7 April 2020 - - US-based ribonucleic acid interference therapeutics specialists Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY), and Dicerna Pharmaceuticals, Inc. (NASDAQ: DRNA) have formed a development and commercialisation collaboration on investigational RNAi therapeutics for the treatment of alpha-1 antitrypsin deficiency-associated liver disease (alpha-1 liver disease), the companies said.

In addition, the companies have completed a cross-license of their respective intellectual property for Alnylam's lumasiran and Dicerna's nedosiran investigational programmes for the treatment of primary hyperoxaluria.

These agreements will enhance and accelerate Alnylam's and Dicerna's ability to bring these orphan product candidates to market.

Under the development and commercialisation agreement, Alnylam's ALN-AAT02 and Dicerna's DCR-A1AT, investigational RNAi therapeutics, each in Phase 1/2 development, will be explored for the treatment of alpha-1 liver disease.

Under the agreement, Dicerna assumes responsibility for both ALN-AAT02 and DCR-A1AT at its cost, and may progress one or both of these investigational medicines through clinical development.

Dicerna will select which product candidate(s) to advance in development for the treatment of patients with alpha-1 liver disease.

At the completion of Phase 3, Alnylam has the no-cost opportunity to opt-in to commercialise the selected candidate in countries outside the US, where it already has a commercialisation infrastructure in place.

If Alnylam exercises its opt-in right, each party shall pay tiered royalties to the other party based on net product sales generated in its territory at rates dependent on which candidate is commercialised.

In the event Alnylam waives its commercialization option, Dicerna will retain worldwide rights to commercialise the selected candidate(s) in exchange for milestones and royalties payable to Alnylam, also at a rate dependent on which candidate is ultimately commercialised.

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 investigational programs to ensure that each party has the freedom to develop and commercialise 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.

Alnylam's lumasiran has achieved positive Phase 3 results in the ILLUMINATE-A study and is currently the subject of a rolling new drug application with the US 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.

The transaction related to alpha-1 liver disease is subject to the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 and other customary conditions.

ALN-AAT02 and DCR-A1AT are investigational, subcutaneously administered RNAi therapeutics targeting alpha-1 antitrypsin in development for the treatment of A1AT deficiency-associated liver disease (alpha-1 liver disease).

ALN-AAT02 utilises Alnylam's enhanced stabilization chemistry plus -GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index.

DCR-A1AT utilizes Dicerna's GalXC technology, which enables subcutaneous delivery and optimizes the activity of the RNAi pathway so that it operates in the most specific and potent fashion.

The safety and efficacy of ALN-AAT02 and DCR-A1AT have not been evaluated by the FDA, EMA or any other health authority.

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. A1AT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation.

About 95 % of people with A1AT deficiency are homozygous and carry two copies of the abnormal Z allele which expresses the Z-AAT protein.

In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma.

There are estimated to be approximately 120,000 individuals with the PiZZ mutation in the US and major European countries, and of these, 10% or more have an associated liver pathology (alpha-1 liver disease) caused by the aggregates of the misfolded Z-AAT protein.

The only treatment options presently available for alpha-1 liver disease patients are supportive care and, in the case of advanced cirrhosis, liver transplantation.

RNAi-mediated inhibition of A1AT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.

Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting glycolate oxidase, in development for the treatment of primary hyperoxaluria type 1, an ultra-rare life threatening disease.

GO is encoded by the hydroxyacid oxidase 1 gene. Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate the metabolite that directly contributes to the pathophysiology of PH1.

Lumasiran utilises Alnylam's Enhanced Stabilization Chemistry -GalNAc-conjugate technology, which enables quarterly subcutaneous maintenance dosing with increased potency and durability and a wide therapeutic index.

Lumasiran has received both US and EU Orphan Drug Designations, a Breakthrough Therapy Designation and pediatric rare disease designation from the US Food and Drug Administration, and a Priority Medicines (PRIME) designation from the European Medicines Agency.

The safety and efficacy of lumasiran have not been evaluated by the FDA, EMA or any other health authority.

Nedosiran (formerly referred to as DCR-PHXC) is the only RNAi drug candidate in development for primary hyperoxaluria types 1, 2 and 3 and is Dicerna's most advanced product candidate utilizing the proprietary GalXC RNAi technology platform.

Nedosiran is designed to inhibit the lactate dehydrogenase A enzyme an enzyme that catalyzes the final step in a common pathway resulting in oxalate overproduction in patients with PH1, PH2 and PH3.

Dicerna is evaluating the safety and efficacy of nedosiran in patients with all known forms of PH as part of its PHYOX clinical development programme.