Delivering on the Promise of New Modalities: An Interview with Christopher Thanos, President, CEO & Co-Founder, Actym Therapeutics

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As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs.

We continue our interview series with Christopher Thanos, President, CEO & Co-Founder of Actym Therapeutics, Inc., a biotechnology company focused on the discovery and development of novel therapies intended to transform the treatment of cancer. They have developed a systemically dosed therapeutic platform that can overcome the solid tumor immune microenvironment, which is hostile to T-cells. The platform, called STACT™ (S.Typhimurium-Attenuated Cancer Therapy) is based on a gene-edited, immunologically cloaked microbe capable of enriching in solid tumors. Once there, payload combinations are delivered directly to tumor-resident, antigen-presenting cells to generate antitumor immunity. Actym raised a $34 million Series A financing to advance development of immunotherapies from this platform. They recently announced a manufacturing pact with Wacker Biotech to produce Actym’s lead clinical candidate, ACTM-838, for the treatment of solid tumors.

Thanks for joining us, Chris, and congratulations on being named one of the “Top 25 BioTech CEOs of the year!” For cancer therapy drug discovery and development, what are the challenges in current therapeutic intervention, or current new modality solutions?

Christopher: Thank you for the kind words and the invitation to discuss new modalities. Unfortunately, treatment of solid tumors remains a big challenge, with the FDA-approved checkpoint therapies providing benefit in only a fraction of patients. To generate durable responses in this setting, new modalities must overcome several challenges. First, they must be systemically administered, but with tumor-specific effects, which is particularly critical in a metastatic setting. Tumor-specific target engagement will be required to limit systemic immunotoxicities. Second, new modalities must safely pack more of a therapeutic punch. Multi-pathway target engagement is a likely prerequisite to reverse the known immunosuppressive cascades within the tumor microenvironment (TME), which prevent antitumor immunity. Finally, new modalities must be technically and economically feasible to develop, manufacture, and distribute, without being increasingly burdensome to patients and caregivers. We specifically designed STACT with attributes to overcome these challenges.

Could you please share more details of your new modality, STACT?

Christopher: STACT is an IV-dosed, programmable, avirulent, microbial-based modality, which naturally enriches in tumors, selectivity delivering payload combinations in a single therapeutic composition.

To facilitate systemic dosing, we used gene-editing to eliminate a number of inflammatory components on the surface of STACT, resulting in dramatically improved tolerability through the reduction of inflammatory cytokine responses. We have dosed up to 3 billion CFUs intravenously in NHPs with no impact on tolerability.

STACT has a designed auxotrophy for multiple tumor-specific metabolites of the adenosine pathway, which are elevated in many types of tumors. This engineering enables STACT to naturally expand in the extracellular milieu of the TME, an environment well-known to be hospitable for the growth of all kinds of bacteria. Many types of tumors possess an elevated adenosine pathway signature, suggesting this approach may have broad utility.

Once enriched in the tumor, STACT is naturally and selectively internalized by tumor-resident myeloid cells, such as macrophages and dendritic cells, through a process called phagocytosis. After internalization, STACT is rapidly destroyed and cytoplasmic, facilitating payload delivery. We are exploiting this unique mechanism to engage intractable “big-lever” immunomodulatory pathways of interest to pharma by deploying payloads in STACT that are known to be too inflammatory and too toxic if dosed systemically via conventional modalities (such as biologics and small molecules).

We plan on entering the clinic next year with our lead STACT candidate, ACTM-838, which encodes an IL-15 cytokine and an engineered STING variant. Both the IL-15 and STING pathways are clinically validated, which significantly reduces risk in our approach. In preclinical, difficult-to-treat, checkpoint refractory tumor models, the STACT IL-15 + STING combination generates durable anti-tumor immunity, repolarizes tumor-resident myeloid cells, and is synergistic with anti-PD1 therapy.

How is your technology different from other new modalities attempting to achieve the coveted “systemic delivery, tumor-specific effect” mechanism of action?

