The blood-brain barrier (BBB) protects the central nervous system (CNS) by preventing toxins, pathogens, and other circulating molecules from entering the brain. While essential for maintaining brain health, it also blocks more than 98 percent of small molecule drugs and virtually all biologic therapeutics, making neurological diseases among the most difficult to treat.
For decades, researchers have focused on finding elaborate ways to get more drugs across the BBB. Montara Therapeutics is taking an alternative approach. Rather than simply trying to force more drugs into the brain, the company is using the BBB to its advantage to achieve brain-selective pharmacology, allowing drugs to remain active in the brain while preventing their activity elsewhere in the body.
The strategy recently attracted approximately $1 million in funding from The Michael J. Fox Foundation (MJFF), which will support the development of a brain-selective mTOR therapy for Parkinson's disease. More broadly, however, Montara's approach represents an exciting opportunity to revive promising drug classes that have long been abandoned because of dose-limiting peripheral toxicities.
Historically, the brain has been one of the most challenging organs to treat because of the blood-brain barrier. Our technology allows us to deliver therapies into the brain where they can be more efficacious while blocking harmful side effects in the rest of the body.
—Nicholas Hertz, Montara Therapeutics
"We're really tackling one of the toughest challenges in medicine," Nicholas Hertz, Founder and CEO of Montara Therapeutics, told DDN. "Historically, the brain has been one of the most challenging organs to treat because of the blood-brain barrier. Our technology allows us to deliver therapies into the brain where they can be more efficacious while blocking harmful side effects in the rest of the body."
Turning the blood-brain barrier from obstacle into advantage
Most strategies for CNS drug development focus on overcoming the BBB by just improving brain penetration. Montara's BrainOnly platform takes that strategy one step further.
BrainOnly pairs two small molecules: a brain-penetrant therapeutic, known as a BrainTAC, with a proprietary peripheral blocker. The blocker is deliberately designed not to cross the BBB, preventing the BrainTAC from acting in peripheral tissues while allowing it to remain active in the brain, thereby creating brain-selective pharmacology.
By suppressing the drug's activity outside the brain, the platform is designed to widen its therapeutic window, enabling higher concentrations of the therapeutic to be delivered to the brain while minimizing dose-limiting toxicities in the rest of the body.
Although the concept may sound novel, Hertz pointed out that medicine has employed similar principles for decades. An existing Parkinson's disease therapy combines levodopa, which enters the brain and is converted into dopamine, with carbidopa, which remains largely outside the brain and inhibits the enzyme that metabolizes levodopa in the peripheral tissues. Likewise, Bristol Myers Squibb's schizophrenia therapy Cobenfy combines a brain-active muscarinic agonist with a peripherally acting antagonist to minimize unwanted side effects.
The difference, according to Hertz, is that these were bespoke combinations developed for individual diseases. "What differentiates Montara is that our technology is target agnostic," he said. "Rather than developing two entirely new molecules for every program, we have a modular peripheral blocker that can be combined with BrainTACs designed for different therapeutic targets."
A modular platform built around peripheral blockade
Central to that strategy is MT1110, the company's lead peripheral blocker. Montara discovered the molecule shortly after licensing the underlying technology from the University of California, San Francisco (UCSF), where the BrainOnly platform was developed through research led by scientific co-founder Kevan Shokat and first described in a 2022 paper published in Nature.
MT1110 works by saturating FKBP12 (FK506-binding protein 12) binding sites in tissues outside the brain. This prevents FKBP12-dependent drugs from engaging their targets in peripheral organs while allowing them to remain active once they cross the BBB.
The company's lead program, MTX-E1, pairs MT1110 with the approved mTOR inhibitor everolimus (an FKBP12-dependent drug) to treat tuberous sclerosis complex (TSC)-associated epilepsy. Although everolimus is the standard of care for TSC-related seizures, systemic inhibition of mTOR can cause numerous adverse effects including immunosuppression, hyperlipidaemia, and hyperglycaemia. In fact, 95 percent of TSC patients treated with everolimus report at least one adverse event. By restricting everolimus activity to the brain, Montara aims to reduce peripheral toxicity while preserving its anti-seizure efficacy.
"TSC is a genetic disease in which mutations drive mTOR hyperactivation and disrupt brain network development. The resulting seizures can be effectively treated with mTOR inhibitors,” Hertz said. "The problem is that the approved mTOR inhibitors were developed as immunosuppressive agents. At the doses needed to achieve anti-seizure activity in the brain, you end up driving severe immune suppression throughout the body."
Preclinical data presented at the American Epilepsy Society Annual Meeting showed that the MT1110-everolimus combination provided greater seizure control than an equivalent dose of everolimus alone in a conditional Tsc1 knockout mouse model, while also reducing treatment-related adverse effects. The program is expected to enter first-in-human studies in early 2027.
Hertz believes the blocker can become a modular platform component that supports multiple therapeutic programs. "We've shown that MT1110 can be used with multiple different BrainTACs," he said. Although MT1110 is designed as a modular blocker that can be paired with multiple therapeutics, Montara is also developing a portfolio of next-generation peripheral blockers. These molecules are being engineered with different tissue-distribution profiles, allowing them to preferentially block drug activity in organs where toxicity is expected to be greatest rather than serving as a one-size-fits-all solution.
“We are also developing a brain-selective LRRK2 inhibitor for Parkinson's disease. We know that inhibiting LRRK2 in the lung can cause irreversible damage, so that's a case where we'd want a blocker that provides particularly strong activity in the lung while allowing different levels of activity in other tissues,” Hertz explained. “Developing blockers with different tissue distributions gives us another level of flexibility and differentiation across future programs.”
Like Montara's mTOR programme, the company's brain-selective LRRK2 program is also supported by funding from the MJFF.
A world of possibilities
While MTX-E1 represents Montara's first clinical program, the BrainOnly platform could extend well beyond TSC. The company's most recent MJFF grant supports the application of the platform to Parkinson's disease, where Montara aims to pair a blocker with a brain-penetrant mTOR inhibitor. By selectively inhibiting mTOR in the brain, the company hopes to activate autophagy to clear toxic alpha-synuclein aggregates while avoiding systemic immunosuppression.
The implications could extend far beyond Parkinson's disease. Alpha-synuclein pathology is also implicated in multiple system atrophy and dementia with Lewy bodies, and is frequently observed as a co-pathology in patients with Alzheimer's disease. More broadly, impaired autophagy and the accumulation of toxic protein aggregates are hallmarks of many neurodegenerative disorders. By enabling brain-selective inhibition of mTOR, Montara hopes to harness autophagy to clear these aggregates while avoiding any systemic toxicities.
The company's ambitions also extend beyond repurposing existing medicines. "Repurposing approved drugs lets us move more quickly because we already understand their pharmacology and toxicities. But in collaboration with pharma companies, we're also looking at investigational targets where the biology is compelling, but toxicity has limited development,” Hertz said.
If successful, the approach could shift how researchers think about CNS drug discovery and development. By enabling therapies to act selectively in the brain, BrainOnly could open the door to both repurposed medicines and entirely new therapeutic targets that have previously been considered unfeasible because of dose-limiting peripheral toxicities.
