million plus royalty payments for the programs.

No targets for the program were identified at the deal's inception, but Alexion's R&D chief, John Orloff, said Wednesday that the company would be targeting "other upstream complement cascade factors" than C5, the complement system protein that is the target of the company's best-selling product, Soliris (eculizumab), as well as Ultomiris, the company's long-acting C5 complement inhibitor, formerly called ALXN-1210 and now in preregistration as a potential treatment for patients with paroxysmal nocturnal hemoglobinuria.

Though C5 is one entry point to complement inhibition, the pathway is "fairly sophisticated and has multiple branches" presenting between 10 and 20 gene targets, Dicerna CEO Doug Fambrough told BioWorld. "Some of them look more central and like better mediators of therapeutic effect than others. But there are several intervention points that have not been drugged or not been thoroughly explored that way and where the complement actor is largely expressed in the liver," he said.

That's where Dicerna's GalXC's platform is designed to shine by employing a structure of double-stranded RNA molecules configured for subcutaneous delivery to the liver, where it said that a single GalXC molecule incorporated into the RNAi machinery can destroy hundreds or thousands of mRNAs from the targeted gene.

"These therapies migrate to the liver where complement proteins are produced and degrade the messenger RNA before the complement protein can be translated," Leerink analyst Geoffrey Porges wrote. "As such, these treatments would operate more upstream than Alexion's current complement antibodies that block the complement proteins after they have been created, and the mechanism should also provide a longer duration of effect than antibodies."

For Dicerna, the deal represents a new opportunity to monetize its platform for the benefit of a partner while continuing to advance its own GalXC-based candidate, DCR-PHXC, for the treatment of primary hyperoxaluria. It has one such deal already, a November 2017 agreement with Boehringer Ingelheim GmbH, which enlisted its help to discover and develop new therapies for chronic liver diseases. But other potential partners had been slow to engage with the company prior to the settlement in April of its long-running legal dispute with Alnylam Pharmaceuticals Inc. (See BioWorld, Nov. 3, 2017, and April 23, 2018.)

For Alexion though, a company that has focused heavily on diversifying in light of its need to reduce its continued reliance on sales of Soliris due to competitive and market challenges, the deal was "a strong strategic fit," according to Orloff. "I'm very proud of the progress we have made rebuilding our pipeline, and I'm excited for what lies ahead in our development portfolio," he said. (See BioWorld Today, March 19, 2007, and April 5, 2018.)

The deal is structured such that Dicerna will lead discovery and research efforts through the preclinical stage, and Alexion will lead development efforts beginning with phase I studies. Along the way, Dicerna is eligible to receive development milestones of up to $105 million for each product and, should all four programs reach the market, aggregate sales milestones of up to $160 million. Alexion would also pay the company mid-single to low-double-digit royalties on sales for certain periods.

It's unclear when Alexion might decide whether to exercise its option on the latter two molecules in the deal, each with a $10 million payday for Dicerna attached. However, Fambrough clarified that neither of those programs would be the undisclosed rare disease program currently listed on the company's pipeline chart. Dicerna will file an investigational new drug application for that candidate next year, he said.

Shares of both companies fell on Wednesday amid a down day for the broader market. Alexion shares (NASDAQ:ALXN) fell $12.01, or 9.8 percent, to $110.99 despite a better-than-consensus earnings report. Dicerna shares (NASDAQ:DRNA) fell 19 cents, or 1.6 percent, to close at $12.03.