Spyre Therapeutics, Inc. · NASDAQ:SYRE

Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (May 2022)

42 slides from Spyre Therapeutics's investor presentation, May 5, 2022

  1. Slide 1: Reimagining The Potential Of Human Enzyme Therapeutics

    Reimagining The Potential Of Human Enzyme Therapeutics Corporate Overview – May 2022 Nasdaq: AGLE Exhibit 99.2

  2. Slide 2: Forward Looking Statements

    Forward Looking Statements ©2022 Aeglea BioTherapeutics. External 2 This presentation and the accompanying oral presentation contain “forward-looking” statements that are based on our management’s beliefs and assumptions and on information currently available to management. Forward-looking statement

  3. Slide 3: Addressing Metabolic Imbalances to Improve the Lives of Patients

    Addressing Metabolic Imbalances to Improve the Lives of Patients ©2022 Aeglea BioTherapeutics. External 3 Aeglea BioTherapeutics At Aeglea, we believe that every patient deserves a chance at a better life. We are committed to helping people with rare and devastating metabolic diseases who have limit

  4. Slide 4: Looking Ahead Key Highlights

    Looking Ahead Key Highlights 4 Pegzilarginase Submit EU MAA in 2022 Continue preparations for strong, rapid launch in U.S., Europe and Middle East Publication of long-term data AGLE-177 Clinical data from Ph 1/2 trial (2H 2022) Working to open U.S. sites AGLE-325 (Cystinuria) IND-enabling studies fo

  5. Slide 5: Aeglea's Human Enzyme Platform for Rare Metabolic Diseases

    5 Aeglea’s Human Enzyme Platform for Rare Metabolic Diseases 1 Ex-U.S. license and supply agreement with Immedica to commercialize pegzilarginase in Europe and certain countries in the Middle East (European Economic Area, United Kingdom, Switzerland, Andorra, Monaco, San Marino, Vatican City, Turkey

  6. Slide 6: Pegzilarginase for Arginase Deficiency

    Pegzilarginase for Arginase 1 Deficiency

  7. Slide 7: The Progressive Impact of Persistently High Plasma Arginine

    The Progressive Impact of Persistently High Plasma Arginine1-4 Arginase 1 Deficiency (ARG1-D) Disease Overview 7 Infancy2-4,7,8 Initial 6-12 months may be uneventful May present with seizures, episodes of hyperammonemia: irritability, feeding difficulties, poor appetite, nausea/vomiting, decreased a

  8. Slide 8: Pegzilarginase Program Overview

    8 Pegzilarginase Program Overview Commercial Opportunity >2,500 patients in global addressable markets1 >1,150 patients in territories with regulatory and launch plans underway High unmet medical need No approved therapies to address high arginine levels Regulatory Designations U.S. Rare Pediatric D

  9. Slide 9: PEACE Phase 3 Study Design

    Double-blind portion of trial complete – topline data announced December 2021 9 PEACE Phase 3 Study Design *Dosing is weekly and, if needed, dose is modified based on plasma arginine levels with maintenance of blinding. ǂThe first 8 weeks of the open-label extension will be blinded. All study partic

  10. Slide 10: Primary Endpoint Met – Marked and Sustained Reduction in Plasma Arginine

    10 Highly elevated plasma arginine despite standard of care Mean plasma arginine* Pegzilarginase Baseline: 365.4 µM 24-week: 105.5 µM Placebo Baseline: 471.7 µM 24-week: 448.8 µM Primary Endpoint Met – Marked and Sustained Reduction in Plasma Arginine Reduction in Plasma Arginine* *Based on arithmet

  11. Slide 11: Normalization of Plasma Arginine Levels in ARG1-D Patients

    90.5% of pegzilarginase treated patients achieved normal plasma arginine levels (p<0.0001)* No meaningful change in plasma arginine levels in placebo arm Treatment with pegzilarginase surpassed current clinical guideline goals of reducing arginine levels below 200 µM 11 Normalization of Plasma Argin

  12. Slide 12: Mobility Assessed by GMFM-E and 2MWT

    Mobility Assessed by GMFM-E and 2MWT 12 Mean Change from Baseline in 2MWT Mean Change from Baseline in GMFM-E 1 MCID is minimal clinically important difference defined in Cerebral Palsy population. 2Oeffinger D et al 2008; GMFM-E = Gross Motor Function Measure Part E; 2MWT = 2-minute walk test; GMFC

  13. Slide 13: Patient-Level Outcomes Across Efficacy Endpoints

    ©2022 Aeglea BioTherapeutics. External 13 In a patient-level analysis clinically important differences between treatment arms were evident for both arginine normalization and clinical responses 16 of 17 pegzilarginase treated patients normalized arginine levels compared to NO patients receiving plac

  14. Slide 14: Patient-Level Outcomes: Mobility in Select Patients

    ©2022 Aeglea BioTherapeutics. External 14 Patient-Level Outcomes: Mobility in Select Patients Pegzilarginase-Treated Patients Achieving Clinical Response on ≥2 Mobility Outcomes and No Worsening at Week 24 Ages are at the time of enrollment; Normalization defined at ±15% of age/sex-matched mean dist

