Slide 1: RLY-2608 Initial Clinical Data Presentation at AACR Annual Meeting
RLY-2608 Initial Clinical Data Presentation at AACR Annual Meeting April 2023 Exhibit 99.1
Slide 2: Disclaimer
Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding the progress and timing of the clinical development of the programs across
Slide 3: Relay Tx – Patient-Driven, Clear Focus, Validated Approach
Relay Tx – Patient-Driven Clear Focus Validated Approach Execution-Focused New Breed of Biotech EXPERIMENTATION COMPUTATION FGFR2 RLY-4008 SHP2 GDC-1971 Pre-clinical ERα Degrader CDK2 RLY-2139 5+ Add'l programs ~$1B Cash, cash equivalents and investments as of the end of 4Q 2022 Targets & Therapeuti
Slide 4: Relay Tx – Dynamo Platform
Relay Tx – Dynamo™ Platform Dynamo™ Platform… …is focused on making medicines Modulation Hypothesis Hit Identification Lead Optimization Target Identification Develop-ment Commercial-ization Focus of platform Chemical biology insights Deep structural understanding EXPERIMENTATION Physics-based simul
Slide 5: Relay Tx – Extensive Precision Medicine Pipeline
Target Program Annual US Patient # Breast Cancer1 PI3Kα franchise PI3KαPAN RLY-2608 ~10-68K breast cancer ~76-238K all solid tumors RLY-5836 PI3KαSPECIFIC H1047R-specific ~4-25K breast cancer ~15-48K all solid tumors Challengers CDK2 RLY-2139 ~46K2 (Patients receiving CDK4/6i) Challengers Degrader E
Slide 6: Relay Tx – Emerging Breast Cancer Franchise
Target Program Breast Cancer PI3Kα franchise PI3KαPAN RLY-2608 RLY-5836 PI3KαSPECIFIC H1047R-specific Challengers CDK2 RLY-2139 Challengers Degrader ERα Degrader Undisclosed 1 program FGFR2 RLY-4008 – Mutant + WT Tumor Agnostic SHP2 GDC-1971 Undisclosed 2 programs GD Genetic diseases 2 programs Rela
Slide 7: Breast Cancer – Significant Unmet Need
First Line Therapy Second Line Therapy (post CDK4/6) Adjuvant Tx Neo-adjuvant Surgery Endocrine Therapy (ET) ± CDK4/6 Chemo PFS (mo) CBR ORR PFS (mo) 4-23% 53-59% 14-46% 78-85% 1.9-7.3 25-28 Breast Cancer – Significant Unmet Need Of patients treated for early-stage disease attain long-term disease-f
Slide 8: PI3Kα – A Validated Target with Significant Unrealized Therapeutic Potential
PI3Kα – A Validated Target with Significant Unrealized Therapeutic Potential PI3Kα mutants Other Kinase Helical PI3Kα regulates glucose homeostasis WT PI3Kα and off-isoform toxicity limit the clinical benefit of alpelisib PI3Ki PI3Kα InsR Insulin Glycogen Glucose Less uptake increases blood glucose
Slide 9: PI3Kα – Existing Inhibitors Have Limited Therapeutic Window
PI3Kα – Existing Inhibitors Have Limited Therapeutic Window Potency (nM) H1047R E542K E545K WT Alpelisib H1047R E542K E545K WT Alpelisib and inavolisib are equipotent for WT and mutant PIK3α Both also retain nM potency against other PI3K isoforms Inavolisib Limited Efficacy Limited based Limited Tar
Slide 10: PI3Kα – Proprietary Insights Unlock Novel Approaches
PI3Kα – Proprietary Insights Unlock Novel Approaches A differentiated understanding of the structure of PI3Kα and its relationship to function equips Relay Tx to design optimal mutant-selective inhibitors of PI3Kα Designed pan-mutant selective PI3Kα inhibitor (PI3KαPAN) Discovered novel allosteric p
Slide 11: Relay Tx – Extensive Precision Medicine Pipeline
Target Program Breast Cancer PI3Kα Franchise PI3KαPAN RLY-2608 RLY-5836 PI3KαSPECIFIC H1047R-specific Challengers CDK2 RLY-2139 Challengers Degrader ERα Degrader Undisclosed 1 program FGFR2 RLY-4008 Mutant + WT Tumor Agnostic SHP2 GDC-1971 Undisclosed 2 programs GD Genetic diseases 2 programs Relay
