Modulating RNA to Quell Disease

Episode Summary

Executive Summary: The episode centers on Abivax’s ABX464, a first-in-class oral small molecule designed to upregulate miR-124 and broadly reduce inflammatory cytokines rather than block a single immune target. CEO Hartmut Ehrlich discusses promising ulcerative colitis and Crohn’s data, longer-term maintenance results, combination development in rheumatoid arthritis, and additional potential in COVID-19 and other infectious diseases.

Main Topics: ABX464’s novel RNA-based anti-inflammatory mechanism (Priority: 5/5): ABX464 binds the CBC complex, increases miR-124, and lowers translation of multiple cytokines, offering a broader approach than single-cytokine blockade. Inflammatory bowel disease as the lead indication (Priority: 5/5): The company is pursuing ulcerative colitis and Crohn’s because their inflammatory biology is similar and cytokine-driven. Clinical trial results and durability (Priority: 5/5): Phase 2a and maintenance data suggested higher remission rates than existing therapies, with ongoing phase 2b and planned phase 3 development. Oral dosing and practical advantages (Priority: 4/5): ABX464 is taken as a daily capsule, which may improve convenience and lower administration burden versus injectable biologics. Rheumatoid arthritis combination strategy (Priority: 3/5): In RA, ABX464 is being studied with methotrexate rather than alone to build on established treatment regimens. Infectious disease potential, especially COVID-19 (Priority: 4/5): The drug showed antiviral activity against HIV and SARS-CoV-2 in preclinical and clinical work, while its anti-inflammatory effect could help prevent severe COVID outcomes.

Key Arguments: IBD inflammation in ulcerative colitis and Crohn’s is driven by highly similar, redundant cytokine pathways, so a broader regulatory approach may be advantageous. ABX464 works upstream of individual cytokines by increasing miR-124, which suppresses translation of TNF-alpha, IL-6, MCP-1 and related inflammatory proteins. Because the mechanism reduces multiple cytokines across the board rather than fully blocking one, it may function as a kind of “natural brake” on excessive inflammation. Oral once-daily dosing may improve patient acceptance and avoid the logistics and cost of injection-based biologics. Early clinical results in ulcerative colitis were compelling enough to justify a larger phase 2b study and planned phase 3 program. The company believes the effect is durable, since maintenance data showed continued remission over long treatment periods. In rheumatoid arthritis, ABX464 is being paired with methotrexate to test additive benefit alongside standard care. For COVID-19, ABX464 may address both viral replication and the inflammatory cascade that drives severe disease, making early intervention especially relevant.

Data Points: Phase 2a induction duration: 2 months - Initial ABX464 induction study in inflammatory bowel disease Maintenance follow-up duration: More than 2 years - Patients from the first study continued on ABX464 in long-term maintenance Longest patient exposure: Nearly 3 years uninterrupted treatment - First patient approaching three years on ABX464 Typical clinical remission on marketed therapies: About 10% after 2 months - Comparator benchmark for current IBD treatments Typical clinical response on marketed therapies: About 60% after 2 months - Existing IBD therapies often yield response without full remission No response with current therapies: About 30% to 40% - Proportion of patients not responding adequately to current products ABX464 clinical remission signal: 20% to 25% after placebo subtraction - Observed in the earlier ABX464 study Cytokine reduction with ABX464: Approximately 30% to 70% - Broad across-the-board reduction rather than complete blockade Phase 2b IBD study size: Roughly 230 patients - Larger confirmatory trial now underway Top-line phase 2b readout timing: May next year - Expected induction study results Phase 3 timing: Within the subsequent 6 months - Planned transition after phase 2b readout Rheumatoid arthritis background therapy: Methotrexate - ABX464 is being tested in combination with standard RA treatment ABX464 compound library size: About 2,200 molecules - Company library being explored for additional antiviral candidates COVID phase 2b/3 trial size: Just over 1,000 patients - Clinical study evaluating ABX464 versus placebo in COVID-19 Severe COVID share: Roughly 20% to 25% of patients - Proportion that may progress to severe disease Ventilator survival estimate: Around 30% to 40% - Survival chances for patients once on mechanical ventilation

Pivotal Quotes: "ABX464 is a small molecule belonging to the group of quinolines... it stabilizes this complex, and as a result... we get to the upregulation of... MIR124, which has very potent anti-inflammatory properties." — Hartmut Ehrlich: Explaining the drug’s mechanism of action "We are seeing clinical remissions in 20 to 25%. And this is what we are consider to be transformative." — Hartmut Ehrlich: Discussing early ulcerative colitis trial results "What we are trying to do here is essentially prevent... the cytokine storm... and the need for mechanical ventilation." — Hartmut Ehrlich: Describing the rationale for ABX464 in COVID-19

Implications: If validated in late-stage trials, ABX464 could offer a convenient oral alternative to biologics for inflammatory disease and a dual antiviral/anti-inflammatory approach for COVID-19, potentially broadening RNA-based therapeutics in immunology and infection.