UNITED STATES
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FORM
CURRENT REPORT
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01 Regulation FD Disclosure.
Relay Therapeutics, Inc. (the “Company”) intends to host a conference call and live webcast on April 18, 2023 at 1:30 p.m. E.T. to discuss the initial clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective phosphoinostide 3 kinase alpha, also known as PI3Kα, inhibitor that is being presented at the American Association for Cancer Research (“AACR”) Annual Meeting 2023. The Company has made available a slide presentation to accompany the call, a copy of which is being furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information in this Item 7.01, including Exhibit 99.1 attached hereto, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 8.01 Other Events.
On April 18, 2023, the Company issued a press release announcing the initial clinical data for RLY-2608 that was presented at the AACR Annual Meeting 2023, a copy of which is filed herewith as Exhibit 99.2 to this Current Report on Form 8-K and incorporated herein by reference.
Item 9.01 Exhibits.
99.1 |
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99.2 |
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Press release issued by Relay Therapeutics, Inc. on April 18, 2023. |
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Cover Page Interactive Data File (embedded within Inline XBRL document). |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
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RELAY THERAPEUTICS, INC. |
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Date: |
April 18, 2023 |
By: |
/s/ Brian Adams |
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Brian Adams |
RLY-2608 Initial Clinical Data Presentation at AACR Annual Meeting April 2023 Exhibit 99.1
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 our portfolio, including the expected therapeutic benefits of our programs, timing of enrollment completion, and potential efficacy and tolerability; the timing of a clinical data update for RLY-4008, RLY-2608, and RLY-5836, and the clinical initiation of RLY-2139, and the nomination of a development candidate for our ERα degrader program; the possibility that unconfirmed results from these trials will not be confirmed by additional data as our clinical trials progress; the potential of RLY-2608 or RLY-5836 to address a major unmet medical need; expectations regarding our pipeline, operating plan, use of capital, expenses and other financial results; our cash runway projection; the competitive landscape and potential market opportunities for our product candidates; the expected strategic benefits under our collaborations; our ability to successfully establish or maintain collaborations or strategic relationships for our product candidates; expectations regarding current and future interactions with the U.S. Food and Drug Administration (FDA); our ability to manufacture our product candidates in conformity with the FDA’s requirements; the capabilities and development of our DynamoTM platform; our plans to develop, manufacture and commercialize our current product candidates and any future product candidates; and the implementation of our business model and strategic plans for our business, current product candidates and any future product candidates. The words “may,” “might,” “will,” “could,” “would,” “should,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions, or the negative thereof, are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this presentation are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation, including, without limitation, risks associated with: the impact of global economic uncertainty, geopolitical instability, or public health epidemics or outbreaks of an infectious disease, such as COVID-19, on countries or regions in which we have operations or do business, as well as on the timing and anticipated results of our clinical trials, strategy, future operations and profitability; the delay of any current or planned clinical trials or the development of our drug candidates; the risk that the preliminary results of our preclinical or clinical trials may not be predictive of future or final results in connection with future clinical trials of our product candidates; our ability to successfully demonstrate the safety and efficacy of our drug candidates; the timing and outcome of our planned interactions with regulatory authorities; and obtaining, maintaining and protecting our intellectual property. These and other risks, uncertainties and important factors are described in the section entitled "Risk Factors" in our most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as well as any subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent our views only as of the date of this presentation and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, the occurrence of certain events or otherwise. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in this presentation relating to or based on such internal estimates and research. This presentation contains trademarks, trade names and service marks of other companies, which are the property of their respective owners.
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 & Therapeutic Areas Oncology Genetic diseases Modalities Small molecules Degraders Validated Targets only Chaperones Clinical PI3KαPAN RLY-2608 RLY-5836
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 simulations AI / ML COMPUTATION 1 2 …aims to address selectivity on validated targets 3 Selectivity Efficacy Tolerability Target Inhibition PEOPLE
