Adagene (ADAG) Leerink’s Global Healthcare Conference 2025 summary

Program overview and scientific rationale

• Lead program ADG126 (muzastotug) targets CTLA-4, aiming to deplete Tregs in the tumor microenvironment, especially in MSS CRC where PD-L1 expression is low and TILs are scarce.

• Exclusion of patients with liver and peritoneal metastases is based on their poor response to immunotherapy and regulatory precedent, focusing on populations more likely to benefit.

• The molecule differentiates itself by using epitope-driven Fc activity for Treg depletion, allowing higher dosing and improved tumor penetration without increased systemic toxicity.

• The therapeutic window is widened by combining high tumor exposure with controlled systemic exposure, supported by a loading dose and maintenance strategy.

• Maintenance dosing is considered important in MSS CRC to sustain Treg depletion and prevent tumor relapse, as indicated by biomarker (CEA) rebound upon dose interruption.

Clinical development and dosing strategy

• Dose responsiveness is observed in both efficacy and toxicity, with higher doses (20 MPK loading) showing promising activity but increased grade 3 toxicity.

• Variability in drug exposure is slightly higher than standard IgG antibodies, attributed to tumor-specific factors, but remains manageable within the dosing regimens.

• Lower doses (10 MPK Q6W) are safer but may have reduced efficacy in MSS CRC, though effective in other indications like head and neck cancer.

• The dosing regimen allows flexibility for combination with standard therapies, and dose adjustments are possible between induction and maintenance phases.

• Ongoing studies are exploring combinations with standard third- and fourth-line therapies, such as SUNLIGHT (TAS-102 + Beva) and fruquintinib, to potentially expand to broader patient populations.

Regulatory and future outlook

• The company is preparing to engage with FDA and CDE on trial design and dosing regimens, aiming for potential accelerated approval if meaningful ORR and DOR are demonstrated.

• A new neoadjuvant trial in MSS CRC is enrolling 20 patients to systematically correlate Treg depletion with clinical benefit using matched biopsies.

• Next clinical updates will include larger cohorts and longer follow-up on the 20 MPK dose, as well as data from combination regimens.

• The development strategy is focused on cold tumors with high Treg and low PD-L1, differentiating from competitors targeting broader indications.

• The regulatory path is benchmarked against current standards, with a focus on overall survival and response rates in difficult-to-treat populations.