Tuning, Rather than Blocking, Immunity in IBD

Episode Summary

Executive Summary: Abivax CEO Mark DeGaradel argues that ibifazomod/obefazimod, an oral microRNA-124 modulator repurposed from failed HIV work, could improve IBD care by stabilizing immune activity rather than broadly suppressing it. The approach aims to address unmet needs in safety, durability, and convenience in ulcerative colitis and Crohn's disease.

Main Topics: IBD disease burden and heterogeneity (Priority: 5/5): UC and Crohn's differ in location, severity, and how symptoms align with endoscopic inflammation. Limits of current therapy (Priority: 5/5): Existing advanced therapies work initially but often lose effect and raise infection risks. Origin of obifazimod (Priority: 5/5): The compound began as an HIV candidate before functional testing revealed anti-inflammatory potential. Mechanism of action (Priority: 5/5): microRNA-124 modulates upstream inflammatory pathways, especially macrophage and TH17 signaling. Clinical evidence and safety (Priority: 5/5): Phase 2 and phase 3 data suggest durable efficacy with a reassuring safety profile so far. Combination and expansion strategy (Priority: 4/5): Abivax is testing oral combination partners and exploring other autoimmune uses beyond IBD. Financing and commercialization (Priority: 4/5): Large raises supported late-stage development, with a U.S. launch path and ex-U.S. partnering planned.

Key Arguments: IBD patients need oral, safer, more effective options; physicians asked for all three in market research. Current immunoblocking therapies often work for about two years before resistance or adverse events emerge. microRNA-124 is upstream and acts as an 'immunostabilizer,' not a full immunoblocker. Obefazimod appears to reduce TH17 and macrophage-driven cytokines like IL-6 and IL-23. If inflammation is absent, the drug appears to do nothing, supporting a potentially safer profile. Phase 3 UC data included severe and JAK-resistant patients and still showed consistent responses. Only 5% of U.S. patients remain on the same IBD drug after three years, showing major persistence problems. Early long-term follow-up showed about 90% remission and lower dropout in an open-label extension. Abivax plans to file in the U.S. by end of 2026 and seeks approval for a Q3 2027 launch.

Data Points: UC diagnosis age: 35 - Average age at diagnosis for ulcerative colitis patients Symptom frequency: several times per day - Typical stool frequency in ulcerative colitis Advanced therapy efficacy window: about two years - How long immunoblocking therapies tend to work before losing effect Physician-reported desired traits: 3 - Oral treatment, safety, and efficacy Efficacy after 8 to 12 weeks: about 40% - Current advanced therapies reaching meaningful efficacy in some patients Phase 2B doses: 25 mg, 50 mg, 100 mg - Obefazimod dose-ranging study; 100 mg omitted due to higher toxicity Phase 3 UC trial size: 1,275 patients - Late-stage ulcerative colitis study launched in late 2022 Countries in phase 3: 6 countries - Geographic scope of the UC phase 3 trial JAK-resistant patients: 124 patients - Most severe subgroup included in the UC phase 3 trial Placebo-corrected clinical remission difference: 16-point difference - Statistically significant remission result after 8 weeks for the 15 mg dose Headache discontinuation rate: less than 1% - Phase 3 induction discontinuations due to headaches Long-term follow-up cohort: about 100 patients - Open-label extension population with multi-year data Open-label remission rate: about 90% - Reported remission among long-term follow-up patients U.S. persistence at 3 years: 5% - Real-world data on patients staying on the same IBD drug Capital raised: nearly $1.5 billion - Total financing referenced for company and program execution Phase 3 UC program cost: nearly $300 million - Approximate cost to run the phase 3 program Crohn's strictures: 40% - Patients who develop strictures and may need surgery Maintenance trial duration: 44-week trial - Ongoing phase 3 maintenance study Maintained follow-up dataset: 80% of the patients - Proportion of phase 3 participants in the ongoing safety review

Pivotal Quotes: "we want three things. One is we want an oral treatment" — Mark DeGaradel: He summarizes what physicians told Abivax they still need in IBD "it's not, again, an immunoblocker. It's an immunostabilizer." — Mark DeGaradel: He distinguishes obefazimod's mechanism from existing therapies "If you are not inflamed, nothing happens." — Mark DeGaradel: He describes the drug's inflammation-selective preclinical behavior

Implications: The key unanswered issue is whether longer maintenance data will confirm durability and support regulatory success, while investors and clinicians watch for phase 3 completion.