Slide 12: Allosteric Mutant Selective PI3Kα Inhibitor
RLY-2608 – Allosteric Mutant Selective PI3Kα Inhibitor Potency (nM) Alpelisib Inavolisib RLY-2608 Pazolli M, Discovery and characterization of RLY-2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα. Oral presentation at: AACR-NCI-EORTC Virtual International Conference on Mo
Slide 13: Robust Efficacy with Limited Impact on Glucose Homeostasis in Preclinical Models
RLY-2608 – Shows Robust Efficacy with Limited Impact on Glucose Homeostasis in Preclinical Models Tumor regression in PI3Kα mouse breast cancer models Minimal perturbation of insulin levels Pazolli M, Discovery and characterization of RLY-2608, the first allosteric, mutant, and isoform-selective inh
Slide 14: RLY-2608 – First Mutant Selective Inhibitor to Enter the Clinic
Favorable Target Inhibition Favorable Vehicle RLY-2608 25mg/kg BID RLY-2608 100mg/kg BID RLY-2608 50mg/kg QD Maintains approx. 80% mutant PI3Kα inhibition in mouse model Limited potency against WT PI3Kα and other PI3K isoforms RLY-2608 – First Mutant Selective Inhibitor to Enter the Clinic Potency (
Slide 15: Data Disclosure Goals
RLY-2608 – Data Disclosure Goals Part 1: Dose Escalation Demonstrate clinical proof of mechanism Part 2: Dose Expansion Establish early efficacy & confirm dose Part 3: Pivotal Trial Establish definitive efficacy RP2D Target Inhibition Tolerability Selectivity Early Signals of Efficacy Interpretable
Slide 16: Summary of AACR 2023 Data Disclosure
RLY-2608 – Summary of AACR 2023 Data Disclosure RLY-2608 Initial Data Support Selective Targeting of Mutant PI3Kα 2H 2023: Expansion initiation Initial Clinical Proof of Mechanism Goal for Expansion Cohorts Interpretable Efficacy (CBR, ORR) Longer-Term Tolerability Potential for greater dose intensi
Slide 17: Trial Design
RLY-2608 – Trial Design 1. Excludes PIK3CAmut clear cell OvCA, HNSCC, Cervical cancer, and colorectal patients; 2. Double mutation defined as one major PIK3CA mutation (E542X, E545X, H1047X) + ≥1 additional PIK3CA mutation per local assessment; 3. Patients with previous PI3Kα inhibitor include those
Slide 18: ReDiscover Trial – Interim Part 1 Results
ReDiscover Trial – Interim Part 1 Results RLY-2608 + fulvestrant PIK3CA-mutant, HR+, HER2– advanced / metastatic breast cancer (N=23) RLY-2608 PIK3CA-mutant advanced solid tumors (N=19) Start: April 2022 Start: Dec 2021 Current enrollment focus 300mg BID 200mg BID 100mg BID 50mg BID 400mg BID 400mg
Slide 19: ReDiscover Trial – Baseline Demographics and Tumor Genotype
ReDiscover Trial – Baseline Demographics and Tumor Genotype RLY-2608 (N=19) RLY-2608 + fulvestrant (N=23) Total (N=42) Age, median (range), years 63 (42-85) 57 (40-83) 60 (40-85) Female, n (%) 11 (58%) 23 (100%) 34 (81%) Ethnicity, % White / Asian / American Indian / Black / Unknown 95% / 0% / 0% /
Slide 20: Broad PIK3CA Mutation Landscape Among ReDiscover Patients
PIK3CA mutations: 14 Kinase, 22 Helical, 5 double mutations* PIK3CA mutation profile at baseline N=42 * * * * * RLY-2608 Mono RLY-2608 + Fulvestrant Freq. E81K R88Q I112F N345K N345T G364R E453K E542K E545K E545Q Q546K N1044T H1047R Indication ABD C2 Helical Kinase 2% 2% 2% 14% 2% 2% 2% 26% 21% 2% 2
Slide 21: Favorable PK Profile
RLY-2608 – Favorable PK profile RLY-2608 C1D15 300mg 200mg 100mg 50mg 400mg 400mg 200mg 100mg 800mg 600mg RLY-2608 + fulvestrant C1D15 RLY-2608 Plasma Concentration (ng/mL) Mean+SD RLY-2608 Plasma Concentration (ng/mL) Mean+SD ~80% pAKT inhibition (predicted from mouse PK/PD models) ~50% pAKT inhibi
Slide 22: Multiple Doses Achieve ~80%+ Target Inhibition at Trough
