Outsmarting Resistance with Rhythm

Episode Summary

Executive Summary: Immuneering's CEO Ben Zeskin discusses how the company's deep cyclic inhibition approach, using informatics-driven dosing pulses of its MEK inhibitor atabimetinib, aims to improve survival and quality of life in pancreatic cancer by counteracting resistance and reducing toxicity. Phase 2a data shows 64% overall survival at 12 months in first-line pancreatic cancer, nearly double the standard of care benchmark of 35%, with excellent tolerability.

Main Topics: Challenges of Resistance and Toxicity in Targeted Therapies (Priority: 5/5): Traditional targeted therapies shrink tumors transiently but lead to rapid resistance and harsh side effects, limiting durability and quality of life. Deep Cyclic Inhibition Mechanism (Priority: 5/5): A novel dosing regimen that pulses a MEK inhibitor to shut down the MAPK pathway deeply for hours, then releases it, restoring normal signaling in healthy cells while ambushing tumors and preventing adaptation. Platform Technology and Informatics (Priority: 4/5): Immuneering uses transcriptomic and informatics tools to analyze gene expression and optimize the timing of inhibition and release, enabling the design of deep cyclic inhibitors. Clinical Data for Atabimetinib in Pancreatic Cancer (Priority: 5/5): Phase 2a results show 64% overall survival at 12 months (vs. 35% benchmark), with consistent separation over time and dramatic quality-of-life improvements, including a patient regaining ability to drive and walk. Combination Therapy Potential (Priority: 4/5): Atabimetinib's tolerability enables combinations with immunotherapies (e.g., anti-PD-1) and other targeted agents, with preclinical synergy supporting broader use. Pipeline and Future Indications (Priority: 3/5): Beyond pancreatic cancer, atabimetinib is being explored in lung cancer (with Regeneron), colorectal cancer, melanoma, and AML, with a pipeline of deep cyclic inhibitors against other targets. Company Strategy and Funding (Priority: 3/5): Immuneering is fully funded into 2029, with a Phase 3 trial starting mid-2025, and uses partnerships (e.g., Sanofi investment) to maximize impact.

Key Arguments: Deep cyclic inhibition restores normal signaling rhythms in healthy cells, reducing side effects, while repeatedly ambushing tumors to delay resistance. Targeting MEK downstream in the MAPK pathway blocks a wider range of resistance mutations than upstream targets like RAS. Atabimetinib's tolerability (only two grade 3+ adverse events >10%, both from chemo) enables better quality of life and easier combination with other therapies. The 64% 12-month overall survival in pancreatic cancer nearly doubles the standard of care, validating the deep cyclic inhibition approach. Pulsatile MEK inhibition specifically enhances immunotherapy efficacy, as shown by preclinical data from Jed Walchuk.

Data Points: 12-month overall survival (atabimetinib + chemo): 64% - First-line pancreatic cancer patients in Phase 2a study 12-month overall survival (standard of care gemcitabine/nab-paclitaxel): 35% - Benchmark from pivotal study 6-month overall survival (atabimetinib + chemo): 94% - vs. 67% benchmark 9-month overall survival (atabimetinib + chemo): 83% - vs. 47% benchmark Median follow-up time: 13.4 months - Phase 2a study Patient sample size: 34 patients - Phase 2a study Cash runway: Into 2029 - Funding from $200M raise (Sept 2024) Phase 3 first patient dosing: Mid-2025 - Pancreatic cancer

Pivotal Quotes: "We're essentially restoring that normal, healthy cadence of signaling. So we're taking the pathway back to grow and divide, grow and divide. So the healthy cells are getting the intermittent signaling that they need to grow and divide. So you don't have the same kind of side effects." — Ben Zeskin: Explaining how deep cyclic inhibition improves tolerability by mimicking natural signaling. "This patient regained the ability to drive independently, which is remarkable. The patient had been participating in a walking group in her neighborhood, had to stop due to the cancer. On our trial, she was able to resume that activity, rejoin the walking group." — Ben Zeskin: Describing a case study from the Phase 2a trial showing quality-of-life improvement. "We're thrilled to have a great group of investors who enabled us to raise the funds we need to really take this drug all the way through phase three and beyond that top line readout." — Ben Zeskin: Discussing the company's financial position and ability to execute on Phase 3.

Implications: Immuneering's deep cyclic inhibition could redefine targeted therapy by prioritizing durability and quality of life. If Phase 3 succeeds, it may set a new standard for pancreatic cancer and expand to other MAPK-driven tumors, potentially shifting industry focus from continuous to pulsatile dosing.