Spyre Therapeutics, Inc. · NASDAQ:SYRE

Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (April 2020)

40 slides from Spyre Therapeutics's investor presentation, Apr 27, 2020

  1. Slide 1: Aeglea Corporate Overview

    Aeglea Corporate Overview Exhibit 99.1

  2. 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

  3. Slide 3: Reimagining The Potential Of Human Enzyme Therapeutics For Patients With Rare Genetic Diseases

    Reimagining The Potential Of Human Enzyme Therapeutics For Patients With Rare Genetic Diseases Aeglea’s platform unlocks opportunities for innovative disease-modifying solutions in areas of high unmet medical need NASDAQ: AGLE Austin, Texas Cash, cash equivalents and marketable securities at March 3

  4. Slide 4: Looking Beyond the Conventional with Next Generation Human Enzyme Therapeutics

    Looking Beyond the Conventional with Next Generation Human Enzyme Therapeutics Discovery risk Development and regulatory risks Commercial risks Distinctive disease selection approach Validated metabolite targets Human enzyme scaffolds Translatable disease models Reduced toxicology risk Established m

  5. Slide 5: Pipeline: Rethinking the Potential of Human Enzyme Therapeutics

    Pipeline: Rethinking the Potential of Human Enzyme Therapeutics Product & Target Indication Preclinical Clinical Addressable Markets Discovery IND Enabling Phase 1 Phase 2 Phase 3 Pegzilarginase Arginine Arginase 1 Deficiency >2,500 patients ACN00177 Homocysteine Homocystinuria >5,000 patients AEB51

  6. 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 Leslie Sloan, PhD Chief Operating Officer Charles N. York II, MBA Chief Financial Officer Scott Rowlinson, PhD Vice President of Research Ravi M. Rao, MD PhD Chief Medical Officer Mich

  7. Slide 7: Arginase Deficiency

    Arginase 1 Deficiency A debilitating and progressive genetic disease with no effective therapeutic options, leaving patients with a considerable daily burden and early mortality Pegzilarginase: Lead Program

  8. Slide 8: Pegzilarginase: Arginase Deficiency Unmet Medical Need

    Pegzilarginase: Arginase 1 Deficiency Unmet Medical Need Very high - no effective therapy Early mortality and serious complications with continued disease progression Severe progressive spasticity Developmental delay and intellectual disability Seizures Episodic hyperammonemia Patient Population (Ad

  9. Slide 9: Pegzilarginase Consistently, Substantially, and Sustainably Controlled Plasma Arginine

    ** Current Treatment Guidance #s are medians 101A and Open Label Extension (OLE) All patients demonstrated a marked and sustained reduction in plasma arginine from baseline Statistically significant reductions in arginine from baseline to dose 1, dose 8 and OLE (p˂0.001) Median reduction of 274µM fr

  10. Slide 10: 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 100% of patients who were designated responders at dose 20 and have data available as of week 48 maintained their overall clinical response status th

  11. Slide 11: Clinically Impactful Improvements with Pegzilarginase

    Clinically Impactful Improvements with Pegzilarginase Patient 5: Baseline Patient 5: After 20 Doses Unable to cross legs and dependent on walking aid Able to cross legs and less dependent on walking aid Plasma arginine Baseline: 363 µM After 20 doses: 108.5 µM 108.5 µM = last 4 using PEACE criteria

  12. Slide 12: Safety: Pegzilarginase Was Well Tolerated

    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 su

  13. Slide 13: Pivotal Phase 3: PEACE Trial Design

    Pivotal Phase 3: PEACE Trial Design Dose adjustments in the double-blind treatment period can be made to optimize plasma arginine control for levels outside the range of 50-150µM. If needed, weekly doses can be increased to 0.15 and 0.2 mg/kg or reduced to 0.05mg/kg Key Endpoints Primary: plasma arg

  14. Slide 14: Arginase Deficiency Market Opportunity

    Arginase 1 Deficiency Market Opportunity Patient identification strategy informed by critical insights from our disease analysis and trial experience and includes: Conventional patient-finding initiatives (e.g., KOL dialogue) Innovative approaches (e.g., genetic testing collaborations) Patient ident

  15. Slide 15: Arginase Deficiency Market Opportunity

    Arginase 1 Deficiency Market Opportunity 1 Therrel BL et al 2017 2 Aeglea data on file Prevalence Estimate Methodologies Addressable Markets* Market Size Newborn screening- based: underestimation of birth incidence1 Limitations: Low arginine levels in newborns Geographic availability Lack of standar

  16. Slide 16: Arginase Deficiency Key Highlights and Next Steps

    Arginase 1 Deficiency Key Highlights and Next Steps Phase 1/2 & OLE data demonstrates clinical impact PEACE: A single, global pivotal trial designed with input from FDA and EMA Progress with PEACE trial and patient finding Sustained control of plasma arginine 79% (11/14) of patients at 20 doses were

