Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (April 2023)
37 slides from Spyre Therapeutics's investor presentation, Apr 25, 2023
Slide 1: Redefining the Possible: Human Enzyme Therapies for People with Rare Diseases
Redefining the Possible. Human Enzyme Therapies for People with Rare Diseases Corporate Overview – April 2023 Nasdaq: AGLE Exhibit 99.1
Slide 2: Forward Looking Statements
Forward Looking Statements ©2023 Aeglea BioTherapeutics This presentation by Aeglea BioTherapeutics, Inc. (“we”, “our” or “us”) contains “forward-looking” statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are based on our management’s beliefs and assumptions
Slide 3: Recent Developments and Upcoming Milestones
Recent Developments and Upcoming Milestones Pegtarviliase in Homocystinuria: Announced interim results from Cohorts 1-3 in April 2023 Data from Cohorts 1 and 2 suggested a dose-dependent treatment effect Cohort 3 data confounded by presence of anti-drug antibodies (ADAs) and does not support interac
Slide 4: Aeglea's Human Enzyme Therapies for Rare Metabolic Diseases
Program Research Phase 1/2 Phase 3 Regulatory Review Addressable Market Geographic Rights Pegtarviliase Homocystinuria ~25,000 Patients1 Worldwide rights Pegzilarginase Arginase 1 Deficiency >2,500 Patients2 Retain rights outside of Europe and Middle East3 Preclinical Programs Including Cystinuria C
Slide 5: Pegtarviliase – Potential Treatment for Homocystinuria
Pegtarviliase – Potential Treatment for Homocystinuria
Slide 6: Classical Homocystinuria: A Rare Metabolic Disorder With Serious Complications
Classical Homocystinuria (HCU) Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications ystathionine beta synthase (CBS) deficiency, Classical Homocystinuria is a serious and progressive metabolic disorder characterized by elevated amino acid homocysteine
Slide 7: Persistently High Homocysteine Levels Leave Patients at Risk
With Persistently High Total Homocysteine Levels, Patients Remain at Risk for Serious and Life-Threatening Complications Compliance with severe dietary restrictions and amino acid supplementation is extremely challenging and represents a lifelong burden Vitamin B6 is largely ineffective at lowering
Slide 8: Classical HCU: A Sizeable Patient Population at Serious Risk
Classical HCU: A Sizeable Patient Population at Serious Risk of Severe Complications Over 80% of patients are unable to achieve total homocysteine levels <50 µM with B6 alone, the definition of B6 responsiveness This translates into an estimated ~25,000 treatment candidates in global addressable mar
Slide 9: Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine
Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine Pegtarviliase Mechanism Engineered Cystathionine g-Lyase (CGL) enzyme mutated to change its native substrate specificity from cystathionine to both homocysteine and its dimer Concentration gradient drives homocysteine out of tissu
Slide 10: Phase 1/2 Clinical Trial Design
Phase 1/2 Clinical Trial Design Cohort 2 Cohort 3 PART 1 (Intravenous) PART 2 (Subcutaneous) Dose 0.45 mg/kg n = 4 Dose 1.35 mg/kg n = 4 Dose 0.15 mg/kg n = 3 Cohort 1 Cohort 5 Completed Dosing in Cohort 3 Endpoints & Design Key Inclusion Criteria Safety and tolerability Pharmacokinetics Reduction i
Slide 11: Interim Results from Phase 1/2: Lowering of Homocysteine
©2023 Aeglea BioTherapeutics. External Interim Results from Phase 1/2 Clinical Trial: Lowering of Homocysteine Data from Cohorts 1 and 2 showed that treatment with pegtarviliase lowered total homocysteine levels when compared to baseline values Cohort 3 data confounded by presence of anti-drug antib
Slide 12: Interim Results from Phase 1/2: Safety Summary
Interim Results from Phase 1/2 Clinical Trial: Safety Summary ©2023 Aeglea BioTherapeutics. Confidential Information Adverse Events Participants N=13 Any treatment-emergent AE 13 (100%) AE leading to discontinuation 0 AE leading to dose reduction 0 AE of special interest: HSR ISR 2 (15.3%) 10 (76.9%
Slide 13: Pegtarviliase Program Summary
Efficacy Data from Phase 1/2 clinical trial indicated pegtarviliase is capable of lowering homocysteine levels Results from cohort 3 did not show consistent homocysteine lowering, likely due to the presence of ADAs ADAs frequently seen with other pegylated enzyme therapies; potential to dose through
Slide 14: Pegzilarginase for Arginase Deficiency
Pegzilarginase for Arginase 1 Deficiency
Slide 15: The Progressive Impact of Persistently High Plasma Arginine
The Progressive Impact of Persistently High Plasma Arginine1-4 Arginase 1 Deficiency (ARG1-D) Disease Overview 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 ale
Slide 16: Pegzilarginase Program Overview
Pegzilarginase Program Overview Commercial Opportunity >2,500 patients in global addressable markets1 High unmet medical need No approved therapies to address high arginine levels Regulatory Designations U.S. Rare Pediatric Disease (PRV eligible) Breakthrough Therapy U.S. Orphan Drug EU Orphan Drug
Slide 17: PEACE Phase 3: Reduction in Plasma Arginine
PEACE Phase 3 Trial: Marked and Sustained Reduction in Plasma Arginine Primary Endpoint: Reduction in Plasma Arginine* ǂ Statistical analysis based on geometric mean; † Clinical Guideline Primary Endpoint Met – 24 Week Analysis 76.7% reduction from baseline in mean plasma arginine with pegzilarginas
