Slide 1: Targeted Protein Degradation
TARGETED PROTEIN DEGRADATION Progress on ASP3082, a first-in-class KRAS G12D selective protein degrader Chinatsu Sakata, Ph.D. Vice President, Primary Focus Lead, Targeted Protein Degradation Astellas Pharma, Inc.
Slide 2: Cautionary statement regarding forward-looking information
Cautionary statement regarding forward-looking information 2 In this material, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas Pharma. These sta
Slide 3: Contents
Contents 3 Presenter I Introduction Chinatsu Sakata, Ph.D. Targeted Protein Degradation Primary Focus Lead, Targeted Protein Degradation II strategy Q&A participants III Progress on ASP3082 IV Pipeline update V Q&A Masahiko Hayakawa, Ph.D. Ahsan Arozullah, M.D., M.P.H. Head, Engineered Small Molecul
Slide 4: Introduction
| INTRODUCTION Wastellas
Slide 5: Targeted protein degraders could overcome limitations of traditional small molecules
Targeted protein degraders have the potential to overcome limitations of 5 traditional small molecules and tackle “undruggable” targets Historically, the efficacy of small molecule inhibitors has been limited by target selectivity, cell resistance and difficulty binding to disease-related or multi-d
Slide 6: Targeted Protein Degradation Strategy
6 TARGETED PROTEIN DEGRADATION STRATEGY
Slide 7: We aspire to evolve TPD into a key capability for Astellas
We aspire to evolve TPD into a key capability for Astellas and a 7 major driver of our pipeline expansion Our three-step strategic roadmap charts a clear path for continued innovation: Step 1 Step 2 Step 3 Harvest KRAS hetero- Generate post-KRAS Expand into non- bifunctional degrader pipeline pipeli
Slide 8: Mutated KRAS is a historically undruggable target; G12D most common
Mutated KRAS is a historically “undruggable” target and KRAS 8 G12D is the most common KRAS driver mutation1 Expression rate (%) of the G12D mutation: Pancreatic ductal Colorectal Non-squamous non-small cell adenocarcinoma (PDAC) cancer (CRC) lung cancer (NSCLC) ~40% ~15% ~5% While approved KRAS G12
Slide 9: High unmet need in cancers expressing KRAS G12D mutations
There is high unmet need in cancers expressing KRAS G12D mutations 9 – take PDAC as an example PDAC is the 7th leading cause of cancer death in the world.1 <10-17% ORR associated with 2L+ treatments in studies. 2-10 5-7 months median overall survival in 2L+. 2-10 of 2L patients receiving irinotecan,
Slide 10: Progress on ASP3082
i PROGRESS ON ASP3082 10
Slide 11: ASP3082 is the first KRAS G12D protein degrader to enter the clinic
Our lead program, ASP3082, is the first protein degrader for 11 mutated KRAS G12D to enter the clinic Combining unique capabilities with speed and potency ASP3082 is in Phase 1 trials for the treatment of solid tumors harboring the KRAS G12D mutation, having demonstrated a superior anti-tumor effect
Slide 12: Phase 1 study design of ASP3082
Phase 1 study design of ASP3082 12 Key Eligibility Criteria Dose Escalation Key Endpoints Eligible patients had: Primary endpoints: • Locally advanced or • DLT, AE 600mg metastatic disease with • MTD, RP2D a KRAS G12D mutation 450mg Secondary endpoints: • Received prior standard 300mg • ORR, DCR the
Slide 13: Phase 1 study population primarily advanced pancreatic, colorectal and NSCLC
Our Phase 1 study population primarily had advanced 13 pancreatic, colorectal and non-small cell lung cancer Patient demographics and baseline characteristics ASP3082 monotherapy QW Characteristic 300–600mg (n = 48) Overall (N = 111) Median age, years (range) 66 (39–81) 64 (31–89) Male, n (%) 30 (62
Slide 14: ASP3082 safety profile in doses up to 600mg
ASP3082 safety profile in doses up to 600mg 14 ASP3082 monotherapy QW Any grade Grade 3 Characteristic, n (%) 300–600mg (n = 48) Overall (N = 111) 300–600mg (n = 48) Overall (N = 111) TRAEs 43 (89.6) 83 (74.8) 5 (10.4) 7 (6.3) TRAEs occurring in ≥ 5% of all patients Infusion-related reaction 17 (35.
