Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (September 2019)
36 slides from Spyre Therapeutics's investor presentation, Sep 3, 2019
Slide 1: Aeglea Corporate Overview September 2019
Aeglea tm Biotherapeutivs Aeglea Corporate Overview September 2019 @ Aeglea BioTherepeutics I External
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: Aeglea Biotherapeutics
Aeglea Biotherapeutics Clinical-Stage Biotechnology Company that Engineers Next Generation Human Enzymes with Enhanced Properties and Novel Activity to Provide Solutions for Diseases with Unmet Medical Need Aeglea BioTherapeutics, Inc.|NASDAQ: AGLE|Austin, Texas Lead Investigational Program Pegzilar
Slide 4: Pipeline Building Using a Unique Drug Hunting Approach
Pipeline Building Using a Unique Drug Hunting Approach Product &Target Indication Indication Discovery IND Enabling Phase 1 Phase 2 Phase 3 Pegzilarginase Arginine Arginase 1 Deficiency AEB4104 Homocysteine/ Homocystine Homocystinuria AEB5100 Cysteine/Cystine Cystinuria Research Programs Undisclosed
Slide 5: Strong Momentum with Multiple Near-term Catalysts
Strong Momentum with Multiple Near-term Catalysts Recent Milestones Pegzilarginase: ARG1-D Breakthrough Therapy Designation granted by the FDA First patient dosed in the pivotal Phase 3 PEACE trial Statistically significant reductions in plasma arginine (p<0.001) with accompanying clinical improveme
Slide 6: Highly Experienced Leadership Team in Drug Discovery & Development
Highly Experienced Leadership Team in Drug Discovery & Development Anthony G. Quinn, MD PhD Chief Executive Officer Roche AstraZeneca, Lilly, Ipsen, Synageva, Pfizer, PWC James Wooldridge, MD Chief Medical Officer Scott Rowlinson, PhD Vice President of Research Charles N. York II, MBA Chief Financia
Slide 7: Arginase Deficiency
Arginase 1 Deficiency A serious progressive disease with early mortality and high unmet medical need due to an autosomal recessive disorder of arginine metabolism Pegzilarginase: Lead Program Aeglea Biotherapeutics 6
Slide 8: Pegzilarginase: An Innovative Approach to Treat Arginase Deficiency
Pegzilarginase: An Innovative Approach to Treat Arginase 1 Deficiency Indication Patient Population (Addressable Markets) Diagnosis (Blood Arginine Levels Unmet Medical Need Mechanism of Action Development Status Arginase 1 Deficiency (ARG1-D) Greater than 1,000 patients Greater than 200 patients id
Slide 9: Pegzilarginase Consistently, Substantially, and Sustainably Controlled Plasma Arginine
Pegzilarginase Consistently, Substantially, and Sustainably Controlled Plasma Arginine 101A and Open Label Extension (OLE) Arginine (UM) 700 600 500 400 300 200 100 0 389 171 127 116Pc0.1001 for CFB BL Part 1 Dose 1 Response Dose 8 Response Ole Mean **200µm 115 µm 40 µmPart 2 101A Marked and sustain
Slide 10: Subcutaneous Dosing Controls Plasma Arginine Similarly to IV
Subcutaneous Dosing Controls Plasma Arginine Similarly to IV Pegzilarginase IV & SC Comparison Arginine Conc (UM) 200 150 100 50 0 0 56 112 168 Time (hrs) Mean IV (n=6) mean SC (n=6) Providing potential advantages such as improved compliance and/or convenience 9 @ Aeglea BioTherapeutics I External I
Slide 11: Overall Clinical Response Rate of 79% After 20 Doses
Overall Clinical Response Rate of 79% After 20 Doses 79% (11 of 14) patients were defined as responders at dose 20 based on a ≥1 MCID improvement in at least one of the 6MWT, GMFM-D or GMFM-E assessments All 5 patients (100%) who reached dose 44 maintained their dose 20 overall clinical response sta
Slide 12: Marked Time Dependent Increase in Mobility Responders After 20 Doses
Marked Time Dependent Increase in Mobility Responders After 20 Doses Longer duration of dosing markedly increases the percentage of responders for all three selected mobility assessments: 6MWT, GMFM-D and GMFM-E 6MWT mean change after 20 doses was 32 meters across all patients and 66 meters in the 7
Slide 13: Clinically Impactful Improvements at Patient Level with Pegzilarginase
