Alnylam and Dicerna Form RNAi Therapeutics Collaboration in Rare Disease

Rare Daily Staff

Alnylam Pharmaceuticals and Dicerna Pharmaceuticals are combining their RNAi therapeutic know-how in a collaboration and cross-licensing agreement to advance development of treatments for two rare diseases: alpha-1 antitrypsin deficiency-associated liver disease and primary hyperoxaluria.

Alpha 1-antitrypsin deficiency (A1AT) is an inherited autosomal co-dominant disorder that can cause lung disease in adults and liver disease in adults and children.  Alpha-1 antitrypsin (AAT) is a protein that protects the lungs. The liver usually makes the protein, and releases it into the bloodstream. Because of a mutation in the SERPINA1 gene, some people have little or no AAT. Not having enough AAT may lead to emphysema or liver problems. Smoking increases the risk. A deficiency of AAT can be treated but not cured. One treatment involves adding to or replacing the missing protein. More severe cases may require a lung transplant. RNAi-mediated inhibition of A1AT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.

Primary hyperoxaluria (PH) is an ultra-rare disease with three known types, each resulting from a mutation in one of three different genes. In patients with PH, excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract that can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, especially in patients with type 1 and type 2 PH, leading to severe illness and death. Treatment options are limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a few patients are fully responsive to vitamin B6 therapy, there are no approved therapies for PH.

“The new agreements allow for Alnylam and Dicerna to join forces in areas of common interest, namely alpha-1 liver disease and primary hyperoxaluria,” said John Maraganore, CEO of Alnylam.

Under a development and commercialization agreement, Alnylam’s ALN-AAT02 and Dicerna’s DCR-A1AT, both experimental RNAi therapeutics, in phase 1/2 development, will be explored for the treatment of alpha-1 liver disease. Dicerna will assume responsibility for both experimental therapies, and may select one or both to advance through clinical development. At the completion of phase 3, Alnylam will have a no-cost opportunity to opt-in to commercialize the selected candidate in countries outside the United States, where it already has a commercialization infrastructure in place. If Alnylam exercises its opt-in right, each party shall pay tiered royalties to the other party. If Alnylam waives its commercialization option, Dicerna will retain worldwide rights to commercialize the selected candidate(s) in exchange for milestones and royalties payable to Alnylam.

In a separate agreement, Alnylam and Dicerna granted each other a non-exclusive cross-license to their respective intellectual property related to their PH treatment experimental  programs to ensure that each party has the freedom to develop and commercialize its respective product candidate: Alnylam’s lumasiran targeting glycolate oxidase for the treatment of PH type 1 and Dicerna’s nedosiran targeting lactate dehydrogenase A for the treatment of PH types 1, 2, and 3.

“These agreements between Alnylam and Dicerna represent biopharma collaboration at its best, unifying the strengths of two leaders in RNAi innovation to rally behind the common goal of delivering much-needed new therapies to patients with rare diseases,” said Douglas M. Fambrough, president and CEO of Dicerna. “By joining our efforts in alpha-1 liver disease, we believe we can be more strongly assured of bringing forward the therapy with the greatest potential to benefit patients. At the same time, our agreement related to lumasiran and nedosiran clears a path for each company to offer a new and differentiated treatment to patients with PH.”

Alnylam’s lumasiran has achieved positive phase 3 results in the ILLUMINATE-A study and is currently in the process of a rolling new drug application (NDA) with the U.S. Food and Drug Administration. Dicerna’s nedosiran is currently being evaluated in the PHYOX clinical development program in patients with PH. The cross-license agreement provides for Alnylam to pay mid- to high-single-digit royalties to Dicerna based on global net sales of lumasiran and for Dicerna to pay low-single-digit royalties to Alnylam on global net sales of nedosiran.

Lumasiran has received both U.S. and EU Orphan Drug designations, a Breakthrough Therapy designation and Pediatric Rare Disease designation from the FDA, and a Priority Medicines (PRIME) designation from the European Medicines Agency.

Photo: John Maraganore, CEO of Alnylam