Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (September 2022)
43 slides from Spyre Therapeutics's investor presentation, Sep 6, 2022
Slide 1: Reimagining The Potential Of Human Enzyme Therapeutics
Exhibit 99.1 Reimagining The Potential Of Human Enzyme Therapeutics Corporate Overview – September 2022 Nasdaq: AGLE
Slide 2: Forward Looking Statements
Forward Looking Statements 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 statements include all statements other than state
Slide 3: Addressing Metabolic Imbalances to Improve the Lives of Patients
Addressing Metabolic Imbalances to Improve the Lives of Patients Our vision is to redefine the possible, pioneer bold science with human enzymes and deliver groundbreaking medicines that transform lives. We are on a mission to change lives by bringing innovative therapies to underserved rare disease
Slide 4: Building an Enzyme Therapy Company to Serve Patients and Drive Near and Long-Term Growth
Building an Enzyme Therapy Company to Serve Patients and Drive Near and Long-Term Growth • Innovative enzyme engineering platform • Differentiated product profiles Pioneering Bold • Expertise in metabolic disease and enzyme engineering creates Science complementary opportunities in areas with limite
Slide 5: Aeglea's Human Enzyme Platform for Rare Metabolic Diseases
Aeglea’s Human Enzyme Platform for Rare Metabolic Diseases Regulatory Addressable Geographic Program Research Phase 1/2 Phase 3 Review Market Rights Pegtarviliase (AGLE-177) Worldwide >30,000 1 rights Patients Homocystinuria Retain rights outside of Europe 3 Pegzilarginase >2,500 and Middle East 2 P
Slide 6: Program Highlights and Upcoming Milestones
Program Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: • Completed cohort 2, currently enrolling cohort 3 • Active clinical trial sites in UK, Australia and U.S. • Interim clinical data from Phase 1/2 clinical trial expected in fourth quarter of 2022, including data from cohort
Slide 7: Pegtarviliase (formerly AGLE-177) – Potential Best-in-Class Treatment for Homocystinuria
Pegtarviliase (formerly AGLE-177) – Potential Best-in-Class Treatment for Homocystinuria
Slide 8: Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications
Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications Serious Disease Complications Classical Homocystinuria (HCU) Eyes Cystathionine beta synthase (CBS) deficiency, also known as Lens dislocation, glaucoma, severe near-sightedness Classical Homocystin
Slide 9: Inadequate Treatment Options to Control Homocysteine Levels and Prevent Disease Progression
Inadequate Treatment Options to Control Homocysteine Levels and Prevent Disease Progression Favorable competitive & regulatory Current standard of care: landscape • B6 (pyridoxine) • Betaine approved on tHcy lowering alone, • Low-methionine diet + amino acid despite limited effectiveness supplements
Slide 10: Increased Mortality and High Risk of Severe Complications
Increased Mortality and High Risk of Severe Complications Natural History Study of 629 Untreated Classical Homocystinuria Patients MORTALITY B6-non-responsive B6-responsive B6-responsive = 231 Elevated levels of homocysteine All patients = 629 Mortality by age 30 23% 4% B6-non-responsive = 231 Most
Slide 11: Sizeable Patient Population and Significant Commercial Opportunity
Sizeable Patient Population and Significant Commercial Opportunity 1 >30,000 Classical HCU patients B6-responsive • Currently available treatments work primarily for patients patients considered B6-responsive • B6-non-responsive patients and B6-partial responders Partial responders have poorer tHcy
Slide 12: Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine
Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine Depiction of Normal and Therapeutic Metabolism Pegtarviliase Mechanism Engineered Cystathionine γ-Lyase (CGL) enzyme mutated to change its native substrate specificity from cystathionine to both homocysteine and its dimer è Concen
Slide 13: Pegtarviliase Treatment Resulted in Dose-Dependent Lowering of Homocysteine in Mouse Model
Pegtarviliase Treatment Resulted in Dose-Dependent Response and Statistically Significant Lowering of Homocysteine in Mouse Model Single Subcutaneous Dose in CBS Experimental Design: 1 Knockout Mouse Model • 10-day old CBS knockout mice were 375 dosed with pegtarviliase twice per week for 5 weeks to
Slide 14: Pegtarviliase Treatment Improved Pathologies in a Mouse Model of Homocystinuria
Pegtarviliase Treatment Improved Pathologies and Corrects Disease Manifestations in a Mouse Model of Homocystinuria 2 Reversal of Severe Liver Abnormalities in Beneficial Impact on Osteoporosis 1 CBS Knockout Mouse Model Disease Resolution Disease R eversa l P = 0.0407 p = 0.0407 70 Dosing Begins =
