Astellas Pharma (4503) Status Update summary

R&D strategy and targeted protein degradation (TPD) overview

• TPD is a priority investment area, aiming to transform treatment for refractory cancers and other diseases by degrading undruggable proteins, such as KRAS G12D, using the ubiquitin-proteasome system.

• TPD offers advantages over traditional inhibitors: access to undruggable targets, deep tissue penetration, and high specificity, potentially reducing toxicity.

• The strategic roadmap includes establishing hetero-bifunctional degrader programs, expanding the pipeline in oncology and non-oncology, and exploring beyond current TPD modalities.

• Mutated KRAS, especially G12D, is a common driver mutation in several cancers, with high unmet need in pancreatic, colorectal, and non-small cell lung cancers.

• Strategic investments and collaborations are advancing TPD as a transformative modality for hard-to-treat diseases.

ASP3082 clinical development and data

• ASP3082 is the first in-house, KRAS G12D-selective protein degrader to enter clinical trials, showing potent, selective degradation and tumor growth inhibition in preclinical models.

• Phase 1 trials enrolled heavily pretreated patients with advanced pancreatic, colorectal, and non-small cell lung cancers, with dose escalation up to 600 mg.

• Dose-dependent KRAS G12D degradation and target exposure were observed at doses ≥300 mg, with promising antitumor activity: ORR 18.5% and DCR 48.1% in PDAC, and ORR 23.1% and DCR 84.6% in NSCLC.

• The safety profile was manageable up to 600 mg, with grade 3 adverse events in 6.3%, no grade 4/5 events, and mostly mild infusion site reactions.

• Several patients remain on treatment; duration of response and PFS data are maturing, with proof of concept expected by H1 2025.

Pipeline expansion and technology platform

• The pipeline includes ASP3082, ASP4396, pan-KRAS degraders, and preclinical assets, leveraging advanced AI, robotics, and molecular design for rapid candidate optimization.

• Degrader Antibody Conjugate (DAC) programs aim to enhance tumor targeting and efficacy, with expectations for improved safety and reduced dosing frequency.

• In-house expertise leverages advanced biophysical assays, AI-driven modeling, and a proprietary E3 binder-linker library to accelerate TPD drug discovery.

• Collaborations with partners like PeptiDream, FIMECS, and Cullgen expand the range of POI/E3 binders and enhance functional capabilities of degraders.

• Strategic investments are being made to advance TPD as a transformative modality for hard-to-treat diseases.