Slide 15: ASP3082 exceeded target exposure at ≥300mg QW; KRAS G12D degraded
ASP3082 exceeded target exposure in the body ≥ 300mg QW 15 and KRAS G12D was degraded in a dose-dependent manner ASP3082 exposure in blood KRAS G12D degradation by IHCb aEfficacy targets based on quantitative systems pharmacology model using 9 KRAS G12D tumor cell lines evaluated in mouse tumor grow
Slide 16: Antitumor activity in patients with PDAC and NSCLC
Antitumor activity was observed in patients with PDAC and 16 NSCLC receiving doses between 300–600mg PDAC NSCLC ** Response by prior lines of therapy ASP3082 monotherapy QW Parameter ≤ 2 (n = 17) a ≥ 3 (n = 10) Overall (n = 27) Parameter 300–600mg (n = 13) ORRb, n (%) 4 (23.5) 1 (10.0) 5 (18.5) ORRd
Slide 17: Responses to ASP3082 over time in PDAC and NSCLC
Responses to ASP3082 over time in patients with PDAC and 17 NSCLC PDAC* NSCLC • At data cutoff, 6 of 27 (22.2%) patients remained on • At data cutoff, 8 of 13 (61.5%) patients remained on treatment treatment • DOR and PFS endpoints were not mature at data cutoff • DOR and PFS endpoints were not matu
Slide 18: Next steps
The results and safety profile of ASP3082 support further 18 clinical investigation Icon Safety profile Dose-dependent Antitumor activity in doses degradation of KRAS in patients with up to 600 mg G12D mutant protein PDAC and NSCLC • Phase 1 study ongoing, as a single agent or in combination therapy
Slide 19: Pipeline Update
19 | PIPELINE UPDATE Wastellas
Slide 20: Robust early research pipeline leveraging advantages of protein degraders
Robust early research pipeline leveraging advantages of 20 protein degraders Discovery Preclinical P1 Target “undruggable” proteins with shallow pockets or scaffold proteins undisclosed ASPxxx ASP4396 ASP3082 (e.g., KRAS) Tumor targeting by antibody and enhanced payload activity due to its undisclos
Slide 21: Our portfolio consists of targeted protein degraders
Our portfolio consists of targeted protein degraders – 21 addressing historical “undruggables” Program Mechanism Indication Origin/Partner Current phase Phase 1 ASP3082 KRAS G12D degrader KRAS G12D+ solid tumor PoC judgment: 1H CY2025 KRAS G12D degrader ASP4396 KRAS G12D+ solid tumor Phase 1 (differ
Slide 22: Our in-house expertise further advances this complex modality
Our in-house expertise further advances this complex modality 22 Over the past four years since the discovery of ASP3082, we have been developing follow-on programs while enhancing our TPD drug discovery platform to enable the quick and efficient creation of optimized TPDs. Identify Binders Optimize
Slide 23: Collaboration with external partners to acquire novel POI/E3 binders
Collaboration with external partners – acquiring novel POI/E3 23 binders to develop innovative targeted protein degraders With our partners, we’re already developing next-generation targeted protein degraders capable of recruiting various E3 ligases with disease- or tissue-specific characteristics,
Slide 24: Strategic investments in TPD to realize the platform's potential
24 At Astellas, we believe the TPD modality could transform the treatment landscape for some of the world’s most devastating diseases. We are making strategic investments in TPD to accelerate our research and development, bringing together the right expertise and capabilities to realize the platform
Slide 25: Q&A
I Q&A 25