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 ERα Degrader ~29-196K3 Undisclosed 1 program To be announced FGFR2 RLY-4008 Mutant + WT ~11-35K4 Tumor Agnostic SHP2 GDC-1971 ~37-69K5 Undisclosed 2 programs To be announced GD Genetic diseases 2 programs To be announced Relay Tx – Extensive Precision Medicine Pipeline Preclinical Early Clinical Late Clinical CCA + other Breast Cancer 1. Unless otherwise indicated, all breast cancer patient numbers refer to HR+/HER2- breast cancer tumors; 2. ~46K HR+/HER2- breast cancer patients expected to receive CDK 4/6 inhibitors in adjuvant setting, first-line setting, and second-line setting in 2023, per Decision Resources Breast Cancer Market Forecast report dated June 2022; 3. HR+/HER2- US late-line breast cancer patients compared to HR+/HER2- US incident breast cancer patients; 4. FGFR2 altered late-line solid tumors compared to comprehensive annual FGFR2 altered incident solid tumors including additional FGFR gene fusions and rearrangements resulting from truncation of the protein at exon 18 and all breast cancer patients with FGFR2 alterations; 5. SHP2 combo only includes KRAS G12C in lung and colorectal, EGFR mutations in lung, and ALK fusions in lung Note: Unless otherwise indicated, patient #’s refer to total annual number of US patients with late-line cancers compared to comprehensive annual incidence that may be amenable to treatment with our programs
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 Tx – Emerging Breast Cancer Franchise Preclinical Early Clinical Late Clinical CCA + other Breast Cancer
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-free-survival Metastatic Setting – Significant unmet need "Early Setting" (Patients with tumor Stages I-III) ~25% Relay Tx BC portfolio aspirational positioning ~75% 25.3 - 28.2 ET ± CDK4/6 1.9 - 2.8 PI3K Path. + ET CDK4/6 + ET SERD 7.3 Relay Tx BC portfolio planned initial positioning PFS = Progression Free Survival CBR = Clinical Benefit Rate ORR = Objective Response Rate Significant need for improved PFS in 2L ~196,000 new HR+/HER2- breast cancer cases diagnosed each year in USA ~50,000 met HR+/HER2- BC cases/yr in US Of patients require treatment in advanced or metastatic setting Figures generated based on publicly available data for both approved and investigational products (alpelisib, ribociclib, elacastrant (investigatonal), fulvestrant (investigatonal), palbociclib, ribociclib, abemaciclib, capivasertib (investigational)). Sources: SEER, Metastatic Breast Cancer Network (MBCN), Johnston 2019 NPJ Breast Cancer 5:5, Goetz 2017 JCO 35:3638, Rugo 2019 Breast Cancer Res Treat 174:719, Ibrance Label, Finn 2016 N Engl J Med 375:1925, Hortobagyi 2018 Ann Oncol 29:1541, Kisqali label, SABCS 2021 #P1-18-03, SABCS 2022 #GS3-04, ASCO 2022 #LBA1004, Bardia 2022 Cancer Research 82, ASCO 2022 LBA3, ASCO 2022 LBA1001, Wander 2021 J NCCN 24:1, ASCO 2022 #1055, Xi J 2019 J NCCN 17:141
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 Alpelisib, the only FDA-approved PI3Kα inhibitor for solid tumors, is not mutant-selective and disrupts glucose metabolism, causing hyperglycemia AEs frequently leading to treatment discontinuation for alpelisib 65% (37%) 36% (10%) 60% (7%) All Gr (Gr3+) Hyperglycemia Diarrhea Rash AE PI3Kα is the most frequently mutated kinase in solid tumors PI3Kα 14% EGFR ERBB2 6% 6% ALK BRAF 6% 1% % of tumors with alteration ~100K breast cancer patients with PI3Kα mutation in US annually E542X E545X $5.9B $11.7B H1047X ~$7B Total 2022 Revenue: (Global) ~$9B ~$2B *Tafinlar + Mekinist Sources: Internal analysis based on third party industry data; Alpelisib data: SOLAR-1 (long-term follow up): Andre 2021 Ann Oncol 32:208 * ~$3B
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 Target Inhibition Limited Regimen Interruption Reduction Discont. Alpelisib6,7 58% 38% 15% Alpelisib + fulv1 74% 64% 25% Inavolisib + fulv8 41% 18% 2% Capivasertib+fulv18 35% 20% 13% Alpelisib: Observed coverage (based on IC80) at median dose intensity 9-13hr7 Regimen ORR CBR PFS (mo) Alpelisib Mono Ph 1a7 4% 17% 5.5 Alpelisib + fulv Ph 24 19% 46% 7.3 Inavolisib + fulv Ph 1b13 19% 48% 7.1 Capivasertib + fulv Ph 318 29% NR* 7.3 Data from RP2D of alpelisib, inavolisib, and capivasertib Compound All Gr3+ Tox Hyperglycemia GI Tox (all Gr) Rash (all Gr) All Gr Gr3+ Alpelisib1-7 44-78% 33-65% 13-37% 33-60% 20-36% Inavolisib8-12 33-54% 55-70% 5-22% 27-50% 7-27% Capivasertib14-18 21-62% 16-43% 2-20% 64-82% 22-53% Limited Tolerability Limited AKT inhibitor Limited Selectivity Limited * NR = Not Recorded Note: fulv = fulvestrant; all referenced studies are for their patient populations which are analogous to ongoing breast cancer pt populations within RLY-2608 clinical trials; Alpelisib and fulvestrant are FDA approved, inavolisib and capivasertib are in Phase 3 clinical trials Sources: Alpelisib – 1. SOLAR-1: Andre 2019 N Engl J Med 380:1929, 2. Ph 1b: SABCS 2013 P2-16-14, 3. Ph 1b: SABCS 2014 PD5-5, 4. Ph 2 ByLIEVE: Rugo 2021 Lancet Oncol 22:489, SABCS 2021 #P1-18-03, 5. Ph 1b mono: Annals of Oncol 25 2014 (suppl 4), 6. Ph 2 mono: Savas Cancer Discov 2022 Sep 12:2058, 7. Ph 1a mono: Juric 2018 J Clin Oncol 36:1291; Inavolisib – 8. ASCO 2022 #1052 (note: pooled rates across cohorts), 9. SABCS 2020 #PS11-11, 10. AACR 2020 CT109, 11. SABCS 2019 OT1-08-04; 12. SABCS 2019 P1-19-46, 13. SABCS 2021 #P5-17-05; Capivasertib – 14. Ph 1 mono: Banerji 2018 Clin Cancer Res 24:2050, ASCO 2015 #2500; 15. Ph 2 mono: SABCS 2019 P1-19-14; 16. Ph 1 combo: Smyth 2020 Clin Cancer Res 26:3947; 17. Ph 2 FAKTION: ASCO 2022 #1005; 18. Ph 3 CAPItello-291: SABCS 2022 #GS3-04 Note: These data are derived from different clinical trials at different points in time, with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted.