Slide 15: Preclinical Data Support Potential Advantages of Pegtarviliase
Preclinical Data Support Potential Advantages of Pegtarviliase Pegtarviliase demonstrated significant survival Pegtarviliase demonstrated pharmacological benefit at substantially lower dose than effect on homocysteine levels in normal animals competitor enzyme that is not seen with competitor enzyme
Slide 16: Phase 1/2 Clinical Trial to Generate Proof-of-Concept and Path to Pivotal Trial
Phase 1/2 Clinical Trial to Generate Proof-of-Concept and Path to Pivotal Trial PART 1 (IV) PART 2 (SC) Cohort 4 Cohort 5 Cohort 3 (optional) (optional) ü ü Currently enrolling Cohort 1 Cohort 2 Dose 0.15 mg/kg Dose 0.45 mg/kg n = 3 n = 4 Endpoints & Design Key Inclusion Criteria • Safety and tolera
Slide 17: Pegtarviliase: a Potential Best-in-Class Treatment for Classical Homocystinuria
Pegtarviliase: a Potential Best-in-Class Treatment for Classical Homocystinuria Preclinical Clinical • Demonstrated significant survival benefit in CBS -/- • Showed total homocysteine reduction with no mice at low total weekly doses safety concerns at 0.15 mg/kg once weekly in Phase 1/2 trial • Redu
Slide 18: Pegtarviliase: Preparing to Move Rapidly into Pivotal Trial
Pegtarviliase: Preparing to Move Rapidly into Pivotal Trial CMC Phase 3 Trial Design • Discuss interim data with FDA • Registration manufacturing campaign in process • Align on pivotal trial design and endpoints • Currently manufacturing at commercial scale • Product characterization and analytical
Slide 19: Pegzilarginase for Arginase Deficiency
Pegzilarginase for Arginase 1 Deficiency
Slide 20: Arginase Deficiency (ARG1-D) Disease Overview
Arginase 1 Deficiency (ARG1-D) Disease Overview ARG1-D is a serious, progressive disease with early The Progressive Impact of Persistently 1-4 mortality and high unmet medical need. It is High Plasma Arginine caused by a mutation in the arginase 1 enzyme, 2-4,7,8 resulting in persistently high level
Slide 21: Pegzilarginase Program Overview
Pegzilarginase Program Overview First Clinical Program Ever Conducted Pegzilarginase is a novel recombinant human enzyme engineered to lower arginine levels in ARG1-D PEACE Phase 3 Clinical Trial Commercial Opportunity 1 • First placebo-controlled trial ever conducted • >2,500 patients in global add
Slide 22: PEACE Phase 3 Trial: Marked and Sustained Reduction in Plasma Arginine
PEACE Phase 3 Trial: Marked and Sustained Reduction in Plasma Arginine Primary Endpoint: Reduction in Proportion of Patients Reaching * † Plasma Arginine Normal Arginine Levels (p<0.0001 ) 700 630 560 490 100% 90.5% 85.7% 420 80% 350 60% 280 47.6% 210 40% 200 µM Clinical Guideline 140 115 µM 20% Nor
Slide 23: PEACE Phase 3 Trial: Mobility Assessed by GMFM-E and 2MWT
PEACE Phase 3 Trial: Mobility Assessed by GMFM-E and 2MWT Mean Change from Baseline in GMFM-E Mean Change from Baseline in 2MWT Pegzilarginase Placebo Pe Pg eg zz il ilarg arg in in asa ese PlP ala ce ceb bo o Pegzilarginase Placebo 10 5 1, 2 4.2 MCID 7.3 GMFCS I 6.8 (4.0 units) 2.9 GMFCS II (2.8 un
Slide 24: PEACE Phase 3 Patient-Level Outcomes Across Efficacy Endpoints
PEACE Phase 3 Patient-Level Outcomes: Impact of Pegzilarginase Across Efficacy Endpoints GMFCS Level I-III Patients • In a patient-level analysis clinically important differences between Patient pArg GMFM-E 2MWT GMFM-D treatment arms were evident for both arginine normalization and 1 2 clinical resp
Slide 25: PEACE Phase 3: Pegzilarginase Safety Profile
PEACE Phase 3: Pegzilarginase Safety Profile • No discontinuations due to treatment- emergent adverse events • Most treatment-emergent adverse events were mild or moderate in severity • Hypersensitivity reactions were mild/moderate, infrequent and managed with routine medical care • Serious adverse
Slide 26: Regulatory and Program Update
Regulatory and Program Update U.S. Regulatory Status Next Steps MAA Filing Under Review with EMA as of August 2022 Refusal to File (RTF) Received for BLA • MAA filings typically have ~1 year review timeline • Items included in RTF • Manufacturing in place to support commercialization in – CMC: Readi
Slide 27: Human Enzyme Engineering Platform
Human Enzyme Engineering Platform
Slide 28: Cystinuria Overview
Cystinuria Overview 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 hypert
Slide 29: AGLE-325 Preclinical Advancement
AGLE-325 Preclinical Advancement New candidate advanced through lead optimization with preclinical efficacy INNOVATIVE ENZYME APPROACH and PK/PD profile which support attractive clinical dosing schedule 1 1 µCT Kidney Stone Volume Kidney Pathology ** p=0.0077 5 Severe 3 4 Enzymatic Lowering of Cysti
