SAN FRANCISCO – Seal Rock Therapeutics Inc., a small West Coast company moving a preclinical candidate for nonalcoholic steatohepatitis (NASH) toward a 2020 clinical debut, poked its head above water for the first time during Friday's kickoff of the American Association for the Study of Liver Diseases. The startup, founded in late 2016 and led by several Takeda Pharmaceutical Co. Ltd. veterans, revealed an internally discovered inhibitor of apoptosis signal-regulating kinase 1 (ASK1) as its lead candidate.

The molecule, called SRT-015, has demonstrated statistically significant positive effects on both metabolic parameters and liver-specific pathology in mouse models so far.

ASK1 mediates apoptosis, inflammation and fibrosis in liver cells under stress. Inhibiting it has been shown in several trials, most prominently by Gilead Sciences Inc. with selonsertib, to prevent some of the dire consequences of fatty build-up in the organ, ultimately reducing fibrosis. Though '015 is much earlier in its development, Seal Rock CEO Neil McDonnell told BioWorld that he expects its liver-selectivity to prove a differentiating factor that may support relatively high dosing while maintaining a strong safety profile.

The company recently received preclinical data from a fast-food-diet mouse model. Results showed that, following treatment with '015, liver fat, inflammation and, most importantly, fibrosis in the liver were all significantly reduced. Further findings from the data will be presented during the upcoming Keystone Symposia Integrated Pathways of Disease in NASH and NAFLD meeting, in Santa Fe, N.M., in January. Meanwhile, McDonnell is working to scale up manufacturing of the candidate in advance of a planned late 2019 filing of an investigational new drug application.

Seal Rock's moniker comes from a set of namesake landmarks shared across the Seattle area, its official headquarters, along with the San Francisco Bay Area, which is home to its scientific staff, and San Diego, where the company's founders have common history. (A team photo at San Francisco's Seal Rock is in the works this week.)

The founders also have experience working with ASK1 inhibition, presumably through Takeda's long-simmering preclinical ASK1 program. Takeda's work in the area has most recently focused on cardiovascular disease, though it has also explored autoimmune diseases, diabetes, inflammatory disorders and neurodegenerative disorders, according to Cortellis.

McDonnell previously served as CEO of San Diego-based Metacrine Inc., which has its own NASH candidate in play, the farnesoid X receptor agonist MET-409. Prior to that, he was senior vice president and therapeutic area leader for cardiovascular and metabolic diseases at Takeda.

Artur Plonowski, Seal Rock's chief scientific officer, served as director of pharmacology at San Diego-based Akarna Therapeutics Ltd., a NASH startup that was acquired by Allergan plc in 2016. Prior to Akarna, he also worked at Takeda, where he led the cardiovascular, renal and metabolic disease pharmacology group. (See BioWorld Today, Sept. 21, 2016.)

Kathleen Elias, Seal Rock's vice president research and translational medicine, worked at Takeda as director of preclinical research and led efforts to develop small-molecule, antibody and antibody-drug conjugate candidates for immune, metabolic and oncology indications. Prior to that, she was at Cytokinetics Inc.

Seal Rock has been funded to date through institutional investors, life science investor networks and wealthy individuals, McDonnell said, though he declined to say how much his team has raised to date. The company is funded well into next year, he said. A partnership or series A financing ahead of phase I testing are possible next steps in the company's financing journey.