The company's lead molecule was initially invented to treat CNS diseases like Alzheimer's. A pivot occurred when a postdoc with an interest in oncology tested the compounds against refractory tumors, uncovering their true potential and leading to the company's formation around a new indication.
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Voyager CEO Al Sandrock outlines a focused strategy: remain specialists in neurology, but broaden the therapeutic modalities (gene therapy, proteins, oligonucleotides). This allows them to pursue well-validated CNS targets that are considered "undruggable" by traditional small molecules, which have historically been the only option for crossing the blood-brain barrier.
The drug exhibits a multimodal mechanism. It not only reverses chemoresistance and halts tumor growth but also 'turns cold tumors hot' by forcing cancer cells to display markers that make them visible to the immune system. This dual action of direct attack and immune activation creates a powerful synergistic effect.
The GSK3 inhibitor was developed for CNS diseases, requiring high specificity and the ability to cross the blood-brain barrier. These same pharmaceutical characteristics—potency and lipophilicity—proved highly advantageous for treating cancer, demonstrating an unexpected but effective therapeutic pivot from neuroscience to oncology.
Despite pancreatic cancer being notoriously difficult, Actuate prioritized it as a lead indication for strategic reasons. Strong preclinical data allowed the company to bypass later-line trials and move directly into a first-line setting, a 'leapfrog' maneuver that significantly accelerates the drug's overall development and regulatory path.
Instead of hoarding early capital, Actuate's CEO synthesized a kilogram of their molecule and sent it to labs worldwide. The goal was to fail fast by seeing if promising results could be replicated, a crucial de-risking step before committing larger funds.
Actuate employed a master protocol that tested their drug alongside eight different standard-of-care chemotherapies in patients who had already failed them. This design efficiently demonstrated the drug's ability to reverse chemo-resistance across multiple histologies, informing their Phase 2 strategy.
To demonstrate its drug could overcome resistance, Actuate designed a trial where patients who had already failed a specific chemotherapy were given the exact same regimen again, but this time with Actuate's drug added. The resulting increased efficacy across eight different cancers provided powerful, direct proof of the drug's mechanism.
Actuate’s drug was designed to be highly lipophilic (fat-soluble) to cross the blood-brain barrier for CNS treatment. This same property proved crucial for its success in oncology, as it allows the drug to easily penetrate cancer cell membranes and reach the nucleus.
After several tau-targeting antibodies failed, including J&J's pazdenimab, confidence in blocking extracellular tau is waning. The field's new hope is Biogen’s Biv80, an antisense drug that prevents tau protein production at the mRNA level, a mechanism that has shown potential to reverse pathology in early data.
The CEO addresses the old belief that inhibiting its target, GSK3-beta, could be dangerous because it was once considered a tumor suppressor. He explicitly states this theory has 'lost its scientific founding' and 'faded into the myth' as research progressed, demonstrating a command of the target's evolving scientific narrative to stakeholders.