Slide 30: Leveraging Aeglea's Next Generation Human Enzyme Platform: Undisclosed Rare Disease Indication
Leveraging Aeglea’s Next Generation Human Enzyme Platform: Undisclosed Rare Disease Indication PROOF OF CONCEPT Vehicle Control Therapeutic Enzyme Pegylated enhanced human enzyme Therapeutic Approach • Enzymatic control of high levels of a metabolite considered important in disease pathogenesis • Ve
Slide 31: Summary
Summary
Slide 32: Program Highlights and Upcoming Milestones
Program Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: • Completed cohort 2, currently enrolling cohort 3 • Active clinical trial sites in UK, Australia and U.S. • Interim clinical data from Phase 1/2 clinical trial expected in fourth quarter of 2022, including data from cohort
Slide 33: Financial Summary
Financial Summary 1 “Non-GAAP” cash, cash equivalents and marketable securities as of June 30, 2022: $90.4 million (no debt) 2 As of June 30, 2022, 94.2 million common shares and pre-funded warrants outstanding Three Months ended Six Months Ended 6/30/22 6/30/22 $ Millions Revenue $0.6 2.0 R&D Expen
Slide 34: Las Cimas Parkway Suite Austin, TX 78746 aeglea.com
805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com
Slide 35: PEACE Baseline Demographics
PEACE Baseline Demographics Pegzilarginase Placebo Overall Demographic Characteristic n=21 n=11 N=32 Age at Enrollment, y Mean (SD) 9.6 (6.16) 12.9 (6.77) 10.7 (6.47) Range 2-28 5-29 2-29 Age Category, n (%) 2y to less than 6y 5 (23.8) 1 (9.1) 6 (18.8) 6y to less than 12y 8 (38.1) 4 (36.4) 12 (37.5)
Slide 36: PEACE Baseline Clinical Characteristics
PEACE Baseline Clinical Characteristics Pegzilarginase Placebo Overall Clinical Characteristic n=21 n=11 N=32 Plasma Arginine, µM/L * Mean (SD) 471.7 (79.9) 402.0 (101.8) 365.4 (93.7) Median (range) 483.7 (294-573) 398.2 (202-573) 368.2 (202-572) GMFCS level, n (%) 1 5 (45.5) 14 (43.8) 9 (42.9) ≥2 6
Slide 37: Pegzilarginase Significantly and Sustainably Reduces Plasma Arginine Levels in Phase 1/2 & OLE
Pegzilarginase Significantly and Sustainably Reduces Plasma Arginine Levels in Phase 1/2 & OLE Baseline: Plasma Arginine in Response to • Baseline plasma arginine on standard disease management was markedly elevated Pegzilarginase in Phase 1/2 & OLE Studies 1 20 Week Analysis : • Median plasma argin
Slide 38: Mobility Assessments Capture Potential Clinical Benefit of Pegzilarginase in Phase 1/2 Trial & OLE
Mobility Assessments Capture Potential Clinical Benefit of Pegzilarginase in Phase 1/2 Trial & OLE 1 Change from Baseline at 56 Week Analysis Continuous Analysis 20 17 17 Baseline Deficit Mean Change from Baseline 14 GMFCS – Level II/III 15 Analysis GMFCS – Level I Endpoint 10 20 weeks 56 weeks CE =
Slide 39: Improvements in Mobility Measures Sustained Over Time in Phase 1/2 and OLE
Improvements in Mobility Measures Sustained Over Time in Phase 1/2 and OLE Mean Change from Baseline in GMFM-E 8 Change from Baseline for Phase 1/2 & OLE 7.1 3 Studies 5.8 6 1, 2 MCID Endpoint 20-week 32-week 56-week 104-week 4.2 4.1 GMFCS I 4 (4.0 units) analysis analysis analysis analysis GMFCS II
Slide 40: Measuring the Functional Impact of Spasticity in ARG1-D
Measuring the Functional Impact of Spasticity in ARG1-D Classification of Mobility: Gross Motor Function Classification System (GMFCS) Overall description of current motor function based on: • Movements such as sitting, walking Level V not pictured: adapted seating and assistance with transfers, and
Slide 41: PEACE Phase 3 Study Design
PEACE Phase 3 Study Design Double-blind portion of trial complete – topline data announced December 2021 Pegzilarginase 0.1 mg/kg* IV Patients with ARG1-D R ǂ n=21 Long Term Extension N=32 2:1 • ≥2 years old N=31 Placebo IV • Plasma arginine >250 µM (mean) • Baseline deficit in clinical n=11 respons
Slide 42: Patient-Level Outcomes: Mobility in Select Patients
Patient-Level Outcomes: Mobility in Select Patients Pegzilarginase-Treated Patients Achieving Clinical Response on ≥2 Mobility Outcomes and No Worsening at Week 24 Patient (Age) GMFM-E (Score Range, 0-72 units) 2MWT* GMFM-D (Score Range, 0-39 units) • Improved by 7 • Improved by 34m to 152m • Improv
Slide 43: Attractive Commercial Opportunity and a Targeted Launch Plan
Attractive Commercial Opportunity and a Targeted Launch Plan 1 Prevalence of >2,500 Patients A Focused Effort to Ensure a Successful Launch with Significant Unmet Need Patient Disease Education Identification and Awareness Accelerating the diagnosis and Driving HCP dialogue about identification of p
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