RLY-2608 – Multiple Doses Achieve ~80%+ Target Inhibition at Trough Patient Plasma Sample* (Pre-dose) RLY-2608 Trough Concentration (ng/mL) pAKT Inhibition (%) PIK3CA-mutant cancer cells 80% pAKT inhibition (human) 50% pAKT inhibition ~80%+ pAKT inhibition at trough: 400mg BID mono 600mg & 800mg BID
Slide 23: Limited Observed Impact on Glucose Homeostasis Across All Doses
Glucose Concentration (mg/dL) Glucose Concentration (mg/dL) RLY-2608 RLY-2608 + Fulvestrant Alpelisib label criteria Grade 3 (250-500 mg/dL) Grade 2 (160-250 mg/dL) Grade 1 (115-160 mg/dL) Grade 3 (250-500 mg/dL) Grade 2 (160-250 mg/dL) Grade 1 (115-160 mg/dL) Alpelisib label criteria No Grade 3 hyp
Slide 24: Limited Impact on Glucose Homeostasis for Doses Above Target Exposure
RLY-2608 – Limited Observed Impact on Glucose Homeostasis Supports Mutant Selective Targeting for Doses Above Target Exposure No Grade 3 hyperglycemia per CTCAE v5.0 No dose interruptions or dose reductions due to hyperglycemia Glucose Concentration (mg/dL) Grade 3 (250-500 mg/dL) Grade 2 (160-250 m
Slide 25: Anti-tumor Activity: Partial Response per RECIST
RLY-2608 – Anti-tumor Activity: Partial Response per RECIST* *Response confirmed after data cut-off Courtesy Varkaris, MGH 58 y/o female, PIK3CA H1047R + E453K mutation, HR+ HER2- (IHC2+FISH-) 12 prior lines of therapy (chemo, endocrine, multiple HER2-directed, including Enhertu) RLY-2608 400mg BID
Slide 26: Evidence of Anti-Tumor Activity Supports Selective Target Engagement
RLY-2608 – Evidence of Anti-Tumor Activity Supports Selective Target Engagement 16 Breast Cancer Patients – Measurable Disease Only Breast Cancer Patients (RECIST Measurable Disease) N=16 SD uPR* Stable Disease Unconfirmed Partial Response* Progressive Disease PD BOR = Best Overall Response: 56% of
Slide 27: Decline of Mutant PIK3CA ctDNA
RLY-2608 – Decline of Mutant PIK3CA ctDNA PIK3CA variant allele frequency (%) 31 patients with evaluable paired C1D1-C2D1 ctDNA samples 6 patients have ≥2 PIK3CA mutations 23 patients had declines in PIK3CA ctDNA 9 patients completely cleared by C2D1 Doses Below Target Exposure RLY-2608 RLY-2608 + f
Slide 28: Breast Cancer Disease Control Across Dose Levels
RLY-2608 – Breast Cancer Disease Control Across Dose Levels 27 Breast Cancer Patients – Measurable and Non-Measurable Disease RLY-2608 Breast Cancer Patients (Measurable and Non-Measurable Disease) N=27 19/27 patients (70%) ongoing Duration on treatment: Median: 16 weeks Range: 4 – 44 weeks 21/24 RE
Slide 29: Treatment-Emergent Adverse Events
RLY-2608 – Treatment-Emergent Adverse Events (TEAEs) ≥15% 0% 0% 0% 0% Nausea Blood Creatinine Increased Fatigue Headache Hypokalaemia Decreased Appetite Diarrhea Hyperglycemia RLY-2608 TEAEs Across Monotherapy and Combo Arms (N=42) All Gr Gr3 Most AEs low grade, manageable, reversible Grade 3 TEAEs
Slide 30: TEAEs Consistent with Mutant-Selective Inhibition
RLY-2608 – TEAEs Consistent with Mutant-Selective Inhibition 0% 0% 0% 0% 0% Nausea Blood Creatinine Increased Fatigue Headache Hypokalaemia Decreased Appetite Diarrhea Hyperglycemia RLY-2608 Single Agent (N=19) RLY-2608 + Fulvestrant (N=23) Doses Above Target Exposure1 (N=17) 0% 0% 0% 0% 0% 0% 0% 0%
Slide 31: Tolerability Profile of Non-Selective Inhibitors
Tolerability Profile of Non-Selective Inhibitors for Relevant Off-Target Toxicities 1. Grouped term: rash and rash maculo-papular; 2. Capivasertib rash includes events related to rash including: rash, rash macular, maculopapular rash, rash papular and rash pruritic; 3. Alpelisib median dose intensi