  15. Slide 15: Pegzilarginase Safety Profile – Results from PEACE

    15 Pegzilarginase Safety Profile – Results from PEACE AE = Adverse Event; *Serious AEs were hyperammonemia/hyperammonemia-related events and vomiting Pegzilarginase was Well-Tolerated with No Discontinuations in Pivotal Study Due to Adverse Events No discontinuations due to treatment-emergent advers

  16. Slide 16: Generated and Submitted Comprehensive BLA Package

    ©2022 Aeglea BioTherapeutics. External 16 Phase 1/2 study, n=16 Open-Label Extension (OLE) study, n=14 13 patients with at least 2 years of treatment 2 patients with almost 4 years of treatment PEACE Phase 3 and Long-Term Extension (LTE) study, n=32 31 patients with at least 25 weeks of treatment 12

  17. Slide 17: Attractive Commercial Opportunity and a Targeted Launch Plan

    17 Attractive Commercial Opportunity and a Targeted Launch Plan 1 Catsburg C et al 2022 2 Licensing and supply agreement signed with Immedica Pharma AB in March 2021; countries in agreement include European Economic Area, United Kingdom, Switzerland, Andorra, Monaco, San Marino, Vatican City, Turkey

  18. Slide 18: Continued patient identification momentum across key markets

    Continued patient identification momentum across key markets Gaining valuable insights into disease management and patient characteristics Progress is outpacing relevant benchmarks Driving increased awareness of ARG1-D to facilitate accurate diagnosis THINK ARGININE™: a disease awareness initiative

  19. Slide 19: Laying the Groundwork to Transition Smoothly to Commercial Operations

    Laying the Groundwork to Transition Smoothly to Commercial Operations 19 High-touch patient services model is being developed based on our deep understanding of the needs of the ARG1-D patient community Thoughtful, targeted approach to payer engagement focused on payers most likely to have ARG1-D co

  20. Slide 20: AGLE-177 for Homocystinuria

    AGLE-177 for Homocystinuria

  21. Slide 21: Homocystinuria Disease Overview

    Homocystinuria Disease Overview 21 1 >30,000 represents estimated prevalence of Classical Homocystinuria (including B6-responsive and B6-non-responsive) in 38 addressable markets. 2 Mudd et al 1985. 3 Kožich et al, 2020. 4 ~6,000-6,600 represents estimated prevalence of B6-non-responsive Homocystinu

  22. Slide 22: Natural History Study of Untreated Classical Homocystinuria Patients

    Natural History Study of 629 Untreated Classical Homocystinuria Patients 22 Increased Mortality and High Risk of Severe Complications B6-responsive = 231 All patients = 629 B6-non-responsive = 231 MORTALITY NATURAL HISTORY Mudd et al, 1985. Kluijtmans et al, Am. J. Hum. Genet. 65,59-67, 1999 B6-non-

  23. Slide 23: AGLE-177 for Homocystinuria Overview

    AGLE-177 for Homocystinuria Overview 23 Intracellular Metabolism – Normal & Disease State Plasma Metabolism – AGLE-177 Homocysteine (monomer) Homocystine (dimer) AGLE-177 Homocysteine (protein bound) Decrease in plasma homocysteine and homocystine X AGLE-177 Mechanism Engineered Cystathionine -Lyas

  24. Slide 24: Preclinical Data Support Potential Advantages of AGLE-177

    24 Preclinical Data Support Potential Advantages of AGLE-177 Marked survival benefit with total weekly dose as low as 2 mg/kg 1 Daige C. et al. Poster presented at ASHG 2020 Virtual Meeting. 2 Majtan T. et al., Life Sci. 2018; May 1;200:15-25. 3 Mice were maintained on betaine until weaning; tHcy =

  25. Slide 25: Phase 1/2 Clinical Trial Design

    Phase 1/2 Clinical Trial Design 25 Endpoints Key Inclusion Criteria Enrollment & Dosing Safety and tolerability PK Reduction in plasma total homocysteine levels Classical Homocystinuria diagnosis Plasma homocysteine >80 µM ≥12 years of age Anticipate enrolling 16-20 patients Weekly dosing for 4 week

  26. Slide 26: Phase 1/2 Clinical Trial – Study Acceleration

    Phase 1/2 Clinical Trial – Study Acceleration 26 Cohort 2 Cohort 3 PART 1 (IV) PART 2 (SC) Dose 0.45 mg/kg n = 4 Dose 1.0 mg/kg n = 4 Dose 0.15 mg/kg n = 3 Cohort 1 Dose 0.15 mg/kg Cohorts 4 & 5 (optional) Working to Open U.S. Trial Sites; Clinical Data Expected in 2H 2022 ©2022 Aeglea BioTherapeuti