Christopher: STACT is distinct from other experimental modalities such as protease-activated prodrug approaches, engineered T-cells, and cationic lipid nanoparticles containing encoded mRNAs. As a microbe, STACT can naturally enrich in tumors and be internalized by macrophages and dendritic cells, facilitating tumor-specific delivery of payload combos. For tumor-specificity, STACT does not rely on a protease-activated prodrug approach, where the cleaved, active therapeutic product can enter circulation and induce toxicities, and multiplexing options are limited. While T-cell based therapies can encode multiplexed payloads, they poorly infiltrate into tumors, are inactivated by the hostile TME, have on-target toxicities in healthy tissue, and are a significant challenge to manufacture. Furthermore, T-cell therapies require lymphodepletion, which is poorly tolerated, or high dose IL-2, which is even more poorly tolerated, and have an extended vein-to-vein time. Unfortunately, cancer patients often succumb to their disease before their engineered T-cells are ready. Approaches utilizing payload-encoding mRNAs encapsulated within cationic lipid nanoparticles can be multiplexed, but lack systemic delivery and have an unproductive inflammatory profile, limiting their utility as cancer treatments.

STACT was designed to be technically and economically feasible to develop, manufacture, and distribute. STACT will be delivered in an IV bag and is reversible with standard antibiotics. Many thousands of doses can be produced via fermentation in a single 24-hour manufacturing run, with a stable shelf life. The platform is now codified such that multiple product candidates can be generated in a similar manner.

What are the critical challenges in realizing the full potential of your new modality? Any key milestones anticipated in near-term?

Christopher: We’ve received clear feedback from the FDA on our approach. The near-term milestones for the company are production of GMP material, completion of GLP tox studies, regulatory submissions, and expansion of our pipeline. The value-creating inflection point for Actym is demonstration of proof-of-concept in a Phase I clinical trial. A key challenge for this type of modality is making sure that we identify patients with tumor types that are most amenable to STACT’s mechanism of action. To that end, we’ve performed a detailed analysis that revealed a number of high unmet-need cancers predicted to have elevated of levels of adenosine pathway metabolites, which are necessary for STACT tumor-specific enrichment.

Many new modalities have been approved by the FDA recently. Do you think the 2030 class of new FDA approvals may look similar or different from those of today?

Christopher: I am bullish on the next ten years in the immuno-oncology field. We’re going to see novel modalities emerge with improvements in both durable responses and safety. Additional immuno-modulatory targets will become validated, traditionally intractable targets will become druggable, exciting new treatment combinations will emerge, and cancer vaccines will make a big push forward as well.

Thanks for your insights! One last question, how important is global collaboration to your company?

Christopher: It’s difficult to survive in the biotechnology industry without global collaboration. First, in terms of access to capital, we’re strongly supported by an international set of top tier investors. Despite being a small and new biotechnology company, Actym is engaged in R&D activities across multiple continents, including several countries in the EU, as well as China and Australia. You have to go to where the subject matter experts are, regardless of the country or continent. I can’t imagine where we’d be without our global network of investors, advisors, and collaborators!

Christopher Thanos, Ph.D.

President, CEO & Co-Founder, Actym Therapeutics, Inc.

Chris assembled the founding team at Actym, raised initial capital, and co-invented Actym’s therapeutic technology platform. Chris has 30 years of R&D experience, and is an inventor on over 30 issued patents. Previously, Chris was Head of Biotherapeutics Discovery at Halozyme (NASDAQ: HALO) leading Molecular Biology, Immunology, Protein Engineering and Cell Biology Groups at the company. Prior to that, Chris was Head of Protein Engineering at Sutro Biopharma (NASDAQ: STRO), and Cofounder of Catalyst Biosciences. He was a National Cancer Institute Postdoctoral Fellow under Professor Jim Wells at UCSF and Sunesis. Chris earned a Ph.D. in Molecular Biology and Biochemistry from UCLA, where he was an NIH Chemistry/Biology Interface Predoctoral Fellow. Chris was named one of the top 25 CEOs in Biotech for 2022 by Healthcare Technology Report.

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