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 pocket favored in mutant protein Solved first full-length structures of PI3Kα (mutant and wild-type) Mutant PI3Kα
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 Tx – Extensive Precision Medicine Pipeline Preclinical Early Clinical Late Clinical CCA + other Breast Cancer
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 Molecular Targets Conference; October 7-10, 2021; Virtual. Biochemical IC50 H1047R E542K E545K WT H1047R E542K E545K WT H1047R E542K E545K WT RLY-2608 selectively inhibits mutant PI3Kα High selectivity over the kinome and within PI3K family Atypical Protein Kinases Mutant Lipid Pathogen TKL TK OTHER CMGC CAMK AGC STE CK1 Orthosteric Allosteric Non-selective Selective
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 inhibitor of PI3Kα. Oral presentation at: AACR-NCI-EORTC Virtual International Conference on Molecular Targets Conference; October 7-10, 2021; Virtual. 1. This model also carries a second mutation at K567R; 2. HSC2 model; 3. Source: J Clin Oncol 2018 Vol. 36 Issue 13 Pages 1291-1299, SABCS 2019 OT1-08-04 Vehicle Alpelisib 50mg/kg QD Inavolisib 25mg/kg QD RLY-2608 25mg/kg BID RLY-2608 50mg/kg BID RLY-2608 100mg/kg BID Higher doses/exposures lead to increased modulation of pAKT across PIK3CA mutant models Alpelisib & inavolisib increase insulin levels & disrupt glucose homeostasis Not clinically achievable doses of alpelisib & inavolisib3 RLY-2608 –Shows Robust Efficacy with Limited Impact on GlucoseHomeostasis in Preclinical Models Tumor regression in PI3Kαmouse breast cancer models Minimal perturbation of insulin levels H1047R (Kinase mutant) (HCC1954) E545K (Helical mutant) (MDAMB3611) Insulin levels at steady state exposure in tumor-bearing mice2 500 1000 1500 2000 2500 Tumor Volume (Mean SEM, mm3) 0 10 20 30 40 0 Days of Treatment 100 200 300 400 500 1000 1500 2000 Tumor Volume (Mean SEM, mm3) 0 10 20 30 40 Days of Treatment 0 5 10 15 20 4 12 4 12 4 12 4 12 4 12 4 12 Time (hr) Insulin levels (ng/mL) Alpelisib& inavolisibincrease insulin levels & disrupt glucose homeostasis Not clinically achievable doses of alpelisib& inavolisib3 Higher doses/exposures lead to increased modulation of pAKTacross PIK3CAmutant models 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 Molecular Targets Conference; October 7-10, 2021; Virtual. This model also carries a second mutation at K567R; 2. HSC2 model; 3. Source: J Clin Oncol 2018 Vol. 36 Issue 13 Pages 1291-1299, SABCS 2019 OT1-08-04 © 2023 Relay Therapeutics 13 vehical alpelisib 50mg/kg qd inavolsib 25mg/kg qd rly-2608 25mg/kg bid rly-2608 50mg/kg bid rly-2608 100mg/kg bid relay ® therapeutics
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 (nM) Alpelisib Inavolisib RLY-2608 WT Mutant WT Mutant WT Mutant Favorable Selectivity Favorable Efficacy All Data Shown is Preclinical Favorable Favorable Robust tumor regression at tolerable doses in mouse model Vehicle Alpelisib 50mg/kg QD Inavolisib 25mg/kg QD RLY-2608 25mg/kg BID RLY-2608 50mg/kg BID RLY-2608 100mg/kg BID Manageable key toxicities, especially hyperglycemia shown in dog study Favorable Tolerability Favorable Vehicle RLY-2608 10mg/kg BID RLY-2608 50mg/kg BID RLY-2608 20mg/kg BID RLY-2608 –First Mutant Selective Inhibitor to Enter the Clinic All Data Shown is Preclinical Favorable Tolerability Favorable Favorable Efficacy Limited potency against WT PI3Kαand other PI3K isoforms Manageable key toxicities, especially hyperglycemia shown in dog study Robust tumor regression at tolerable doses in mouse model Favorable Target Inhibition Favorable Maintains approx. 80% mutant PI3Kαinhibition in mouse model Potency (nM) 0 10 20 30 40 50 Mutant WT Mutant WT Mutant WT Alpelisib Inavolisib RLY-2608 Glucose levels (mg/dL) 0 50 100 150 200 0 4 8 12 0 4 8 12 0 4 8 12 0 4 8 12 Time (hr) Vehicle RLY-2608 10mg/kg BID RLY-2608 50mg/kg BID RLY-2608 20mg/kg BID % pAKT/tAKT inhibition 0 50 100 150 2 2 4 8 2 4 8 2 4 8 Time post last dose (hr) Vehicle RLY-2608 25mg/kg BID RLY-2608 100mg/kg BID RLY- 2608 50mg/kg QD Vehicle Alpelisib50mg/kg QD Inavolisib25mg/kg QD RLY-2608 25mg/kg BID RLY-2608 50mg/kg BID RLY-2608 100mg/kg BID Tumor volume (mean+- sem, mm3) 0 500 1000 1500 2000 2500 0 10 20 30 40 days of treatment © 2023 Relay Therapeutics relay ® therapeutics
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 Efficacy Focus of Disclosure Focus of AACR 2023 disclosure: Acute safety and tolerability within context of mutant target inhibition