Slide 18: PEACE Phase 3: Mobility Assessed by GMFM-E and 2MWT
PEACE Phase 3 Trial: Mobility Assessed by GMFM-E and 2MWT Positive Trend in GMFM-E in Placebo-Controlled Study Suggests Potential Improvement in Mobility Time LS Mean Difference P Value 12 Weeks 6.4 units p=0.0568 24 Weeks 4.6 units p=0.1087 Mean Change from Baseline in 2MWT Time LS Mean Difference
Slide 19: PEACE Phase 3 Patient-Level Outcomes
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 placebo Clinical response criteria for ≥1 asse
Slide 20: PEACE Phase 3: Pegzilarginase Safety Profile
PEACE Phase 3: Pegzilarginase Safety Profile Enns G, et al. Poster presented at SIMD 2022 Annual Meeting; 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
Slide 21: Summary
Summary
Slide 22: Recent Developments and Upcoming Milestones
Recent Developments and Upcoming Milestones Pegtarviliase in Homocystinuria: Announced interim results from Cohorts 1-3 in April 2023 Data from Cohorts 1 and 2 suggested a dose-dependent treatment effect Cohort 3 data confounded by presence of anti-drug antibodies (ADAs) and does not support interac
Slide 23: Aeglea contact details
805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com
Slide 24: Homocysteine Metabolism & Pegtarviliase Mechanism of Action
Homocysteine Metabolism & Pegtarviliase Mechanism of Action Methionine Homocysteine Cystathionine Cysteine Cystathionine ß-Synthase (CBS) Homocysteine monomer Homocystine dimer/disulfide ~30% ~1% ~70% Protein-Bound Homocysteine Betaine Pyridoxine (B6) Intracellular Serine Dietary Protein Pegtarvilia
Slide 25: Natural History Study of Untreated Classical Homocystinuria Patients
Natural History Study of 629 Untreated Classical Homocystinuria Patients Elevated levels of homocysteine Mortality by age 30 23% 4% Most common cause of death Thromboembolism Lens dislocation in 50% Age 6 Age 10 Median IQ 56 78 Chance of thrombosis by age 15 27% 12% Increased Mortality and High Risk
Slide 26: Dose-Dependent Homocysteine Lowering in Mouse Model
Experimental Design: 10-day old CBS knockout mice were dosed with pegtarviliase twice per week for 5 weeks to ensure they were able to grow to sufficient size for future blood sampling Prior to a single subcutaneous dose of pegtarviliase, there was a two-week wash out To ensure accurate tHcy assessm
Slide 27: Preclinical Data Support Once-Weekly Dosing of Pegtarviliase
©2023 Aeglea BioTherapeutics Preclinical Data Support Once-Weekly Dosing of Pegtarviliase Significant Survival Benefit in Knockout Mouse1,2 1 Daige C. et al. Poster presented at ASHG 2020 Virtual Meeting. 2 Mice were maintained on betaine until weaning; tHcy = total homocysteine Pegtarviliase (10 mg
Slide 28: Pegtarviliase Improved Pathologies in Mouse Model of Homocystinuria
Pegtarviliase Treatment Improved Pathologies and Corrected Disease Manifestations in a Mouse Model of Homocystinuria 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-/- P
Slide 29: PEACE Baseline Demographics
PEACE Baseline Demographics Demographic Characteristic Pegzilarginase n=21 Placebo n=11 Overall 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 30: PEACE Baseline Clinical Characteristics
PEACE Baseline Clinical Characteristics Clinical Characteristic Pegzilarginase n=21 Placebo n=11 Overall N=32 Plasma Arginine, µM/L Mean* (SD) 365.4 (93.7) 471.7 (79.9) 402.0 (101.8) Median (range) 368.2 (202-572) 483.7 (294-573) 398.2 (202-573) GMFCS level, n (%) 1 9 (42.9) 5 (45.5) 14 (43.8) ≥2 12
Slide 31: Pegzilarginase Reduces Plasma Arginine in Phase 1/2 & OLE
Pegzilarginase Significantly and Sustainably Reduces Plasma Arginine Levels in Phase 1/2 & OLE 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 wa
Slide 32: Mobility Assessments in Phase 1/2 Trial & OLE
Mobility Assessments Capture Potential Clinical Benefit of Pegzilarginase in Phase 1/2 Trial & OLE 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 1Adapt
Slide 33: Improvements in Mobility Measures Sustained Over Time
Improvements in Mobility Measures Sustained Over Time in Phase 1/2 and OLE Endpoint Change from Baseline for Phase 1/2 & OLE Studies3 20-week analysis (N=13) 32-week analysis (N=13) 56-week analysis (N=13) 104-week analysis (N=9)4 GMFM-E 4.2 units 4.1 units 5.8 units 7.1 units 6MWT 32.2 m 21.3 m 44.
Slide 34: Measuring the Functional Impact of Spasticity in ARG1-D
Measuring the Functional Impact of Spasticity in ARG1-D 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 without b
Slide 35: PEACE Phase 3 Study Design
Double-blind portion of trial complete – topline data announced December 2021 Key Endpoints Analysis Primary: Plasma arginine reduction Reduction of plasma arginine compared to placebo Secondary: GMFM-E (walking, running & jumping) 2-Minute Walk Test (distance walked in 2 min) Continuous analysis Im
Slide 36: 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 Normalization of Mobility in Progressive Disease Supports the Potential Impact of Pegzilarginase Treatment Patient (Age) GMFM-E (Score R
Slide 37: Attractive Commercial Opportunity and a Targeted Launch Plan
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, S
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