EX-99.3 4 rlay-ex99_3.htm EX-99.3

New Program & Platform Event June 2024 Exhibit 99.3

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, and potential efficacy and tolerability; the timing of clinical data updates across our pipeline, including the progress of doublet and triplet combinations for RLY-2608, the timing of clinical updates for RLY-2608, and the timing of a clinical data and regulatory update for lirafugratinib; the timing of clinical initiation of our various programs, including a potential pivotal trial for RLY-2608, clinical development in vascular malformations, clinical development of our non-inhibitory chaperone for Fabry disease, and clinical development of our NRAS-selective inhibitor; the potential of our product candidates 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, including its role in identifying product candidates; 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. 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Solid Tumors BREAST CANCER Relay Tx – Today’s Updates NRAS-Driven Solid tumors PI3Kα-Driven Breast Cancer 1 CDK4i clinical start by YE 2024 Clinical start in 2H 2025 ~150,000 pts1 ~28,000 pts4 1st PI3Kαi + ET + CDK4i combination in clinic 1st NRAS-selective inhibitor PI3Kα-Driven Vascular Malformations 2 Clinical start in 1Q 2025 ~170,000 pts2 (chronic treatment) 1st mutant-selective PI3Kα inhibitor Fabry Disease 3 4 Clinical start in 2H 2025 ~8,000 pts3 (chronic treatment) 1st non-inhibitory αGal chaperone GENETIC DISEASE 1. Prevalent US patient population with a PIK3CA mutation in adjuvant, first line metastatic and second line metastatic settings (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalence of vascular malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources); 3. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024); 4. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding melanoma stages 0-II (SEER, 3rd party source for alteration rate, Jan 2024); 5. Fabry disease forecasted 2024 market size per EvaluatePharma, includes Galafold® and ERTs (May 2024) Milestones Large US opportunity Program Updates Ongoing mono, doublet, triplet; Data update YE24 $2B current market5

PI3Kα – Large Opportunity Across Indications and Therapeutic Areas PIK3CA mutant HR+/HER2- Breast Cancer PIK3CA mutant Vascular Malformations PIK3CA mutant Other Solid Tumors Cerebral Cavernous Lymphatic Venous PROS 65k pt 65k pt 25k pt 15k pt ~150k Patients (US prevalence)1 ~170k Patients (US prevalence)2 Colorectal Endometrial Bladder Prostate NSCLC HNSCC 28k pt 20k pt 17k pt 16k pt 14k pt 9k pt Relay Tx's PI3Kα Franchise has the potential to address wide range of large disease indications Adjuvant 1st Line 2nd Line 120k pt 18k pt 14k pt ~160k Patients (US incidence)3 1. Prevalent US patient population with a PIK3CA mutation in each line of therapy (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalent US patient population of vascular malformation patients with a PIK3CA mutation (multiple sources); 3. Incident US patient population solid tumors annually with a PIK3CA mutation (SEER; 3rd party source for alteration rate, May 2024) RLY-2608 RLY-2608 Potential for rapid POC with RLY-2608, then distinct molecule for pivotal

Relay Tx – Productive Platform PEOPLE EXPERIMENTATION COMPUTATION PEOPLE Expected platform production by YE 2025 DCs 8 INDs 4 Clinical POC 2 Productive Platform Continued platform Productivity New clinical starts New DCs +3 New INDs +3 +3 ~$750M Cash as of end Q1 2024 Expected to fund current operating plan into 2H 2026 2016 2024 FUTURE EXPECTATIONS Internalize, integrate & expand platform Genetic Disease New Modalities: Chaperones Built computationally enabled platform Solid Tumors Small Molecule Inhibitors & Degraders

2024 Dynamo™ Platform Relay Tx’s Dynamo™ – Productive Computationally Enabled Platform Free energy calculations Digitally encoded libraries Long time-scale MD Differential dynamics Automated Chemical Design Generative design Active learning ADME/PK models ML-DEL + AI models for DEL Giga-scale virtual screening Computational fragment merging COMPUTATION NMR X-ray fragment screening HDX-MS Mechanistic enzymology Cryo-EM REL-DEL Integrated pharmacology Protein design and engineering Ambient temp. X-Ray crystallography Automated Ligand ID System (ALIS) Structure ensembles EXPERIMENTATION Exp. Comp. 2016 PEOPLE High throughput automated chemistry

Focus of the Dynamo™ Platform Experimentation Develop novel modulation hypotheses Rapidly generate multiple lead compounds Optimize lead compounds swiftly and cost-effectively Development & Commercial Target Identification Target Modulation Hypothesis Hit Identification Lead Optimization Computation Relay Tx’s Dynamo™ Platform – Experimentation Closely Integrated with Computation

Dynamo™ Platform Enabled Rapid Creation of First Selective NRAS Inhibitor Compounds evaluated computationally In Vivo PoC 29 compounds synthesized in the lab 1st compound synthesized achieved potent NRAS inhibition 120 days

Outputs Relay Tx’s Dynamo™ – Focused on Output RLY-2608 RLY-5836 RLY-2139 RLY-1013 Migoprotafib Lirafugratinib COMPUTATION PEOPLE EXPERIMENTATION + Multiple unnamed earlier stage research programs Dynamo™ Platform