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 intensity Selective target inhibition over IC80 Continuous pAKT inhibition ~80%+ achieved at 400mg BID mono and ≥600mg BID combo with fulvestrant Limited observed impact on glucose homeostasis No grade 3 hyperglycemia observed1 Favorable safety profile at therapeutically active doses Low rates of hyperglycemia, rash and diarrhea No DLTs and no AEs leading to treatment discontinuation 6/7 600mg BID patients remained on treatment for median of ~4 months Initial anti-tumor activity observed across range of doses uPR* observed in a heavily pretreated breast cancer pt (RLY-2608 monoTx) 9/16 breast cancer patients2 exhibit radiographic tumor shrinkage Declines in mutant ctDNAs observed 19/27 breast cancer pt remained on treatment with mDoE of ~4 months Focus of AACR disclosure DLTs = dose limiting toxicities; 1. per CTCAE v5.0; 2. with measurable disease per RECIST Preliminary data as of 03/09/2023 * Response confirmed after data cut-off
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 with intolerance to PI3Kαi defined as treatment discontinuation due to treatment-related AE (e.g., hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson syndrome; 4. RLY-2608 + fulvestrant + CDK4/6 arm expected to be added in a protocol amendment Part 1: Dose Escalation Part 2: Dose Expansion Focus of data presented at AACR RLY-2608 Arm PIK3CAmut adv solid tumors Includes mixed histologies PIK3CAmut advanced solid tumors (CCOC, HNSCC, Cervical, other1, double PIK3CA mutants2) MTD/RP2D PIK3CAmut, HR+, HER2- advanced breast cancer (with & without prior PI3Kα inhibitor3) RLY-2608 + Fulvestrant Arm PIK3CAmut, HR+/HER2- adv / met breast cancer Includes patients with non-measurable disease MTD/RP2D RLY-2608 + Fulvestrant + CDK4/6 Arm4 PIK3CAmut, HR+, HER2- advanced breast cancer PIK3CAmut, HR+/HER2- adv / met BC MTD/RP2D
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 QD 200mg QD Ongoing N=3 N=3 N=3 N=4 N=3 N=1 N=2 400mg BID 200mg BID 100mg BID 800mg BID 600mg BID Ongoing N=7 N=6 N=3 N=3 N=4 Part 1: Dose Escalations – Bayesian optimal interval design with cohort enrichment RLY-2608 daily via continuous oral administration Across both dose escalation cohorts: No dose limiting toxicities (DLTs) MTD not reached & dose escalation continues Cohort enrichment ongoing Preliminary data as of 03/09/2023
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% / 0% / 5% 78% / 4% / 4% / 4% / 9% 86% / 2% / 2% / 2% / 7% ECOG, n (%) 0 8 (42%) 13 (57%) 21 (50%) 1 11 (58%) 9 (39%) 20 (48%) BMI, kg/m2, median (range) 25 (16-44) 25 (18-38) 25 (16-44) <30, n (%) 14 (74%) 17 (74%) 31 (74%) ≥30, n (%) 5 (26%) 6 (26%) 11 (26%) Prior regimens of therapy in metastatic setting, median (range) 3 (0,12) 1 (1, 12) 2 (0,12) 0 1 (5%) 0 1 (2%) 1 4 (21%) 12 (52%) 16 (38%) 2 2 (11%) 3 (13%) 5 (12%) 3+ 12 (63%) 8 (35%) 20 (48%) Type of prior therapy, n (%) Endocrine therapy + CDK4/6 inhibitor NA 23 (100%) NA Chemotherapy / ADC 12 (63%) 6 (26%) 18 (43%) mTOR / AKT inhibitor 0 4 (17%) 4 (10%) Preliminary data as of 03/09/2023
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% 2% 31% PIK3CA gene function domain Mut * Double mutation defined as one major PIK3CA mutation (E542K, E545X or H1047X) and ≥1 additional PIK3CA mutation. Kinase, Helical, and double mutations are not mutually exclusive Mutation per local assessment Preliminary data as of 03/09/2023 Broad PIK3CA Mutation Landscape Among ReDiscover Patients
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 inhibition Time (h) Time (h) ~80% pAKT inhibition (predicted from mouse PK/PD models) ~50% pAKT inhibition Dose-dependent increase in exposure and low peak to trough fluctuations across dose levels Continuous exposure over IC80 correlates with efficacy in preclinical models* Constant coverage at IC80 across dosing interval at 400mg BID mono and 600mg and 800mg BID combo Exposure associated with efficacy in mouse tumor models * Fritsch et al Mol Can Therapeutics 2014 13(5) 1117-1129. Piqray - European Medicines Agency Public Assessment Report 28 May 2020 BID BID Preliminary data as of 03/09/2023
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 combo * Plasma samples taken at C1D1, C1D15, C2D1, C3D1, C4D1, then odd cycles starting at C5D1 until end of treatment Ex-vivo suppression of pAKT in PIK3CA-mutant cancer cells Preliminary data as of 03/09/2023
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 hyperglycemia per CTCAE v5.0 No dose interruptions or dose reductions due to hyperglycemia RLY-2608 – Limited Observed Impact on Glucose Homeostasis Supports Mutant Selective Targeting Across All Doses Preliminary data as of 03/09/2023 * Data represent mean per cohort +/- standard deviation
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 mg/dL) Grade 1 (115-160 mg/dL) RLY-2608 + Fulvestrant Combination RLY-2608 Alpelisib label criteria Preliminary data as of 03/09/2023 * Data represent mean per cohort +/- standard deviation
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 monotherapy, ongoing at cycle 4 uPR* with -36% tumor reduction per RECIST Marked regression of multiple liver metastases No adverse events reported Variant allele freq. (%) ESR1 D538G -93% PIK3CA H1047R -91% PIK3CA E453K -95% Baseline First Assessment (8 weeks) ctDNA at 4 weeks Preliminary data as of 03/09/2023