Clinically Impactful Improvements at Patient Level with Pegzilarginase Marked improvement in plasma arginine control Improvements in clinical outcome assessments align with observed impact on walk quality and interpersonal interactions Assessment Plasma arginine 6MWT GMFM-E ABAS GAC Normal Populatio
Slide 14: Safety
Safety Pegzilarginase was well tolerated Hypersensitivity and hyperammonemia were the most common treatment-related SAEs, and were expected and manageable More than 650 doses were administered to 16 patients (mean of 41 doses per patient) More than 200 injections were administered to 10 patients sub
Slide 15: ARG1-D: Key Highlights
ARG1-D: Key Highlights Pegzilarginase was highly effective in consistently, substantially and sustainably lowering elevated plasma arginine, a key driver of ARG1-D disease manifestations and progression Plasma arginine reductions were accompanied by improvements in clinical responders (79% or 11/14
Slide 16: PEACE Pivotal Phase 3: Trial Design
PEACE Pivotal Phase 3: Trial Design 24 weeks Pegzilarginase (N=20) 2:1 Randomization All study participants remain on current disease management for the duration of the trial Placebo (N=10) Open Lable extension Pegzilarginase Key eligibility criteria Plasma arginine greater than 250µM (mean) 2 years
Slide 17: Significant Momentum in Patient Identification
Significant Momentum in Patient Identification 200+ patients 170+ Patients 140+ Patients 50+ Patients 2017 September 2018 December 2018 September 2019 United States 80+ Patients Europe 100+ Patients Rest of World 20+ Patients 16 @ Aeglea Biotherapeutics I External Aeglea Biotherapeutics
Slide 18: PEACE: Summary and Next Steps
PEACE: Summary and Next Steps PEACE is a single, global pivotal trial PEACE is aligned with collaborative input from FDA and EMA Phase 1/2 data demonstrates clinical impact Patient finding momentum and PEACE trial underway Primary endpoint: arginine reduction Secondary endpoints: clinical outcomes,
Slide 19: Pipeline Drug Hunting in Human Enzyme Space
Pipeline Drug Hunting in Human Enzyme Space Aeglea Biotherapeutics 18
Slide 20: AEB4104: An Innovative Approach to Treat Homocystinuria
AEB4104: An Innovative Approach to Treat Homocystinuria Indication Patient Population Addressable Markets Unmet Medical Need Mechanism Of Action Development Status Cystathionine beta synthase (CBS) deficiency and other forms Greater than 5,000 patients Very high - no effective therapy for many patie
Slide 21: AEB4104: Therapeutic Approach to Improve Control of Total Plasma Homocysteine
AEB4104: Therapeutic Approach to Improve Control of Total Plasma Homocysteine AEB4104 candidate is an engineered CGL enzyme designed to change its native substrate specificity from cystathionine to both homocysteine and homocysteine Dietary amino Acids Methionine Hornocysteine Cystathionine Cysteine
Slide 22: AEB4104: Improves Survival & Corrects Disease Manifestations in Preclinical Model
AEB4104: Improves Survival & Corrects Disease Manifestations in a Preclinical Model of Homocystinuria Reverses Severe Liver Abnormalities (AEB4104 Candidate) Disease Resolution Dosing Begins Day 10 CBS /- AEB4104 25 mg/kg+ Betaine day 23 CBS-/- Disease reversal AEB4104 25mg /kg Day 60 CBS-/- Healthy
Slide 23: AEB4104: Subcutaneous Administration Chosen for Clinical Development
AEB4104: Subcutaneous Administration Chosen for Clinical Development Cyno PK Bioavailability (AEB4104 Candidate) AEB4104 Conc (Ug/ml)Time (day) IV 8mg/kg (n=3) SC 8mg/Kg Predose sc 8mg/kg (n=3) IV 8 mg/kg predose AEB4104 candidate has >80% bioavailability via subcutaneous route of administration 22
Slide 24: AEB5100: An Innovative Approach to Treat Cystinuria
AEB5100: An Innovative Approach to Treat Cystinuria Indication Patient Population (Addressable Markets ) Unmet Medical need Mechanism of Action Development Status Systinuria Greater Than 10,000 Patients Severe, recurrent flank/abdominal pain and hematuria from an early age Multiple hospitalizations
Slide 25: AEB5100: Novel Therapeutic Approach for Cystinuria – Enzymatic Reduction of Cystine