Relay Tx – Consistent Focus on Validated, Low Translational Risk Programs Breast Cancer Solid Tumors Genetic Disease Productive Dynamo™ Research Engine αGal (Fabry Disease) PI3Kα (Vascular Malformations) Multiple unnamed research stage programs New Programs Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Amenable to Dynamo™️ Platform Target Selection Focus PI3Kα CDK2 ERα NRAS PI3Kα FGFR2 SHP2

Relay Tx – Broad Precision Medicine Pipeline Target Program Preclinical Early Clinical Late Clinical BREAST CANCER PI3Kα RLY-2608 (PI3KαPAN) Endocrine Tx (ET) doublet Ribociclib + ET triplet CDK4i + ET triplet Other Novel Combinations CDK2 RLY-2139 ERα RLY-1013 (Degrader) GENETIC DISEASE Fabry Disease αGal Chaperone Vascular Malformations RLY-2608 (PI3KαPAN) Other PI3KαPAN SOLID TUMORS NRAS NRAS-selective Inhibitor PI3Kα RLY-2608 Monotherapy FGFR2 Lirafugratinib (RLY-4008) SHP2 Migoprotafib (GDC-1971) Paused; IND ready Advance to IND-ready 3 ongoing combo studies (GNE) CDK4i triplet to initiate in 2024 New Programs 5+ additional unnamed research programs

Relay Tx – Milestones 2024-25 Breast Cancer Portfolio Milestones RLY-1013 ERα PI3Kα RLY-2608 RLY-2139 CDK2 IND-ready in 2025 Data update in 4Q 2024 Doublet safety & efficacy data Initial triplet data CDK4i triplet clinic start by YE 2024 Potential pivotal trial start in 2025 IND-ready Genetic Disease Portfolio milestones New Program Fabry Clinical start in 2H 2025 New Program VM Clinical start in 1Q 2025 Solid Tumors portfolio milestones New Program NRAS Clinical start in 2H 2025 Lirafugratinib FGFR2 Tumor agnostic data & regulatory update in 2H 2024 Migoprotafib SHP2 Three ongoing combo trials* * Genentech controls data disclosures ~$750M cash as of end Q1 2024 Expected to fund current operating plan into 2H 2026 Dynamo™ Platform 5+ unnamed research programs

Relay Tx – Extensive Breast Cancer Portfolio in Validated Market Expected to Grow to ~$27B by 20301 …for which Relay Tx’s broad next generation ER+/HER2- BC Portfolio is designed to address HR+/HER2- Breast Cancer is a very large patient population… ~150k US prevalence HR+/HER2- Breast Cancer Patients with PI3Kα mutation2 Evolving SoC PI3Kα Mutant-specific ER Degraders & other SERDs CDK4 or CDK2 selective Current SoC Tx PI3Kα Pathway Non-Selective Inhibitors ET Backbone: AI / fulvestrant CDK4/6 inhibitors RLY-2608 (pan) RLY-1013 (ERα) RLY-2139 (CDK2)3 Atirmo (CDK4) 35% of Breast Cancer Pt with PI3Kα mutation (14% of all solid tumors) ~120k Adjuvant ~18k 1L ~14k 2L 1. Decision Resources Group – Breast Cancer Disease Landscape & Forecast (Nov 2023); 2. Prevalent US patient population with a PIK3CA mutation in each line of therapy (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 3. RLY-2139 is paused and IND-ready

RLY-2608 + Atirmociclib (CDK4i): Pfizer – Relay Tx Clinical Trial Collaboration Potentially Differentiated Safety and Tolerability Profile Encouraging Efficacy Data in Heavily Pre-Treated Patients Source: Pfizer Oncology Innovation Day presentation, Feb 2024

RLY-2608 – Broad Development Program: Doublet Mono Dose Escalation RLY-2608 + Fulvestrant Doublet RLY-2608 + Fulvestrant + CDKi Triplet Dose Expansion Ongoing ReDiscover Trial Initiated 2024 Completed (Started Apr 2022) 400mg BID (n=20) 600mg BID (n=60) Enrolling 600mg BID (N=17) 400mg BID (N=10) 20 pt enrolled before YE 2023 Enrolling Enrolling Enrolling Data Expectations for YE2024 Disclosure All Doses 600mg BID >60 pts >100 pts >40 pts Safety Evaluable 6+ mo Follow-up Triplet: Early safety and tolerability data Doublet Landmark PFS analysis

RLY-2608 – Broad Development Program: Triplet Mono Dose Escalation RLY-2608 + Fulvestrant Doublet RLY-2608 + Fulvestrant + CDKi Triplet Dose Expansion Ongoing ReDiscover Trial Completed (Started Apr 2022) 400mg BID (n=20) 600mg BID (n=60) Enrolling 600mg BID (N=17) 400mg BID (N=10) 20 pt enrolled before YE 2023 Enrolling Enrolling Data Expectations for YE2024 Disclosure All Doses 600mg BID >60 pts >100 pts >40 pts Safety Evaluable 6+ mo Follow-up Doublet Landmark PFS analysis Triplet: Early safety and tolerability data Ribo (CDK4/6) Atirmo (CDK4) Enrolling Clinical start in 2024 Initiated 2024