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 patients (9/16) exhibited radiographic tumor reductions 81% of patients (13/16) with SD/uPR* across genotypes 11/16 patients ongoing RLY-2608 Monotherapy (N=2) RLY-2608 + Fulvestrant (N=14) Arm Ongoing (N=11) Per protocol all combo patients previously treated with endocrine therapy and CDK4/6 * *Response confirmed after data cut-off Preliminary data as of 03/09/2023
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 + fulvestrant 0 Doses Above Target Exposure1 0.1 1 10 100 Patients with paired evaluable ctDNA2 Mono: 9 Combo: 10 Mono: 2 Combo: 10 Patients with paired evaluable ctDNA2 1. Doses above target exposure: 400mg BID mono, 600mg BID combo, 800mg BID combo; 2. 6 patients are represented by more than one PIK3CA mutation in the ctDNA graphs shown 0 0.1 1 10 100 Preliminary data as of 03/09/2023
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 RECIST evaluable patients (88%) had non-CR/non-PD, SD or response Most patients (7/8) discontinued due to progressive disease No AEs leading to treatment discontinuation 200 QD PR Assessment Non-CR/Non-PD SD PD NE RLY-2608 Monotherapy (N=4) RLY-2608 + Fulvestrant (N=23) Arm * *Response confirmed after data cut-off; ‡ = double mutation with two mutations in kinase domain ‡ Mutation Preliminary data as of 03/09/2023
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 10/42 (24%); No Grade 4-5 AEs Dose modifications due to AE: Interruptions 31%; Reductions 2%; Discontinuations 0% Median Relative Dose Intensity: 98%1 18% (0%) 12% (0%) 0% All Gr (Gr3+) Hyperglycemia Diarrhea Rash AE AEs leading to alpelisib discontinuation observed with RLY-2608 (for 400mg BID mono, ≥600mg BID combo; N=17) No Gr3+ Preliminary data as of 03/09/2023 1. Relative dose intensity is calculated as the Actual Dose Intensity/Planned Dose Intensity*100%. Actual dose intensity is calculated as the cumulative dose (mg)/duration of study treatment exposure (day). Planned dose intensity is the assigned dose (mg)/duration of study treatment exposure (day).
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% 0% 0% 0% 0% 0% 0% All Gr Gr3 Note: TEAEs ≥15% across all patients 1. Doses above target exposure: 400mg BID mono, 600mg BID combo, 800mg BID combo Preliminary data as of 03/09/2023
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 intensity 83% Sources: alpelisib: SOLAR-1 (initial publication): Andre 2019 N Engl J Med 380:1929, inavolisib: ASCO 2022 #1052 (note: reported rates are for invavolisib-related AEs pooled across study cohorts including monotherapy and combinations with letrozole, fulvestrant, and palbociclib), capivasertib: CAPItello-291: SABCS 2022 #GS3-04 Note: These data are derived from different clinical trials at different points in time, with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. Hyperglycemia Rash1 Diarrhea 2% Alpelisib
(PI3K inhibitor) Inavolisib
(PI3K inhibitor) 65% Capivasertib
(AKT inhibitor) 62% 16% 38%2 36% 12% 10% 60% 42% 72% 7% Grade 1-2 Grade 3+ 3 Most Common AEs Leading to Alpelisib Discontinuation Dose modifications due to AEs Alpelisib Inavolisib Alpelisib achieves 9-13hr coverage (IC80) at median dose intensity3 Capivasertib Interrup. Reduc. Discont. 74% 25% 64% 41% 2% 18% 35% 13% 20% Capivasertib dosing schedule 4-days-on, 3-days-off
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 target exposure: 400mg BID mono, 600mg BID combo, 800mg BID combo Dose modifications due to AEs Below target exposure (N =25) Above target exposure2 (N =17) Interrup. Reduc. Discont. 24% 0% 4% 41% 0% 0% Low rate of dose mods allowed for median dose intensity ≥98% Preliminary data as of 03/09/2023
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% mutant target inhibition at multiple doses Doses at or above target exposure have not led to key AEs Early anti-tumor activity seen across range of doses RLY-2608 Trough Concentration (ng/mL) pAKT Inhibition (%) RLY-2608 TEAE for doses above target exposure1 18% (0%) 12% (0%) 0% All Gr (Gr3) Hyperglycemia Diarrhea Rash AE RLY-2608 dose modifications due to AEs Below target exposure (N =25) Above target exposure1 (N =17) Interrup. Reduc. Discont. 24% 0% 4% 41% 0% 0% Low rate of dose mods allowed for median dose intensity ≥98% Doses above target exposure: 400mg BID mono, 600mg BID combo, 800mg BID combo Preliminary data as of 03/09/2023 Initial activity across range of PI3Kα mutation types