AEB5100: Novel Therapeutic Approach for Cystinuria – Enzymatic Reduction of Cystine Healthy Blood vessel kidney tubule low cystine functional transporter low cystine in urine healthy Cystinuria defective transporter high cystine = kidney stones high cystine in urine cystine precipitates stone format
Slide 26: AEB5100: Novel Human Enzyme Solution for Cystinuria
AEB5100: Novel Human Enzyme Solution for Cystinuria There are no naturally occurring human enzymes that efficiently degrade cystine Human Cystathionine-Gamma-Lyase (CGL) was engineered to change its native substrate specificity Engineering CGL to Create Novel Cystine Degrading Activity Single IP Dos
Slide 27: AEB5100: Effectively Reduces Stones in Cystinuria Mouse Model
AEB5100: Effectively Reduces Stones in Cystinuria Mouse Model Total Volume of Kidney Stones Number of Kidney Stones mm3 5 Week old untreated control 11 week old 6 weeks post treatment start 1.0 0.5 0.1 0.01 0.00 5 week old untreated control 11 week old 6 weeks post treatment start sic3a1-/- untreate
Slide 28: Cash and marketable securities at June 30, 2019: $107 million
Cash and marketable securities at June 30, 2019: $107 million1 (no debt) Shares outstanding at August 1, 2019: 28.9 million Financial Summary $ millions Three Months Ended 06/30/2019 Six months Ended 06/30/2019 Grant Revenue R&D Expense G&A Expense Net Loss $- &14.8 $3.8 $18.0 $- $29.2 $7.1 $35.2 Ex
Slide 29: Aeglea BioTherapeutics Appendix
Aeglea tm BioTherapeutics @ aeglea Biotherapeutics I External
Slide 30: Arginine Depletion in Cancer
Arginine Depletion in Cancer Extracellular arginine depletion has broad effects on tumor cells1,2,3 Increased autophagy Inhibition of cell proliferation Induction of apoptosis Metabolic pathway remodeling of tumors may increase sensitivity to arginine depletion Downregulation of ASS1 is common Mitoc
Slide 31: Pegzilarginase Oncology Development Program Safety Summary
Pegzilarginase Oncology Development Program Safety Summary All TRAEs Grade 3 or less No infusion reactions were reported following 276 infusions Three patients experienced treatment-related, serious Grade 3 AEs: 1) Asthenia and failure to thrive, 2) vomiting, and 3) dehydration Anti-drug antibody (A
Slide 32: Pegzilarginase Demonstrates Single Agent Clinical Activity In Phase 1
Pegzilarginase Demonstrates Single Agent Clinical Activity In Phase 1 Cutaneous Melanoma % Change in target Lesions Recist 1.1 Patients 10 80 60 40 20 0 -20 -30 -40 Uveal Melanoma % Change in target lesions 100 80 60 40 20 0 -20-30 -40 % Change In Target lesions 10 80 60 40 20 0 -20 -40 ASS1 Negativ
Slide 33: Arginine Depletion in Cancers Summary
Arginine Depletion in Cancers Summary 1 Single agent activity in heavily pre-treated Phase 1 melanoma patient population 2 Pegzilarginase safely and sustainably depletes plasma arginine 3 Anti-tumor activity appeared greater in tumors lacking ASS1 expression 32 @ Aeglea Biotherapeutics I External Ae
Slide 34: Arginase Deficiency (ARG1-D)
Arginase 1 Deficiency (ARG1-D) Progressive metabolic disease with significant morbidity and early mortality Typically presents in childhood with spasticity, neurocognitive impairment, seizures, growth delay and hyperammonemic episodes Deficiency of Arginase-1 leads to: Elevated plasma arginine and r
Slide 35: Designing Enzyme Therapeutics – Pegzilarginase
Designing Enzyme Therapeutics – Pegzilarginase pegzilarginase Substituted Metal Cofactor (Mn2+Replaced with Co2+) Catalytic activity serum stability 1000 800 600 400 200 0 40 30 20 10 0 kcat/km-1s-1 T1/2 (hr) Pegzilarginase pegylated native human arginase 1 pegzilarginase Pegylated native human argi
Slide 36: Pegzilarginase: Clinical Benefit Associated With Extra-Hepatic Enhancement of Arginase 1 Enzyme Activity
Pegzilarginase: Clinical Benefit Associated With Extra-Hepatic Enhancement of Arginase 1 Enzyme Activity Clinical Description 5 y.o. male Spastic quadriplegia Hyperreflexia Mental retardation Loss of speech Unable to sit or crawl Red Blood Cell exchange improved clinical presentationi 700 600 500 40
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