RLY-2608 – Broad Development Program: Mono Dose Escalation RLY-2608 + Fulvestrant Doublet RLY-2608 + Fulvestrant + CDKi Triplet Dose Expansion ReDiscover Trial Completed (Started Apr 2022) Enrolling 600mg BID (N=17) 400mg BID (N=10) Enrolling Data Expectations for YE2024 Disclosure All Doses 600mg BID >60 pts >100 pts >40 pts Safety Evaluable 6+ mo Follow-up Doublet Landmark PFS analysis Triplet: Early safety and tolerability data Ribo (CDK4/6) Atirmo (CDK4) Enrolling Clinical start in 2024 Initiated 2024 Mono Ongoing Enrolling PRs seen in multiple tumor types* * PRs include both confirmed and unconfirmed partial responses 400mg BID (n=20) 600mg BID (n=60) 20 pt enrolled before YE 2023

RLY-2608 – Broad Development Program Dose Escalation RLY-2608 + Fulvestrant Doublet RLY-2608 + Fulvestrant + CDKi Triplet Dose Expansion ReDiscover Trial Completed (Started Apr 2022) 400mg BID (n=20) 600mg BID (n=60) Enrolling 600mg BID (N=17) 400mg BID (N=10) 20 pt enrolled before YE 2023 Enrolling Data Expectations for YE2024 Disclosure All Doses 600mg BID >60 pts >100 pts >40 pts Safety Evaluable 6+ mo Follow-up Doublet Landmark PFS analysis Triplet: Early safety and tolerability data Ribo (CDK4/6) Atirmo (CDK4) Enrolling Clinical start in 2024 Initiated 2024 Mono Ongoing Enrolling PRs seen in multiple tumor types* ReDiscover trial continues broad enrollment across ~25 sites in ~5 countries * PRs include both confirmed and unconfirmed partial responses

Breast Cancer – Large Market in Current and Emerging Standards of Care Endocrine Sensitive CDK4 + next gen oral ET Oral SERD monoTx Inavolisib + palbo + fulv Inavolisib + fulvestrant ADCs 11,000 pts Endocrine Resistant Capivasertib + fulvestrant or Alpelisib + fulvestrant or Everolimus + AI Elacestrant (ESR1m) Chemotherapy CDK4/6 + fulvestrant Chemotherapy CDK4/6 + AI (abema / ribo / palbo) PIK3CA mutated HR+/HER2- BC Treatment Paradigm1 7,000 pts 14,000 pts Fulvestrant (ESR1WT) Current Standard of Care Emerging TX RLY-2608 combinations Current PI3Kα Pathway Total Addressable Market2 (Metastatic HR+/HER2- Breast Cancer) $6B+ 1L 2L 1. Prevalent US patient population with a PIK3CA mutation in each line of therapy (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Relay Tx PIK3CA internal market forecast (patient-based – US, EU5, Japan). Forecast includes estimates for genetic testing, class share, market access, compliance, duration of therapy and assumes current PIK3CA therapy net price (primary sources: SEER; GloboCan; Global Data; Evaluate Pharma; DRG Market Forecast; PIK3CAi PIs)

RLY-2608 – 2L PFS Pivotal Benchmark: ~6 Months 1. SABCS 2021 #P5-17-05; 2. Rugo 2021 Lancet Oncol 22:489, ASCO 2023 1078; 3. Turner N Engl J Med 2023; 388:2058-2070; 4. Based on 4.0-6.2mo mPFS reported in Novartis-sponsored real-world evidence study for alpelisib + fulvestrant (ASCO 2022 #1055); 5. 5.5mo mPFS reported in CDK4/6-experienced patient sub-population of CAPItello-291 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. % prior fulv N Doublet Combination Regimens Capivasertib + fulvestrant CAPItello-2913 0% 355 Alpelisib + fulvestrant BYLieve2 0% 127 Ph1b Arm D1 Inavolisib + fulvestrant 47% 60 29% 56% 19% 46% 19% 48% Data Benchmark FDA Approval Approved 2023 Approved 2019 6.2mo 5.5mo 7.1mo 8.0mo 7.3mo Not approved ORR CBR 5.5mo5 6.2mo4 mPFS Capi ORR & CBR include 30% of pts who are CDK4/6-naïve

Relay Tx – Milestones 2024-25 Breast Cancer Portfolio Milestones RLY-1013 ERα RLY-2139 CDK2 IND-ready in 2025 IND-ready Genetic Disease Portfolio milestones Solid Tumors portfolio milestones New Program NRAS Lirafugratinib FGFR2 Tumor agnostic data & regulatory update in 2H 2024 Migoprotafib SHP2 Three ongoing combo trials* * Genentech controls data disclosures New Program Fabry Clinical start in 2H 2025 New Program VM Clinical start in 1Q 2025 Clinical start in 2H 2025 Dynamo™ Platform 5+ unnamed research programs PI3Kα RLY-2608 Data update in 4Q 2024 Doublet safety & efficacy data Initial triplet data CDK4i triplet clinic start by YE 2024 Potential pivotal trial start in 2025

