Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (November 2022)
43 slides from Spyre Therapeutics's investor presentation, Nov 3, 2022
Slide 1: Reimagining The Potential Of Human Enzyme Therapeutics
Reimagining The Potential Of Human Enzyme Therapeutics Corporate Overview – November 2022 Nasdaq: AGLE Exhibit 99.2
Slide 2: Forward Looking Statements
Forward Looking Statements ©2022 Aeglea BioTherapeutics. External 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
Slide 3: Addressing Metabolic Imbalances to Improve the Lives of Patients
Addressing Metabolic Imbalances to Improve the Lives of Patients ©2022 Aeglea BioTherapeutics. External 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 innovativ
Slide 4: Building an Enzyme Therapy Company to Serve Patients and Drive Near and Long-Term Growth
©2022 Aeglea BioTherapeutics. External Building an Enzyme Therapy Company to Serve Patients and Drive Near and Long-Term Growth Pioneering Bold Science Delivering Groundbreaking Medicines Redefining the Possible Innovative enzyme engineering platform Differentiated product profiles Expertise in meta
Slide 5: Aeglea's Human Enzyme Platform for Rare Metabolic Diseases
Program Research Phase 1/2 Phase 3 Regulatory Review Addressable Market Geographic Rights Pegtarviliase (AGLE-177) Homocystinuria >30,000 Patients1 Worldwide rights Pegzilarginase Arginase 1 Deficiency >2,500 Patients2 Retain rights outside of Europe and Middle East3 AGLE-325 Cystinuria Cystinuria >
Slide 6: Program Highlights and Upcoming Milestones
©2022 Aeglea BioTherapeutics. External Program Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: Currently dosing in cohort 3 at 1.35 mg/kg once weekly Interim clinical data from Phase 1/2 clinical trial expected in fourth quarter of 2022, including data from cohort 3 Pegzilarginas
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 (HCU) Classical Homocystinuria: A Rare Metabolic Disorder With Serious and Potentially Deadly Complications Cystathionine beta synthase (CBS) deficiency, also known as Classical Homocystinuria, is a serious and progressive metabolic disorder characterized by elevated levels
Slide 9: Patients with Classical HCU Live With Both Disease and Treatment Burden
With persistently high tHcy levels, patients remain at risk for serious and life-threatening complications ©2022 Aeglea BioTherapeutics. External Compliance with severe dietary restrictions and amino acid supplementation is extremely challenging and represents a lifelong burden Vitamin B6 is largely
Slide 10: 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 11: Classical HCU: A Sizeable Patient Population at Serious Risk of Severe Complications
©2022 Aeglea BioTherapeutics. External Classical HCU: A Sizeable Patient Population at Serious Risk of Severe Complications Over 80% of patients are unable to achieve tHcy levels <50 µM with B6 alone This translates into an estimated ~25,000 treatment candidates in global addressable markets,1 appro
Slide 12: Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine
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 tissu
Slide 13: Pegtarviliase Dose-Dependent Homocysteine Lowering in Mouse Model
©2022 Aeglea BioTherapeutics. External 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 SC dose of pegtarviliase, there was a two-week wash out To ensure accurate tHcy assessment, an
Slide 14: Pegtarviliase Improved Pathologies in a Mouse Model of Homocystinuria
Pegtarviliase Treatment Improved Pathologies and Corrects Disease Manifestations in a Mouse Model of Homocystinuria ©2022 Aeglea BioTherapeutics. External Disease Resolution Disease Reversal Dosing Begins Day 10 CBS-/- Macro-steatosis Disease Progression AGLE-177-HIS 25 mg/kg + Betaine Day 23 CBS-/-
Slide 15: 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 16: Phase 1/2 Clinical Trial to Generate Proof-of-Concept and Path to Pivotal Trial
©2022 Aeglea BioTherapeutics. External Phase 1/2 Clinical Trial to Generate Proof-of-Concept and Path to Pivotal Trial Cohort 2 Cohort 3 PART 1 (IV) PART 2 (SC) 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) Interim Clinical Data Expected
Slide 17: Advancing a Potential Best-in-Class Therapy for Classical HCU Patients
©2022 Aeglea BioTherapeutics. External 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 and Rare Pediatric Disease designations allow for additional engagement with regulato
Slide 18: Pegzilarginase for Arginase Deficiency
Pegzilarginase for Arginase 1 Deficiency
Slide 19: 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 20: 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 21: 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 22: PEACE Phase 3 Trial: Mobility Assessed by GMFM-E and 2MWT
PEACE Phase 3 Trial: Mobility Assessed by GMFM-E and 2MWT Pegzilarginase Placebo 12 Weeks 24 Weeks 12 Weeks 24 Weeks MCID1, 2 GMFCS I (4.0 units) GMFCS II (2.8 units) Positive Trend in GMFM-E in Placebo-Controlled Study Suggests Potential Improvement in Mobility Time LS Mean Difference P Value 12 We
Slide 23: PEACE Phase 3 Patient-Level Outcomes Across Efficacy Endpoints
©2022 Aeglea BioTherapeutics. External 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
Slide 24: 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 25: Regulatory and Program Update
©2022 Aeglea BioTherapeutics. External Regulatory and Program Update Refusal to File (RTF) Received for BLA Items included in RTF CMC: Readily addressable items related to stability quality and sterilization Clinical: Request for additional data to support effectiveness, such as plasma arginine redu
Slide 26: Human Enzyme Engineering Platform
Human Enzyme Engineering Platform
Slide 27: 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 28: AGLE-325 Preclinical Advancement
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 should
Slide 29: Leveraging Aeglea's Next Generation Human Enzyme Platform: Undisclosed Rare Disease Indication
Leveraging Aeglea’s Next Generation Human Enzyme Platform: Undisclosed Rare Disease Indication High activity human pegylated investigational enzyme Degrades key accumulating metabolite Results in restorative phenotypic improvements in genetically engineered mouse model PROOF OF CONCEPT Vehicle Contr
Slide 30: Summary
Summary
Slide 31: Program Highlights and Upcoming Milestones
©2022 Aeglea BioTherapeutics. External Program Highlights and Upcoming Milestones Pegtarviliase in Homocystinuria: Currently dosing in cohort 3 at 1.35 mg/kg once weekly Interim clinical data from Phase 1/2 clinical trial expected in fourth quarter of 2022, including data from cohort 3 Pegzilarginas
Slide 32: 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 33: Las Cimas Parkway Suite Austin, TX 78746 aeglea.com
805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com
Slide 34: Homocysteine Metabolism & Pegtarviliase Mechanism of Action
Homocysteine Metabolism & Pegtarviliase Mechanism of Action ©2022 Aeglea BioTherapeutics – Confidential Methionine Homocysteine Cystathionine Cysteine Cystathionine ß-Synthase (CBS) Homocysteine monomer Homocystine dimer/disulfide ~30% ~1% ~70% Protein-Bound Homocysteine Betaine Pyridoxine (B6) Intr
Slide 35: 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 36: 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 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 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 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 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 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 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 40: 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 41: PEACE Phase 3 Study Design and Key Endpoints
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 42: Patient-Level Outcomes: Mobility in Select Patients
©2022 Aeglea BioTherapeutics. External 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
Slide 43: 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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