Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (January 2023)
38 slides from Spyre Therapeutics's investor presentation, Jan 9, 2023
Slide 1: Redefining the Possible: Corporate Overview – January 2023
Redefining the Possible. Human Enzyme Therapies for People with Rare Diseases Corporate Overview – January 2023 Nasdaq: AGLE Exhibit 99.1
Slide 2: Forward Looking Statements
Forward Looking Statements ©2023 Aeglea BioTherapeutics 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 al
Slide 3: Our Mission is to Change Lives by Bringing Innovative Therapies to Underserved Rare Disease Communities
Our Mission is to Change Lives by Bringing Innovative Therapies to Underserved Rare Disease Communities Innovative enzyme engineering platform leading to differentiated product profiles Metabolic disease expertise creates complementary opportunities Pioneering Bold Science Focused on disease modifyi
Slide 4: Aeglea's Human Enzyme Platform 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: Highlights and Upcoming Milestones
Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: Currently dosing in cohort 3 at 1.35 mg/kg once weekly in Phase 1/2 clinical trial Enrollment in cohort 3 ongoing Pegzilarginase in ARG1-D: MAA under review with EMA, potential approval in the second half of 2023 Continuing to engag
Slide 6: Pegtarviliase – Potential Best-in-Class Treatment for Homocystinuria
Pegtarviliase – Potential Best-in-Class Treatment for Homocystinuria
Slide 7: Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications
Classical Homocystinuria (HCU) Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications Also known as cystathionine beta synthase (CBS) deficiency, Classical Homocystinuria is a serious and progressive metabolic disorder characterized by elevated levels o
Slide 8: Patients with Classical HCU Live With Both Disease and Treatment Burden
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 for the majo
Slide 9: Classical HCU: A Sizeable Patient Population at Serious Risk of Severe Complications
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 This translates into an estimated ~25,000 treatment candidates in global addressable markets,1 approximately 8,500 of whom ar
Slide 10: Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine
Pegtarviliase Mechanism Engineered Cystathionine -Lyase (CGL) enzyme mutated to change its native substrate specificity from cystathionine to both homocysteine and its dimer Concentration gradient drives homocysteine out of tissue and into plasma Equilibrium in plasma favors dimer over monomer Flux
Slide 11: Pegtarviliase Lowers Homocysteine 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 of a sufficient size Prior to a single subcutaneous dose of pegtarviliase, there was a two-week wash out To ensure accurate total homocysteine assessment, an inhibitor of pe
Slide 12: Preclinical Data Support Potential Advantages of Pegtarviliase
Preclinical Data Support Potential Advantages of Pegtarviliase Pegtarviliase demonstrated significant survival benefit at substantially lower dose than competitor enzyme 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
Slide 13: 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 Cohort 2 Cohort 3 PART 1 (Intravenous) PART 2 (Subcutaneous) Dose 0.45 mg/kg n = 4 Dose 1.35 mg/kg Currently enrolling Dose 0.15 mg/kg n = 3 Cohort 1 Cohort 5 (optional) Continuing to Enroll and Dose Patients in Cohort 3
Slide 14: Advancing a Potential Best-in-Class Therapy for Classical HCU Patients
Data from cohorts 1-3 may be sufficient for discussions with FDA on pivotal trial design Manufacturing at commercial scale Stable, high-concentration liquid formulation Orphan Disease and Rare Pediatric Disease designations allow for additional engagement with regulators Advancing a Potential Best-i
Slide 15: Pegzilarginase for Arginase Deficiency
Pegzilarginase for Arginase 1 Deficiency
Slide 16: 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 17: 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 18: 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 Plasma Arginine* Enns G, et al. Poster presented at SIMD 2022 Annual Meeting; *Based on arithmetic mean of values from visit and preceding 3 visits, boxes represent middle 50% with error bars depict
Slide 19: PEACE Phase 3 Trial: 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 20: 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 21: PEACE Phase 3: Pegzilarginase Safety Profile
PEACE Phase 3: Pegzilarginase Safety Profile 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 adverse events
Slide 22: Regulatory and Program Update
Regulatory and Program Update Continuing to engage with FDA to identify potential paths towards BLA resubmission Refusal to File (RTF) Received for BLA CMC: Readily addressable items related to stability quality and sterilization Clinical: Request for additional data to support effectiveness, such a
Slide 23: Summary
Summary
Slide 24: Highlights and Upcoming Milestones
Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: Currently dosing in cohort 3 at 1.35 mg/kg once weekly in Phase 1/2 clinical trial Enrollment in cohort 3 ongoing Pegzilarginase in ARG1-D: MAA under review with EMA, potential approval in the second half of 2023 Continuing to engag
Slide 25: Financial Summary
Financial Summary $ Millions Three Months ended 9/30/22 Nine Months Ended 9/30/22 Revenue $0.2 2.2 R&D Expense $12.0 $44.3 G&A Expense $6.9 $23.5 Net Loss $18.2 $65.0 “Non-GAAP” cash, cash equivalents and marketable securities as of September 30, 2022: $75.21 million (no debt) As of September 30, 20
Slide 26: Las Cimas Parkway Suite Austin, TX 78746 aeglea.com
805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com
Slide 27: 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 28: 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 29: Pegtarviliase Improves Pathologies in a Mouse Model of Homocystinuria
Pegtarviliase Treatment Improved Pathologies and Corrects 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-/- PB
Slide 30: 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 31: 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 32: Pegzilarginase Reduces Plasma Arginine Levels 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 33: 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 34: 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 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 35: 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 36: 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 37: 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 38: 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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