CDK4i clinical start by YE 2024 ~28,000 pts4 ~170,000 pts2 (chronic treatment) Clinical start in 2H 2025 1st PI3Kαi + ET + CDK4i combination in clinic 1st NRAS-selective inhibitor Clinical start in 1Q 2025 1st mutant-selective PI3Kα inhibitor Clinical start in 2H 2025 1st non-inhibitory αGal chaperone Solid Tumors Relay Tx – Today’s Updates NRAS-Driven Solid tumors PI3Kα-Driven Breast Cancer 1 4 PI3Kα-Driven Vascular Malformations 2 Fabry Disease 3 BREAST CANCER ~150,000 pts1 ~8,000 pts3 (chronic treatment) Milestones Large US opportunity Program Updates GENETIC DISEASE 1. Prevalent US patient population with a PIK3CA mutation in adjuvant, first line metastatic and second line metastatic settings (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalence of vascular malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources); 3. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024); 4. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding melanoma stages 0-II (SEER, 3rd party source for alteration rate, Jan 2024)

~170,000 patients1 (chronic treatment) Limited efficacy Lack of selectivity Approved Tx for PROS only Vijoice® (alpelisib) approved PIK3CAmut 1st mutant-selective PI3Kα inhibitor PI3Kα-Driven Vascular Malformations – Significant Unmet Need First Mutant Selective Inhibitor Dynamo™ Platform GENETIC DISEASE PI3Kα-Driven Vascular Malformations Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach 1. Prevalence of Vascular Malformations with a PIK3CA mutation (sources: Keppler-Noreuil. Am J Med Genet A. 2015; Engel-Nitz. JVA. 2022; Rodriguez-Laguna; OJRD. 2022; Vogel. Ped Derm. 2013; Shah. J Maxillofac Oral Surg. 2010; Poget. Ped Surg Int. 2023; Behravesh; CDT. 2016; Peyre. NEJM. 2021; Fereydooni et al 2019; Penington et al 2023; Gallagher et al 2022; Luks et al 2015; Limaye et al 2015; Stor et al 2023; Broek et al 2019; Choquet et al 2015; Venot et al. 2018; Pagliazzi et al 2021)

Dr. Adrienne Hammill, MD PhD 25 PhD in Cell Regulation “Asymmetric cell division results in differential apoptotic cell fates in a B-cell lymphoma model of tumor dormancy” Board certified in Pediatrics and Pediatric Hematology-Oncology Certificate in Clinical and Translational Research Working in vascular anomalies since 2009 Serving as Research Director of the Hemangioma & Vascular Malformations Center (HVMC) Director, Cincinnati HHT Center of Excellence Director, Cincinnati Sturge-Weber Center of Excellence/Clinical Care Network Center

Vascular Anomalies Dr. Adrienne Hammill, MD PhD 26 Anomalies is an umbrella term for many different diagnoses Includes TUMORS “things that grow” and MALFORMATIONS “present since birth” Distinction less clear than it used to be, a few “unclassified” Vascular Anomalies overall not rare due to high frequency of hemangiomas But many of the individual diagnoses are quite rare

Vascular Malformations Dr. Adrienne Hammill, MD PhD 27 Vascular malformations can include a single type of malformed vessel, or combinations of vessels

Vascular Malformations Dr. Adrienne Hammill, MD PhD 28 Vascular malformations can be localized (“isolated”), diffuse/multifocal, or part of a syndrome with other findings Most frequent syndromic association is overgrowth, particularly in “combined vascular malformations” A range of severity in Vascular Anomalies Sources: Colmenero 2021; Davidson et al, 2015; de Grazia et al Isolated Diffuse, Syndromic

Genetic Causes of Vascular Malformations – Germline Mutations Dr. Adrienne Hammill, MD PhD Key: Cell Membrane Receptor Tyrosine Kinases G-Protein Coupled Receptors PI3K AKT/PKB mTOR S6 eIF-4E Protein Synthesis VEGF Gα TIE2 RAS PTEN TSC1 TSC2 RASA1 PTEN-associated VAs/hamartomas TS-associated angiofibromas CM-AVM, Parkes-Weber RAF MEK ERK EGFR/ VEGFR = known oncogene = known tumor suppressor = vascular anomalies = non-oncogene driver 29

Genetic Causes of Vascular Malformations – Somatic Mutations Dr. Adrienne Hammill, MD PhD Key: Cell Membrane Receptor Tyrosine Kinases G-Protein Coupled Receptors PI3K AKT/PKB mTOR S6 eIF-4E Protein Synthesis VEGF Gα TIE2 RAS PTEN TSC1 TSC2 RASA1 VMCM, BRBNS, sporadic VMs Sturge-Weber syndrome, CM (port wine birthmark) RAF MEK ERK KLA, GSD RICH, NICH EGFR/ VEGFR = known oncogene = known tumor suppressor = vascular anomalies = non-oncogene driver 30 Proteus LM, VM, PROS, GLA

