Novo Nordisk will apply Dicerna Pharmaceuticals’ GalXC™ platform to discover and develop RNA interference (RNAi) therapies for liver-related cardio-metabolic diseases, the companies said this week, through a collaboration that could generate more than $3.8 billion for Dicerna.

As significant as the potential payout, Dicerna said, is the evolved approach to coupling with partners on new treatments solidified by its alliance with Novo Nordisk. That more sophisticated approach enables a much broader scale of drug discovery and development—and offers much greater rewards—than its earlier more limited collaborations, according to the company.

“We have entered a more mature phase of partnering, where we have a right to opt-in to co-develop or co-fund development in exchange for a co-commercialization role and economic participation that reflects that role,” Dicerna president and CEO Douglas M. Fambrough, PhD, told GEN. “In other words, they are structured so we can become full development and commercial partners, by ‘opting-in’ to programs that have generated compelling clinical data.”

Using GalXC, Dicerna and Novo Nordisk aim to develop treatments for various disorders that include chronic liver diseases, nonalcoholic steatohepatitis (NASH), type 2 diabetes, obesity, and unspecified rare diseases. Novo Nordisk will lead programs targeting cardio-metabolic disorders and other indications with Dicerna having the option to opt into two programs during clinical development. Dicerna will retain rights to initiate two new orphan liver disease programs for which Novo Nordisk can opt in.

Each company can co-develop and co-commercialize product candidates discovered under the collaboration. For all co-development programs, the companies will share in the profit/loss of net sales of products consistent with each company’s contribution to co-development costs.

“Potent, safe, highly selective”

Dicerna and Novo Nordisk said they intend to jointly explore and evaluate more than 30 liver targets using Dicerna’s liver targeted GalXC technology. It uses liver-targeted GalXC-based compounds to enable subcutaneous delivery of RNAi therapies designed to specifically bind to receptors on liver cells, leading to internalization and access to the RNAi machinery within the cells.

“GalXC makes it possible to create potent, safe, and highly selective RNAi therapies, selective both for a specific gene and for the liver cells,” Fambrough said.

According to Dicerna, distinct benefits of GalXC-generated cells include their strong potency, high specificity to the targeted, liver-expressed gene, long duration of action, infrequent subcutaneous dosing, and high therapeutic index.

Dicerna first rolled out its “more mature” collaboration approach last month, when it launched an up-to-$1.67 billion partnership with Roche to develop and commercialize the Phase I chronic hepatitis B virus (HBV) candidate DCR-HBVS, as well as discover and develop additional HBV treatments.

DCR-HBVS is designed to function by using RNA interference to selectively knockdown specific genes involved in the creation of HBV messenger RNA (mRNA) and the entry of the virus into liver cells.

Every other target

The Novo Nordisk collaboration, Fambrough added, will enable it to develop treatments for the rest of the liver—every other target that is not covered by the company’s three other liver-related partnerships. In addition to the Roche alliance, Dicerna has partnerships with:

  • Eli Lilly for potentially more than $3.7 billion, initiated in October 2018, to discover, develop, and commercialize new treatments based on more than 10 targets in cardio-metabolic disease, neurodegeneration, and pain.
  • Alexion for up to $637 million, also launched in October 2018, to discover and develop RNAi therapies for complement-mediated diseases.
  • Boehringer Ingelheim for up to $201 million, begun in November 2017, to develop new treatments for chronic liver diseases, with an initial focus on NASH.

Novo Nordisk agreed to pay Dicerna $175 million upfront, as well as make a $50 million equity investment in Dicerna, and pay Dicerna $25 million annually during each of the first three years of the collaboration, contingent on Dicerna delivering RNAi molecules for a defined number of targets.

In addition, Novo Nordisk agreed to pay Dicerna up-to-$357.5 million per target in payments tied to achieving development, regulatory, and commercialization milestones, plus tiered royalties on product sales ranging from the mid-single-digits to mid-teens. With Novo Nordisk intent on developing 10 or more products through the collaboration, its potential total value could top $3.8 billion.

Dicerna agreed to conduct and fund discovery and preclinical development to clinical candidate selection for each liver cell target, with Novo Nordisk set to oversee all further development.

Notwithstanding its big-money collaborations with Roche and other biopharmas, Dicerna has full control of the development program for its lead candidate DCR-PHXC. During the third quarter, the company began dosing patients in the pivotal PHYOX2 clinical trial (NCT03847909 ) assessing DCR-PHXC as a potential treatment for primary hyperoxaluria types 1 and 2. The multi-dose, double-blind, randomized, placebo-controlled trial is expected to enroll approximately 36 participants, and has an estimated primary completion date of June 2020.

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