Sanofi is paying $125 million (€110 million) upfront for a stake in two RIPK1 inhibitors in development at Denali. The agreement covers small molecules designed to treat multiple neurodegenerative and systemic inflammatory diseases. 

Denali, a deep-pocketed CNS biotech staffed by Genentech veterans, picked up the RIK1 program in 2016 through the acquisition of Incro Pharmaceuticals. The Harvard-originated research effort gave rise to two molecules. 

The most advanced of the molecules, phase 1 asset DNL747, penetrates the brain to treat multiple sclerosis (MS), Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Denali thinks DNL747 may stop tissue damage and neuronal death by disrupting a pathway that drives production of cytokines and other proinflammatory factors. The other asset, DNL758, is a non-CNS-penetrating molecule that is still in preclinical development.

Sanofi has bought a stake in both assets. In return for $125 million upfront and milestones that could exceed $1 billion, Sanofi has acquired a 50% share of any profits or losses DNL747 makes in the U.S. and China. Sanofi has full rights to DNL747 in other territories, plus a global license for DNL758, and will pay Denali royalties on sales in these markets.

The split is echoed in the development plan. Sanofi will fund and lead development of DNL747 in MS and ALS up to phase 3. Denali will bankroll the advance of DNL747 in Alzheimer’s up to phase 3. Once the drug gets into pivotal trials, Sanofi will cover 70% of the costs with Denali on the hook for the rest. Sanofi will fully fund all development of DNL758, which is due to enter the clinic next year.

The structure of the deak reflects the respective strengths of Denali and Sanofi. Denali specializes in neurodegenerative diseases, notably Alzheimer’s and Parkinson’s, while Sanofi has broader expertise that extends to the systemic inflammatory diseases targeted by DNL758.

Partnering with Sanofi thereby positions Denali to squeeze all the potential out of the RIPK1 program and move forward on multiple fronts quickly. So far, the RIPK1 program has advanced slower than once anticipated. Denali filed to run a European clinical trial of a CNS-penetrating RIPK1 inhibitor, DNL104, in August 2016. However, three of the 16 subjects who received multiple doses of the drug developed liver test abnormalities, prompting Denali to scrap development of the asset.

Denali thinks the abnormalities stemmed from off-target activity, not inhibition of RIPK1, and as such has reason to believe DNL747 may be free of the problems that affected DNL104. The safety signals detected during preclinical tests of the follow-up asset were limited to "cutaneous/mucocutaneous lesions and immune-mediated histopathology findings" in cynomolgus monkey that received a high dose for 28 days.  

That study and other IND-enabling work teed Denali up to file a CTA in the Netherlands in February and start dosing healthy volunteers the following month.

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