Genetic Causes of Vascular Malformations Dr. Adrienne Hammill, MD PhD Key: Cell Membrane Receptor Tyrosine Kinases G-Protein Coupled Receptors PI3K AKT/PKB mTOR S6 eIF-4E Protein Synthesis VEGF Gα TIE2 RAS PTEN TSC1 TSC2 RASA1 VMCM, BRBNS, sporadic VMs PTEN-associated VAs/hamartomas TS-associated angiofibromas Proteus Lymphedema CM-AVM, Parkes-Weber Sturge-Weber syndrome, CM (port wine birthmark) RAF MEK ERK KLA, GSD RICH, NICH EGFR/ VEGFR = known oncogene = known tumor suppressor = vascular anomalies = non-oncogene driver 31 LM, VM, PROS, GLA

PIK3CA-related Overgrowth Spectrum (PROS) Phenotypes Sources: Mirzaa G et al. PIK3CA-Related Overgrowth Spectrum. 2013 Aug 15 [Updated 2023 Apr 6]. In: GeneReviews® [Internet] Megalencephaly-capillary malformation (MCAP) syndrome Dysplastic megalencephaly (DMEG), hemimegalencephaly (HMEG) and focal cortical dysplasia (FCD) Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome Klippel-Trenaunay syndrome (KTS) Capillary malformation of the lower lip, Lymphatic malformation of the face and neck, Asymmetry of face and limbs, Partial/generalized Overgrowth (CLAPO) syndrome Fibroadipose hyperplasia or overgrowth (FAO) Hemihyperplasia multiple lipomatosis (HHML) Facial infiltrating lipomatosis (FIL) Macrodactyly Isolated tissue dysplasia/overgrowth phenotypes: lymphatic malformations, venous malformations, lipomatosis Dr. Adrienne Hammill, MD PhD 32

PI3Kα-Driven Vascular Malformations – Overview of Biology ~300k US patients affected by Vascular Malformations, driven by prenatal somatic mutations Abnormal development of lymphatic and/or blood vessels leads to a wide range of symptoms Malformations may involve one or more types of vasculature Mutation Frequency by Gene PIK3CA TIE2 Other CCM1-3 Approx. 170k pts in the US Dr. Adrienne Hammill, MD PhD 33 Sources: Fereydooni et al 2019, Penington et al 2023, Gallagher et al 2022, Luks et al 2015, Limaye et al 2015, Stor et al 2023, Broek et al 2019, Choquet et al 2015, Venot et al. 2018, Pagliazzi et al 2021; Photo sources: Delestre et al 2021, Pagliazzi et al, 2021 Note: TIE2 gene also refers to TEK gene

PI3Kα-Driven Vascular Malformations – Patient Treatment Journey Symptom Presentation Diagnosis Treatment PCP, Dermatologist, Surgeon, ENT, etc. Geneticist, “Vascular Anomalist” Surgeon, Int. Radiologist, Dermatologist, Heme-Onc Watch and wait; Compression Therapy Local Treatment: Laser, sclerotherapy, surgery Systemic Therapy: alpelisib, sirolimus Invasive, recurrence is common (~25-40% recurrence rate) Incomplete responses, side effects / toxicities limit widespread use Frequency of use Temporary; 50-75% of diagnosed pts receive local or systemic Tx Current unmet need for selective, systemic therapy for Vascular Malformations Referral Pathway Treatment & Ongoing Management Dr. Adrienne Hammill, MD PhD 34 Source: primary research

PI3Kα-Driven Vascular Malformations – Over 170,000 US Patients US Patients % PIK3CAmut Approved Therapies Lymphatic Malformation (LM) Venous Malformation(VM) Cerebral Cavernous Malformation (CCM) PIK3CA-Related Overgrowth Spectrum (PROS) ~80k 80% ~65k pt ~100k ~20-25% ~20-25k pt ~120k 40-55% ~50-65k pt ~5-15k 100% ~5-15k pt No approved systemic therapy Vijoice® (alpelisib) Total US pt across types >300k pt ~170k pt PIK3CAmut Vascular Malformation Types Dr. Adrienne Hammill, MD PhD 35 Sources: ISSVA classification, NORD, Mayo Clinic, Novartis, Penington et al 2023, Gallagher et al 2022, Luks et al 2015, Limaye et al 2015, Peyre et al 2021, Hong et al 2021. Photo sources: Venot et al. Nature 2018, Wenger et al Genet Med 2022, Limaye et al Nature Genetics 2008, Mayo Clinic

Non-Selective Limited scope, approved in PROS only Not approved in any Vascular Malformation types Non-Selective Immunosuppressive Alpelisib Lymphatic Malformations (LM) Venous Malformations(VM) Cerebral Cavernous Malformations (CCM) PIK3CA-Related Overgrowth Spectrum (PROS) PI3Kα-Driven Vascular Malformations – Systemic Tx Limited by Non-Selective SoC Limited Efficacy - 27% ORR1 1. ORR defined as radiologic response ≥20% lesion reduction; Source: FDA label for VIJOICE® Sirolimus