Slide 32: Low Rates of Hyperglycemia, Rash and Diarrhea
RLY-2608 – Low Rates of Hyperglycemia, Rash and Diarrhea Hyperglycemia Rash1 Diarrhea 16% RLY-2608 - Doses above target exposure2 (N=17) RLY-2608 - Doses below target exposure (N=25) 18% 28% 4% 0% Grade 3 (No Gr4-5) Grade 1-2 RLY-2608 1. Grouped term: rash and rash maculo-papular; 2. Doses above tar
Slide 33: Potential to Achieve Greater Dose Intensity
RLY-2608 – Potential to Achieve Greater Dose Intensity Greater dose intensity against a validated target in breast cancer suggests potential to achieve greater duration of clinical benefit in patients with any PIK3CA mutation Low rate of dose modifications maintained dose intensity Achieved ≥80% mut
Slide 34: Trial Design
RLY-2608 – Trial Design 1. Excludes PIK3CAmut clear cell OvCA, HNSCC, Cervical cancer, and colorectal patients; 2. Double mutation defined as one major PIK3CA mutation (E542X, E545X, H1047X) + ≥1 additional PIK3CA mutation per local assessment; 3. Patients with previous PI3Kα inhibitor include those
Slide 35: Relay Tx – Extensive Precision Medicine Pipeline
Target Program Breast Cancer PI3Kα Franchise PI3KαPAN RLY-2608 RLY-5836 PI3KαSPECIFIC H1047R-specific Challengers CDK2 RLY-2139 Challengers Degrader ERα Degrader Undisclosed 1 program FGFR2 RLY-4008 Mutant + WT Tumor Agnostic SHP2 GDC-1971 Undisclosed 2 programs GD Genetic diseases 2 programs Relay
Slide 36: RLY-5836 – Trial Design
RLY-5836 – Trial Design Part 1: Dose Escalation Part 2: Dose Expansion RLY-5836 + Fulvestrant Arm1 PIK3CAmut, HR+/HER2- advanced breast cancer PIK3CAmut advanced solid tumors RLY-5836 Arm RLY-5836 + Fulvestrant + CDK4/6 Arms2 PIK3CAmut, HR+/HER2- advanced BC, 1 prior CDK4/6 PIK3CAmut, HR+, HER2- adv
Slide 37: Breast Cancer Franchise Continues to Progress
Breast Cancer Franchise Continues to Progress Relay Tx Breast Cancer Portfolio Goal for Expansion Cohorts Initial Data Supporting Selective Targeting of Mutant PI3Kα Initial Clinical Proof of Mechanism Selective target inhibition over IC80 Favorable safety profile at therapeutically active doses Ini
Slide 38: Relay Tx – Continued Dynamo Platform Validation
GDC-1971 (SHP2) Relay Tx – Continued Dynamo™ Platform Validation 1. POC - proof-of-concept. 2. DC - development candidate. 3. Subject to alignment with regulatory authorities RLY-4008 (Selective FGFR2) RLY-2608 (PI3KαPAN) RLY-5836 (PI3KαPAN) RLY-2139 (CDK2) ERα Degrader Pre-Clinical POC1 DC Selectio
Slide 39: Capital, Team & Execution Focus to Deliver on Key Milestones
Relay Tx – Capital, Team & Execution Focus to Deliver on Key Milestones ~$1B Cash, cash equivalents and investments as of the end of 4Q 2022 Current cash, cash equivalents and investments are expected to be sufficient to fund current operating plan into 2025 Tumor Agnostic Breast Cancer Franchise GD
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Slide 41: Tolerability Profile of Non-Selective Inhibitors
Mucosal Inflammation Tolerability Profile of Non-Selective Inhibitors Sources: 1. SOLAR-1 (long-term follow up): Andre 2021 Ann Oncol 32:208, 2. SOLAR-1 (initial publication): Andre 2019 N Engl J Med 380:1929, 3. Alpelsib FDA Label 4. Inavolisib first-in-human study: SABCS 2021 #P5-17-05, 5. CAPItel
Slide 42: Summary of Preliminary AEs
RLY-2608 – Summary of Preliminary AEs Below Above Below Above Below Above Above Below 4% 0% Above Above Below 24% Above 24% Below Below 4% 18% 16% 0% 12% 28% 41% 0% 16% 12% 0% Grade 3+ Grade 1-2 Mucosal Inflammation Appetite Loss Vomiting Nausea Diarrhea GI Toxicity Rash Hyperglycemia Asthenia Anemi