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.
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The investigator-led PLUTO trial found docetaxel chemotherapy provided a better overall survival benefit than lutetium in first-line mCRPC. This result directly confronts the common clinical bias against chemotherapy ("chemophobia"), proving that older treatments can still outperform newer targeted agents and should not be prematurely abandoned.
A key hypothesis for why docetaxel showed better overall survival than lutetium in the PLUTO trial is that patients treated with lutetium upfront may become unfit for subsequent chemotherapy. This highlights a critical factor in trial design: the planned therapeutic sequence and a patient's ability to receive later-line treatments significantly impact survival outcomes.
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.
With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.
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.
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.