Favorable Selectivity Favorable Tolerability Favorable Efficacy PI3Kα-Driven Vascular Malformations – Relay Tx Mutant Selective Approach Selective for mutant PI3Kα Fewer key common PI3K class AEs* Reduction of mutant PIK3CA ctDNA* 6% 10% 59% 60% 29% RLY-26081 Alpelisib2 *interim data from oncology trials1-2 1. Interim AE rates and ctDNA for RLY-2608 part of ongoing ReDiscover trial studying solid tumors (oncology), data as of 07/24/23; 2. Alpelisib AE rates from BYLieve study (oncology), Rugo 2021 Lancet Oncol 22:489 RLY-26081 Potential for rapid POC with RLY-2608, then use a distinct molecule for pivotal studies Lymphatic Malformations (LM) Venous Malformations(VM) Cerebral Cavernous Malformations (CCM) PIK3CA-Related Overgrowth Spectrum (PROS) Hyper- glycemia Diarrhea 6% 6% Rash 12% Grade 1-2 Grade 3+

PI3Kα – Dynamo™: Integration of Experimental and Computational Tools Discovery of 1st mutant-selective PI3Kα inhibitor Target Modulation Hypothesis Hit Identification Lead Optimization CryoEM & X-ray Crystallography Long Time-scale MD DNA-Encoded Libraries (DEL) Differential Dynamics Integrated Pharmacology PK / PD Dose Modeling Platform Tool Examples Solved 1st full-length structures & novel pocket of PI3Kα Identified early chemical matter for mutant selectivity Rapidly designed the 1st mutant-selective inhibitor of PI3Kα 1 2 3 Computational tool Experimental tool

~170,000 patients1 (chronic treatment) Limited efficacy Lack of selectivity Approved Tx for PROS only Vijoice® (alpelisib) approved PIK3CAmut 1st mutant-selective PI3Kα inhibitor Clinical Start in Q1 2025 PI3Kα-Driven Vascular Malformations – Significant Unmet Need GENETIC DISEASE PI3Kα-Driven Vascular Malformations Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach 1. Prevalence of Vascular Malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources) Genetic Disease Portfolio milestones

CDK4i clinical start by YE 2024 ~28,000 pts4 ~150,000 pts1 ~170,000 pts2 (chronic treatment) ~8,000 pts3 (chronic treatment) Clinical start in 2H 2025 1st PI3Kαi + ET + CDK4i combination in clinic 1st NRAS-selective inhibitor Clinical start in 1Q 2025 1st mutant-selective PI3Kα inhibitor Clinical start in 2H 2025 1st non-inhibitory αGal chaperone Solid Tumors Relay Tx – Today’s Updates NRAS-Driven Solid tumors PI3Kα-Driven Breast Cancer 1 4 PI3Kα-Driven Vascular Malformations 2 Fabry Disease 3 BREAST CANCER GENETIC DISEASE 1. Prevalent US patient population with a PIK3CA mutation in adjuvant, first line metastatic and second line metastatic settings (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalence of vascular malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources); 3. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024); 4. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding melanoma stages 0-II (SEER, 3rd party source for alteration rate, Jan 2024) Milestones Large US opportunity Program Updates

~8,000 patients1 (chronic treatment) Limited αGal activation & limited mutational coverage Galafold® (migalastat) approved in Fabry Disease GLA mutations 1st non-inhibitory αGal chaperone Fabry Disease – Large Validated Market With Significant Unmet Need First Non-Inhibitory αGal Chaperone Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach Dynamo™ Platform GENETIC DISEASE Fabry Disease 1. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024)

~$1.6B peak sales1 Fabry Disease – Large Validated Market With Significant Unmet Need Over 1,000 different GLA gene mutations Reduces αGal protein levels Leads to accumulation of toxic Gb3 substrate Broad clinical manifestations; Life threatening cardiac & renal disfunction Fabry disease is a lysosomal storage disorder affecting ~8,000 patients in US Current therapies have established a market but have key limitations Current Therapies Limited αGal activation Limited mutational coverage Not combined with ERT Limitations of Inhibitory Chaperone 1 2 3 Inhibitory Chaperone Therapy (migalastat) Need for a non-inhibitory αGal chaperone ~$780M peak sales2 40% of pts Enzyme Replacement Therapy (ERT, intravenous) 1. Combination of Fabrazyme® (~$1,100M) and Replagal® (~$480M) 2030 forecasted WW sales per EvaluatePharma, April 2024; 2. Galafold® 2030 forecasted WW sales per EvaluatePharma, April 2024

αGal Inhibitory vs Non-Inhibitory Chaperone Normal Mutant Fabry Disease – Dynamo™ Discovered a Novel Allosteric Pocket Active Site

Fabry Disease – Dynamo™: Integration of Experimental and Computational Tools Discovery of 1st non-inhibitory αGal chaperone Discovered & validated novel allosteric pocket Identified & validated initial hits that stabilized Achieved potent αGal non-inhibitory chaperones 1 2 3 Computational tool Experimental tool Target Modulation Hypothesis Hit Identification Lead Optimization Structure Ensembles Long Time-Scale MD NMR Virtual Screening HTP Automated Chem. ADME/PK Models Platform Tool Examples