  27. Slide 27: AGLE-177: a Potentially Differentiated Treatment for Homocystinuria

    27 AGLE-177: a Potentially Differentiated Treatment for Homocystinuria Metabolizes both homocysteine (monomer) and homocystine (dimer) Showed total homocysteine reduction, no safety concerns in cohort 1 of Phase 1/2 trial Demonstrated significant survival benefit in CBS -/- mice at low total weekly

  28. Slide 28: Human Enzyme Engineering Platform

    Human Enzyme Engineering Platform

  29. Slide 29: Cystinuria Overview

    Cystinuria Overview 29 Cystinuria: Cystinuria is a metabolic disorder characterized by high levels of amino acid cystine in the urine, leading to the formation of stones in the kidney, ureter and bladder. Persistent stones can result in serious damage to the kidneys, causing an increased risk of hyp

  30. Slide 30: AGLE-325 Preclinical Advancement

    30 AGLE-325 Preclinical Advancement New candidate advanced through lead optimization with preclinical efficacy and PK/PD profile which support attractive clinical dosing schedule µCT Kidney Stone Volume1 Kidney Pathology1 N=16 N=32 INNOVATIVE ENZYME APPROACH Enzymatic reduction of plasma cystine sho

  31. Slide 31: Leveraging Aeglea's Next Generation Human Enzyme Platform

    Leveraging Aeglea’s Next Generation Human Enzyme Platform 31 High activity human pegylated investigational enzyme Degrades key accumulating metabolite Results in restorative phenotypic improvements in genetically engineered mouse model PROOF OF CONCEPT Vehicle Control Therapeutic Enzyme ©2022 Aeglea

  32. Slide 32: Summary

    Summary

  33. Slide 33: Looking Ahead Key Highlights

    Looking Ahead Key Highlights 33 Pegzilarginase Submit EU MAA in 2022 Continue preparations for strong, rapid launch in U.S., Europe and Middle East Publication of long-term data AGLE-177 Clinical data from Ph 1/2 trial (2H 2022) Working to open U.S. sites AGLE-325 (Cystinuria) IND-enabling studies f

  34. Slide 34: Aeglea contact details

    805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com

  35. Slide 35: Financial Summary

    Financial Summary 35 Cash, cash equivalents and marketable securities as of March 31, 2022: $68.6 million1 (no debt) As of March 31, 2022, 66.0 million2 common shares and pre-funded warrants outstanding Expected funding runway: into first quarter of 2023 1Includes $1.8mm of restricted. 2Includes 49.

  36. Slide 36: PEACE Baseline Demographics

    PEACE Baseline Demographics 36 ©2022 Aeglea BioTherapeutics. External

  37. Slide 37: PEACE Baseline Clinical Characteristics

    PEACE Baseline Clinical Characteristics 37 *Based on arithmetic mean ©2022 Aeglea BioTherapeutics. External

  38. Slide 38: Pegzilarginase Reduces Plasma Arginine in Phase 1/2 & OLE

    Pegzilarginase Significantly and Sustainably Reduces Plasma Arginine Levels in Phase 1/2 & OLE 38 Plasma Arginine in Response to Pegzilarginase in Phase 1/2 & OLE Studies Baseline: Baseline plasma arginine on standard disease management was markedly elevated 20 Week Analysis1: Median plasma arginine

  39. Slide 39: Mobility Assessments in Phase 1/2 Trial & OLE

    Mobility Assessments Capture Potential Clinical Benefit of Pegzilarginase in Phase 1/2 Trial & OLE 39 Continuous Analysis Mean Change from Baseline GMFCS – Level II/III GMFCS – Level I CE = Ceiling Effect 20 Week Analysis: 11/14 (79%) 56 Week Analysis: 11/13 (85%) Categorical Responder Analysis2 1Ad

  40. Slide 40: Improvements in Mobility Measures Sustained Over Time

    40 Improvements in Mobility Measures Sustained Over Time in Phase 1/2 and OLE 48 1 MCID is minimal clinically important difference defined in Cerebral Palsy population. 2Oeffinger D et al 2008; 3 Analysis weeks are calculated by adding the 8 weeks from Part 2 of the Phase 1/2 study to the weeks of t

  41. Slide 41: AGLE-177 Improves Pathologies in Preclinical Homocystinuria Model

    AGLE-177 Improves Pathologies and Correction of Disease Manifestations in a Preclinical Model of Homocystinuria 41 Disease Resolution Disease Reversal Dosing Begins Day 10 CBS-/- Macro-steatosis Disease Progression AGLE-177-HIS 25 mg/kg + Betaine Day 23 CBS-/- AGLE-177-HIS 25 mg/kg Day 60 CBS-/- PBS

  42. Slide 42: Measuring the Functional Impact of Spasticity in ARG1-D

    Measuring the Functional Impact of Spasticity in ARG1-D 42 Gross Motor Function Classification System (GMFCS) Overall description of current motor function based on: Movements such as sitting, walking Use of mobility devices Gross Motor Function Measure (GMFM) Part E Assesses unaided mobility withou

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