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 with intolerance to PI3Kαi defined as treatment discontinuation due to treatment-related AE (e.g., hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson syndrome; 4. RLY-2608 + fulvestrant + CDK4/6 arm expected to be added in a protocol amendment Part 1: Dose Escalation Part 2: Dose Expansion RLY-2608 Arm PIK3CAmut adv solid tumors Includes mixed histologies MTD/RP2D PIK3CAmut, HR+, HER2- advanced breast cancer (with & without prior PI3Kα inhibitor3) RLY-2608 + Fulvestrant Arm PIK3CAmut, HR+/HER2- adv / met BC Includes patients with non-measurable disease MTD/RP2D RLY-2608 + Fulvestrant + CDK4/6 Arm4 PIK3CAmut, HR+, HER2- advanced breast cancer PIK3CAmut, HR+/HER2- adv / met BC MTD/RP2D PIK3CAmut advanced solid tumors (CCOC, HNSCC, Cervical, other1, double PIK3CA mutants2)
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 Tx – Extensive Precision Medicine Pipeline Preclinical Early Clinical Late Clinical CCA + other Breast Cancer
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- advanced breast cancer, with no prior PI3Kα inhibitor (n=~15) PIK3CAmut advanced solid tumor (n=~15) PIK3CAmut, HR+, HER2- advanced breast cancer3 (n=~15 for each arm, ~45 total) MTD/RP2D MTD/RP2D MTD/RP2D RLY-5836 + Fulvestrant combination arm may start after one dose level higher of RLY-5836 single agent is cleared and determined tolerable RLY-5836 + CDK4/6i + ET combination arms may start after one dose level higher of RLY-5836 + Fulvestrant combination is cleared and determined tolerable. Three separate CDK4/6 arms, one for each of the following CDK4/6 agents: pablociclib, abemaciclib, ribociclib One or more of the RLY-5836 + CDK4/6i + Fulvestrant arms may open at Sponsor discretion and SRC agreement BOIN design with molecular enrichment PIK3CA mutation status per local assessment RLY-5836 PO BID or QD RLY-5836 clinical start in Apr 2023
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 Initial anti-tumor activity observed across range of doses Interpretable Efficacy (CBR, ORR) Longer-Term Tolerability Next milestones: RLY-2608 expansion cohorts to be initiated in 2H 2023 and additional PI3Kα franchise clinical data in 2024 RLY-2608 Evolution of Data PI3Kα Franchise RLY-2608 RLY-5836 H1047R-specific RLY-2139 (CDK2) ERα Degrader Other Undisclosed Programs Potential for greater dose intensity RLY-5836 clinical start in Apr 2023 Focus of today's disclosure Preliminary data as of 03/09/2023
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 Selection2 First Patient Dosed Early Clinical Validation Approval3 Pivotal Initiation3 Multiple Inhibitor Degrader Inhibitor, Degrader, Chaperone, etc. Modality Compound
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 GDC-1971 (SHP2) RLY-4008 (Selective FGFR2) Clinical start in early 2024 RLY-2139 (Selective CDK2) Ongoing combo trials; Genentech controls data disclosures PI3KαPAN Development candidate nomination in 2023 ERα Degrader Full dose escalation data in 1H 2023 Non-CCA expansion cohorts data in 2H 2023 Pivotal cohort full enrollment in 2H 2023 Initial RLY-2608 data in 1H 2023 RLY-5836 clinical start in 2Q 2023 RLY-2608 expansion cohorts initiated in 2H 2023 Additional data update in 2024 To be announced 5+ undisclosed programs in preclinical development and additional early-stage efforts across platform Undisclosed
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. CAPItello-291: SABCS 2022 #GS3-04; Placebo + fulv data from SOLAR-1 placebo + fulvestrant group; *Grouped term: rash and rash maculo-papular; ^Gr 3 AE rate for rash + rash maculo-popular not reported, although 6.2% Gr 3 AEs for rash maculo-papular, so assume at 6% Gr 3 for pooled terms Note: These data are derived from different clinical trials at different points in time, with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. Appetite Loss Vomiting Nausea Diarrhea GI Toxicity Asthenia Rash* Anemia Headache Stomatitis Dysgeusia Pruritus Urinary Tract Infection Fatigue Alopecia Hypokalaemia Blood Creatinine Increased Weight Loss Inavolisib 36% Placebo + fulv Capivasertib Placebo + fulv Inavolisib Alpelisib 10% Inavolisib Capivasertib Capivasertib Inavolisib Alpelisib 16% Inavolisib Capivasertib 21% 12% Capivasertib 7% Placebo + fulv 23% Alpelisib 16% Alpelisib Inavolisib 29% Placebo + fulv Alpelisib 60% 65% 0% Capivasertib Inavolisib Placebo + fulv 17% Alpelisib 36% Alpelisib Placebo + fulv 35% Capivasertib 62% Placebo + fulv 9% 38% 10% 72% 16% 10% 47% 32% 17% 2% 42% Grade 1-2 Grade 3+ Hyperglycemia Placebo + fulv Capivasertib Inavolisib Capivasertib Placebo + fulv Alpelisib Inavolisib 20% Capivasertib Capivasertib 2% Alpelisib 13% Inavolisib Placebo + fulv Capivasertib 10% 25% Placebo + fulv Inavolisib Alpelisib Inavolisib Placebo + fulv Alpelisib 21% Capivasertib 25% Placebo + fulv Alpelisib 17% Alpelisib Inavolisib Alpelisib 13% 25% Placebo + fulv 10% Inavolisib 7% 15% 17% 23% Capivasertib 18% 13% 14% 17% 3% 13% 17% Alpelisib Capivasertib Inavolisib Inavolisib Alpelisib Capivasertib Placebo + fulv Alpelisib Inavolisib 67% Capivasertib 28% Placebo + fulv Alpelisib Capivasertib Inavolisib Placebo + fulv Placebo + fulv Alpelisib Capivasertib Inavolisib Placebo + fulv 10% 10% 6% 15% 3% 26% 14% 2% 4% NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR
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 Anemia Headache Stomatitis Dysgeusia Fatigue Alopecia Pruritus Urinary Tract Infection Hypokalaemia Blood Creatinine Increased Weight Loss Below 4% 16% 29% Above Below Above Below Below Above Above Above Below Above Below Above Below 0% 4% 20% 6% 0% 0% 12% 4% 6% 8% 24% 24% Above Above Below Below Below Above Above Below Above 41% Below 12% 12% 0% 0% 12% 18% 24% 6% 8% Preliminary data as of 03/09/2023 1. Doses above target exposure: 400mg BID mono, 600mg BID combo, 800mg BID combo; 2. Grouped term: rash and rash maculo-papular Above/Below = Coverage Compared to Target Exposure1
Exhibit 99.2
Relay Therapeutics Announces Initial Clinical Data Demonstrating that RLY-2608 Selectively Targets Multiple PI3Kα Mutations
Multiple doses achieved sustained target exposure of ~80%+ mutant PI3Kα inhibition
No Grade 3 hyperglycemia, rash or diarrhea observed at target exposures
Favorable initial safety profile at target exposures
Confirmed partial response in breast cancer patient with 12 prior lines of therapy
Initial anti-tumor activity in breast cancer patients observed across range of doses
Relay Therapeutics to host a conference call today, April 18, at 1:30 p.m. ET
Orlando, Fla. – April 18, 2023 – Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, today announced initial clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα. The data support initial clinical proof of mechanism, demonstrating that RLY-2608 achieved selective target engagement at multiple predicted efficacious doses with a favorable initial safety and tolerability profile. These data are being presented today at the American Association for Cancer Research (AACR) Annual Meeting 2023.
“While early, these data suggest that by selectively inhibiting mutant PI3Kα and avoiding key off-target toxicities that typically limit the use of non-selective PI3Kα pathway inhibitors, RLY-2608 has the potential to transform treatment for patients with a broad range of PI3Kα mutations,” said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. “At doses achieving target exposure, there was no observed Grade 3 hyperglycemia, rash or diarrhea – the three most common adverse events leading to discontinuation of existing investigational and approved treatments, and radiographic tumor reductions were seen across multiple dose levels. We are continuing dose escalation and expect to initiate expansion cohorts in the second half of 2023.”
ReDiscover – RLY-2608 First-in-Human Trial
RLY-2608 is currently being evaluated in an ongoing dose-escalation portion of ReDiscover, a first-in-human trial, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity across two separate arms. The monotherapy arm started in December 2021 and enrolled 19 patients with unresectable or metastatic solid tumors with a PI3Kα mutation. This arm included a broad diversity of solid tumors, predominantly tumor types not predicted to be sensitive to single agent PI3Kα inhibition. The RLY-2608 + fulvestrant combination arm started April 2022 and enrolled 23 patients with PI3Kα-mutant, HR+, HER2– locally advanced or metastatic breast cancer. Across both arms of the study, enrolled patients had received a significant level of prior therapy, including all breast cancer patients who had received at least one prior endocrine therapy and CDK4/6 inhibitor. The cut-off date for data reported at AACR was March 9, 2023.
Broad Range of PI3Kα Mutations Represented in Enrolled Patients
Among the 27 patients with breast cancer (4 mono + 23 combo), 12 had kinase mutations, 10 had helical mutations and nine had other mutations.
Sustained Target Exposure of ~80%+ Mutant PI3Kα Inhibition Achieved at Multiple Doses
In the monotherapy arm, patients received seven different doses, ranging from 50mg twice daily (BID) to 400mg BID. In the combination arm, patients received five different BID doses, ranging from 100mg to 800mg BID.
RLY-2608 reached selective target exposure at multiple doses, with target exposure being defined as continuous inhibition of mutant PI3Kα of approximately 80 percent or greater. This was reached at 400mg BID monotherapy and at 600mg BID and 800mg BID combination doses.
Selective PI3Kα Inhibition Demonstrated
RLY-2608 demonstrated mutant selective PI3Kα target engagement at multiple doses. There was limited observed impact on glucose homeostasis overall and no Grade 3 hyperglycemia was observed. Glucose homeostasis is believed to be an important indicator of both RLY-2608’s clinical selectivity profile and its potential ability to avoid this key off-target toxicity associated with wild-type inhibition.