Fabry Disease – Relay Tx Compounds are Non-Inhibitory Chaperones Migalastat inhibited αGal function while Relay Tx compounds did not Note: Biochemical assay run with WT αGal; 1 hr incubation at room temperature

Fabry Disease – Potential Benefits of Non-Inhibitory Chaperone Approach Superior αGal activation1 Broad mutational coverage2 Combinable with ERT3 1 2 3 Relay Tx Solution: Non-Inhibitory Chaperone to Stabilize Protein and Increase Activity Notes: 1. R301Q mut αGal (2hr post compound washout, expressed in GLA KO HEK293 cells); In vitro αGal activity assay (4MU) across multiple GLA mutations expressed in HEK293 GLA KO cells (assessed at 1uM); 3. GLA KO mouse model, activity assessed following single dose of ERT and 14-day treatment with RTX-1

There were no adverse findings in an exploratory rat toxicology study of RTX-1 at exposures equivalent to 100 mg/kg BID Superior αGal Activation 1 Relay Tx Non-Inhibitory Chaperones Can Lead to Higher Levels of In Vivo Activity

Relay Tx Non-Inhibitory Chaperones Have Broad Mutational Coverage In vitro αGal activity assay (4MU) across multiple GLA mutations expressed in HEK293 GLA KO cells Amenable | Non-Amenable (as per migalastat label) Broad Mutational Coverage 2 Note: αGal activity evaluated at 1uM of migalastat and RTX-1

Relay Tx Non-Inhibitory Chaperones Combinable with ERT Combinable with ERT 3

~8,000 patients1 (chronic treatment) Limited αGal activation & limited mutational coverage Galafold® (migalastat) approved in Fabry Disease GLA mutations 1st non-inhibitory αGal chaperone Fabry Disease – Large Validated Market With Significant Unmet Need Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach GENETIC DISEASE Fabry Disease 1. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024) Clinical Start in 2H 2025 Genetic Disease Portfolio milestones

CDK4i clinical start by YE 2024 ~150,000 pts1 ~28,000 pts4 ~170,000 pts2 (chronic treatment) ~8,000 pts3 (chronic treatment) Clinical start in 2H 2025 1st PI3Kαi + ET + CDK4i combination in clinic 1st NRAS-selective inhibitor Clinical start in 1Q 2025 1st mutant-selective PI3Kα inhibitor Clinical start in 2H 2025 1st non-inhibitory αGal chaperone Relay Tx – Today’s Updates NRAS-Driven Solid tumors PI3Kα-Driven Breast Cancer 1 4 PI3Kα-Driven Vascular Malformations 2 Fabry Disease 3 BREAST CANCER GENETIC DISEASE Solid Tumors 1. Prevalent US patient population with a PIK3CA mutation in adjuvant, first line metastatic and second line metastatic settings (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalence of Vascular Malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources); 3. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024); 4. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding melanoma stages 0-II (SEER, 3rd party source for alteration rate, Jan 2024) Milestones Large US opportunity Program Updates

~28,000 patients1 Lack of selectivity Challenging AE profile Limited efficacy Non-selective RAF/MEK/Pan-RAS NRASmut 1st NRAS-selective inhibitor NRAS – Large Validated Market With Significant Unmet Need First NRAS Selective Inhibitor Dynamo™ Platform Solid Tumors NRAS-Driven Solid Tumors Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach 1. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding stage 0-II newly diagnosed melanoma patients (SEER, 3rd party source for alteration rate, Jan 2024)

NRAS – Large Validated Market With Significant Unmet Need NRAS mutations observed in broad range of tumor types NRAS mutations are a key driver of solid tumors, though no NRAS-selective agent exists Head and Neck NSCLC Melanoma2 X ~0.6k ~2.2k ~4.0k ~0.4k ~6.4k ~1.1k Pancreatic Cancer Colorectal (CRC) Bladder Cancer Thyroid Cancer ~5.9k Annual US Patients1 RAF MEK ERK Cell growth and proliferation NRAS HRAS KRAS Downstream RAS pathway (pan-RAF, MEK, ERK) Pan-RAS mut c 1. Newly diagnosed (incident) patients with an NRAS mutation for each tumor type (SEER, 3rd party source for alteration rate, Jan 2024); 2. Melanoma includes incident stage III and IV patients only (excludes stage 0-II patients)

based MEK + RAFi Pan-RAS Limited Therapeutic Window of Current Agents – Pan-RAF/RAS & MEK Inhibitors Limited Efficacy Limited Tolerability MEK + RAFi Pan-RAS Rash Liver Tox 25-80% <10-60% 81% 7-8% Limited Target Inhibition Dose Red. Dose Discont. 16-70% 7-28% 8% 1% High rates of skin toxicity driven by off-target pan-RAS pathway inhibition RAF MEK ERK Cell growth and proliferation NRAS HRAS KRAS Downstream RAS pathway (pan-RAF, MEK, ERK) Pan-RAS mut Regimen (2L NRASmut melanoma) ORR PFS (mo) Naporafenib (RAFi) + trametinib (MEKi) 13-47% 4.2-5.5 Belvarafenib (RAFi) + cobimetinib (MEKi) 39% 7.3 Non-Selective Agents in Development No guidance for Ph3 development Sources: ASCO 2021 #3007 (Belvarafenib + cobimetinib, n=32 all, 13 for efficacy), de Braud 2023 J Clin Oncol 41:2651 (naporafenib + trametinib, n=30 expansion arm), ASCO 2023 #9510 (tunlametinib, n=95), ESMO 2023 652O (RMC-6236, n=111 pts at ≥80mg; liver tox = elevated ALT/AST

