A year after selling their first neuro startup to AbbVie, Kevan Shokat and the former PhD student he co-founded that company with are back with a new idea.
Montara Therapeutics is starting small with an $8 million seed round led by SV Health Investors’ Dementia Discovery Fund and Two Bear Capital. But the San Francisco-based team believes its “BrainOnly” platform can prove widely applicable to a host of neurological diseases.
Kevan ShokatCEO Nicholas Hertz drew a parallel between Montara’s efforts and Shokat’s pioneering work in oncology: drugging the “undruggable” KRAS G12C. Now, they are going after neuro targets that are considered undruggable because these proteins are present in both the brain and other parts of the body, in some cases even playing important functions. Drugging them could thus lead to serious side effects.
“Once you go through a list of targets that are genetically and demonstrably important, you cross off a whole lot of things,” Shokat told Endpoints News in an interview.
A technology developed at his lab at the University of California, San Francisco promises to solve this conundrum by pairing an active, brain-penetrant drug with an inert blocker that can’t go into the brain but can prevent side effects in the periphery.
The idea of a two-drug combination — one acting on the disease and the other counteracting the toxic effects of the drug — isn’t new, with carbidopa and levodopa being a longstanding example in Parkinson’s. Karuna Therapeutics, which has been acquired by Bristol Myers Squibb, is taking a similar approach to treat schizophrenia backed by positive late-stage data. Lowering side effects, in general, is also a major goal for most neuro drug developers.
Montara is now optimizing its “universal” peripheral blocker with hopes of arriving at a pre-development candidate molecule with the seed funding. Its first program will involve an unnamed drug “with proven clinical benefit but severe dose-limiting peripheral side effects.” The company is also in talks with pharma companies about potential partnerships and aims to sign one deal before its Series A, Hertz said.
Sparing the periphery
Shokat said his team stumbled upon the science behind Montara while trying to solve resistance to mTOR inhibitors. They made a bivalent molecule that treated the resistance — but only worked when it could bind to a ubiquitous protein known as FKBP12. When they introduced a compound that would bar access to FKBP12, the bivalent molecule only inhibited targets in the brain but not in the body, Shokat said, across models of alcohol use disorder and glioma.
“People have been working on [FKBP12] since the ‘80s heavily,” he said. “It was like this unbelievable lucky thing.”
Shokat and Hertz previously co-founded Mitokinin based on their work on PINK1, which they found to play a role in Parkinson’s disease. AbbVie lined up an option to acquire Mitokinin back in 2021 and, in October, paid $110 million to seal the deal.
Hertz had been looking for a new venture focused on dementia and the duo soon decided to take the “BrainOnly” platform into Montara, whose 11-person team comprises largely ex-Mitokinin employees. The company closed the seed round in January.
“Last year was a really hard time to fundraise,” Hertz said, but noted they are hoping to build the company incrementally and raise the next round around the end of this year or early next year.
This time around, they brought in two other scientific co-founders, Thomas Südhof of Stanford University and Martin Kampmann, Shokat’s colleague at UCSF. Both are bringing ideas about potential new ways to treat neurodegenerative conditions, with Südhof’s basic research on disease mechanisms and Kampmann’s CRISPR-based screens. But they also said Montara’s tech could be useful on known targets, such as LRRK2 and APOE.
“Fundamentally, any brain disorder for which a target can be identified that is not specific to the brain is a potential indication,” Südhof said.