Declines of PI3Kα mutations in ctDNA from patient samples support initial clinical validation of RLY-2608’s ability to selectively inhibit a wide range PI3Kα mutations in a dose-dependent manner.
Initial Safety Analysis Supports a Meaningfully Differentiated Profile
RLY-2608 has been generally well tolerated in the 42 patients treated as of the cut-off date:
Among patients receiving doses at target exposures (mono: 400mg BID; combo: 600mg BID & 800mg BID; n=17), AEs were mostly low-grade events that were manageable and reversible:
The low rate of AE-related dose modifications allowed for median dose intensity of at least 98 percent across all dose levels.
Partial Response Achieved with Monotherapy in Breast Cancer Patient with 12 Prior Lines of Therapy
A patient with metastatic HR+/HER2- breast cancer, with two PI3Kα mutations (H1047R, E453K), who progressed following 12 lines of prior therapy, including chemotherapy (including Enhertu®), endocrine and HER2-directed therapies, received RLY-2608 400mg BID monotherapy. An unconfirmed partial response by Response Evaluation Criteria in Solid Tumors (RECIST) was recorded at 8 weeks. Subsequent
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to the data cut-off, this partial response was confirmed, and the patient remains on treatment with no AEs reported as of April 4, 2023.
Initial Anti-Tumor Activity Observed in Breast Cancer Patients Across Range of Doses
Early anti-tumor activity was seen across a range of doses and across helical, kinase and other mutations, demonstrating selective target engagement of mutant PI3Kα.
Among the 16 breast cancer patients with measurable disease:
Median duration of treatment for all breast cancer patients was approximately 4 months:
To date, a maximum tolerated dose has not been reached and dose exploration is ongoing to determine the recommended dose(s) for the dose expansion cohorts (part 2), which Relay Therapeutics anticipates initiating in the second half of 2023.
RLY-5836 First-in-Human Trial
In April 2023, Relay Therapeutics initiated a first-in-human trial of RLY-5836, the Company’s second investigational allosteric, pan-mutant, isoform-selective PI3Kα inhibitor, which is chemically distinct from RLY-2608. The trial design is similar to the first-in-human trial of RLY-2608 and can be found here.
Conference Call Information
Relay Therapeutics will host a conference call and live webcast today, April 18, 2023, at 1:30 p.m. ET. Registration and dial-in for the conference call may be accessed through Relay Therapeutics’ website under Events in the News & Events section through the following link: https://ir.relaytx.com/news-events/events-presentations. An archived replay of the webcast will be available following the event.
The data presentation from the AACR Annual Meeting is also available on the Relay Therapeutics website in the “Publications/Presentations” section through the following link: https://relaytx.com/pipeline/.
About RLY-2608 & RLY-5836
RLY-2608 is the lead program of multiple efforts to discover and develop mutant selective inhibitors of PI3Kα. RLY-5836 is Relay Therapeutics’ second pan-mutant, isoform-selective PI3Kα inhibitor, which is chemically distinct from RLY-2608. PI3Kα is the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 and RLY-5836 have
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the potential to address more than 100,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine.
Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo™ platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor and RLY-5836, both designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608 and RLY-5836. RLY-2608 and RLY-5836 are currently being evaluated in first-in-human trials designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here, and for more information on RLY-5836, please visit here.
About Relay Therapeutics
Relay Therapeutics is a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies with the goal of bringing life-changing therapies to patients. As the first of a new breed of biotech created at the intersection of complementary techniques and technologies, Relay Therapeutics aims to push the boundaries of what’s possible in drug discovery. Its Dynamo™ platform integrates an array of leading-edge computational and experimental approaches designed to drug protein targets that have previously been intractable or inadequately addressed. Relay Therapeutics’ initial focus is on enhancing small molecule therapeutic discovery in targeted oncology and genetic disease indications. For more information, please visit www.relaytx.com or follow us on Twitter.
Cautionary Note Regarding Forward-Looking Statements
This press release 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 potential of RLY-2608 or RLY-5836 to address a major unmet medical need; whether initial clinical results of RLY-2608 or RLY-5836 will be predictive of final results in future clinical trials; potential therapeutic effects and anticipated clinical benefits of RLY-2608 or RLY-5836; Relay Therapeutics’ strategy, business plans and focus; the progress and timing of updates on the clinical development of the programs across Relay Therapeutics’ portfolio, including RLY-2608; and expected therapeutic benefits of its programs. The words “may,” “might,” “will,” “could,” “would,” “should,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the impact of global economic uncertainty, geopolitical instability, or public health epidemics or outbreaks
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of an infectious disease, such as COVID-19, on countries or regions in which Relay Therapeutics has operations or does business, as well as on the timing and anticipated results of its clinical trials, strategy, future operations and profitability; the delay of any current or planned clinical trials or the development of Relay Therapeutics’ drug candidates; the risk that the preliminary results of its preclinical or clinical trials, including ReDiscover, may not be predictive of future or final results in connection with future clinical trials of its product candidates; Relay Therapeutics’ ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of its planned interactions with regulatory authorities; and obtaining, maintaining and protecting its intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Relay Therapeutics’ most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Relay Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. Relay Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Contact:
Caroline Glen
617-370-8837
cglen@relaytx.com
Media:
Dan Budwick
1AB
973-271-6085
dan@1abmedia.com
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