NRAS – Dynamo™ Platform Discovered a Novel Allosteric Pocket Exploited differences in protein motion… …to design first NRAS-selective inhibitor NRAS HRAS KRAS NRAS HRAS KRAS

NRAS – Dynamo™: Integration of Experimental and Computational Tools Discovery of 1st NRAS-selective inhibitor Discovered a novel cryptic pocket Identified & validated hits selective for NRAS (over H/KRAS) Rapidly designed & prioritized NRAS inhibitors 1 2 3 Target Modulation Hypothesis Hit Identification Lead Optimization X-ray Fragment Screen Virtual Screening 2D NMR Computational Fragment Merging High Throughput Automated Chem. Free Energy Calculations Platform Tool Examples Computational tool Experimental tool

NRAS Inhibitors Are Potent, Selective & Active Across NRAS Mutations 1. Based on SPR analysis of purified protein; 2. Based on pERK assay of SK-MEL-2, SK-MEL-30, and CALU-6 cell lines evaluated at 24hr timepoint; 3. Based on cell proliferation panel (17 cell lines) evaluated at 3-5d timepoint depending on cell line

*Regressions also achieved with additional NRAS mutant models (NRAS Q61K and NRAS Q61R) NRAS Inhibitors Achieve Complete Regression at Well Tolerated Doses There were no adverse findings in an exploratory rat toxicology study of RTX-2 at exposures equivalent to 100mg/kg QD

~28,000 patients1 Lack of selectivity Challenging AE profile Limited efficacy Non-selective RAF/MEK/Pan-RAS NRASmut 1st NRAS-selective inhibitor NRAS – Large Validated Market With Significant Unmet Need Solid Tumors NRAS-Driven Solid Tumors Genetically Defined Clinically Validated Unmet Medical Need Commercially Attractive Novel Approach 1. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding stage 0-II newly diagnosed melanoma patients (SEER, 3rd party source for alteration rate, Jan 2024) Clinical Start in 2H 2025 Solid Tumors Portfolio Milestones

Solid Tumors BREAST CANCER Relay Tx – Today’s Updates NRAS-Driven Solid tumors PI3Kα-Driven Breast Cancer 1 4 CDK4i clinical start by YE 2024 Clinical start in 2H 2025 ~150,000 pts1 ~28,000 pts4 1st PI3Kαi + ET + CDK4i combination in clinic 1st NRAS-selective inhibitor PI3Kα-Driven Vascular Malformations 2 Clinical start in 1Q 2025 ~170,000 pts2 (chronic treatment) 1st mutant-selective PI3Kα inhibitor Fabry Disease 3 Clinical start in 2H 2025 ~8,000 pts3 (chronic treatment) 1st non-inhibitory αGal chaperone GENETIC DISEASE 1. Prevalent US patient population with a PIK3CA mutation in adjuvant, first line metastatic and second line metastatic settings (Global Data HR+/HER2- Breast Cancer Global Forecast, November 2023; 3rd party source for alteration rate); 2. Prevalence of vascular malformations with a PIK3CA mutation (Gallagher et al 2022 and several other sources); 3. Prevalence of Fabry patients (National Fabry Disease Foundation, Jan 2024); 4. Newly diagnosed (incident) solid tumors with an NRAS mutation, excluding melanoma stages 0-II (SEER, 3rd party source for alteration rate, Jan 2024); 5. Fabry disease forecasted 2024 market size per EvaluatePharma, includes Galafold® and ERTs (May 2024) Milestones Large US opportunity Program Updates Ongoing mono, doublet, triplet; Data update YE24 $2B current market5

Relay Tx Dynamo™ – Internalizing Bespoke Tools In-House Molecular Dynamics (MD) In-House REL-DEL In-House High-Throughput Automated Chemistry Dynamo™ Platform Development & Commercial Target Identification Target Modulation Hypothesis Hit Identification Lead Optimization

Free energy calculations Digitally encoded libraries Long time-scale MD Differential dynamics Automated Chemical Design Generative design Active learning ADME/PK models ML-DEL + AI models for DEL Giga-scale virtual screening Computational fragment merging COMPUTATION EXPERIMENTATION Relay Tx Dynamo™ – Continuing to Focus, Build and Evolve Dynamo™ Platform integrates industry-leading tools and will continue to quickly grow and evolve PEOPLE NMR X-ray fragment screening HDX-MS Mechanistic enzymology Cryo-EM REL-DEL Integrated pharmacology Protein design and engineering Ambient temp. X-Ray crystallography Automated Ligand ID System (ALIS) Structure ensembles High throughput automated chemistry