  17. Slide 17: ACN00177

    ACN00177 Aeglea’s AEB4104 program targets homocystinuria due to cystathionine beta synthase (CBS) deficiency

  18. Slide 18: ACN00177 (AEB4104 Program): Homocystinuria Unmet Medical Need

    ACN00177 (AEB4104 Program): Homocystinuria Unmet Medical Need Very high - no effective therapy for many patients Early mortality and serious complications Lens dislocation, glaucoma and severe short-sightedness Skeletal abnormalities including osteoporosis Learning problems, developmental delay/inte

  19. Slide 19: Patient Needs Not Adequately Addressed by Current Disease Management

    Patient Needs Not Adequately Addressed by Current Disease Management Limited impact of approved therapies for homocystinuria Current standard of care: B6 (pyridoxine) for responsive patients Low-methionine diet + amino acid supplements Betaine Current disease management is inadequate: Limited effect

  20. Slide 20: Increased Mortality and Severe Complication Risk in Patients with Homocystinuria

    Increased Mortality and Severe Complication Risk in Patients with Homocystinuria 1Mudd et al, 1985 2Kluijtmans et al, Am. J. Hum. Genet. 65,59-67, 1999, CBS – Cystathionine β-synthase Natural History Study of Untreated CBS Deficient Patients Mortality B6-responsive = 231 All patients = 629 Complicat

  21. Slide 21: Increased Mortality and Severe Complication Risk in Patients with Homocystinuria

    Increased Mortality and Severe Complication Risk in Patients with Homocystinuria 1Mudd et al, 1985 2Kluijtmans et al, Am. J. Hum. Genet. 65,59-67, 1999, CBS – Cystathionine β-synthase Disease Complications (All patients are un-treated) Osteoporosis risk was ~50% in non-B6-responsive patients and ~25

  22. Slide 22: ACN00177: Therapeutic Approach to Improve Control of Total Plasma Homocysteine

    ACN00177: Therapeutic Approach to Improve Control of Total Plasma Homocysteine AEB4104 program candidate reduces plasma total homocysteine (tHcy) in preclinical model of homocystinuria Candidate from AEB4104 program is an engineered CGL enzyme designed to change its native substrate specificity from

  23. Slide 23: ACN00177: Improved Survival & Correction of Disease Manifestations in Preclinical Model

    ACN00177: Improved Survival & Correction of Disease Manifestations in a Preclinical Model of Homocystinuria HED = Human Equivalent Dose 100% Survival at 18 Weeks Following Subcutaneous Treatment CBS -/- (AEB4104 Program Candidate) AEB4104 SC 1.0 mg/kg HED AEB4104 SC 0.26 mg/kg HED AEB4104 SC 0.13 mg

  24. Slide 24: ACN00177 for Homocystinuria – Phase 1/2 Trial

    ACN00177 for Homocystinuria – Phase 1/2 Trial Key Inclusion Criteria Plasma tHcy >80 µm ≥12 yrs of age Endpoints Safety and tolerability PK Reduction in plasma total homocysteine (tHcy) levels Anticipate enrolling 16-20 pts Weekly dosing for 4 weeks Cohort 2 Cohort 3 Cohort 4 Part 1 (IV) Part 2 (SC)

  25. Slide 25: AEB5100 Program Cystinuria

    AEB5100 Program Cystinuria “gaeqlea

  26. Slide 26: AEB5100 Program: Cystinuria Unmet Medical Need

    AEB5100 Program: Cystinuria Unmet Medical Need Very high - no effective therapy for many patients Serious complications and high treatment burden Severe, recurrent flank/abdominal pain and hematuria from an early age Multiple hospitalizations and invasive procedures including surgical interventions

  27. Slide 27: Patient Needs Not Adequately Addressed by Current Disease Management

    Patient Needs Not Adequately Addressed by Current Disease Management Pearle, Goldfarb et al. 2019 Limited impact of approved therapies for Cystinuria Kidney obstructed with cystine stones Untreated cystine stone Cystine stone after alkali and/or thiol treatment (Image courtesy of Stuart Wolf, UT Aus

  28. Slide 28: Novel Therapeutic Approach for Cystinuria – Enzymatic Reduction of Cystine

    Novel Therapeutic Approach for Cystinuria – Enzymatic Reduction of Cystine Biyani and Cartledge EAU-EBU Update Series 4 (2006) 175-183 Leslie and Nazzal Renal Calculi (Cystinuria, Cystine Stones) (2018) Healthy Low cystine in urine Healthy Functional Transporter kidney tubule blood vessel = low cyst

  29. Slide 29: AEB5100 Program: Novel Human Enzyme Solution for Cystinuria

    There are no naturally occurring human enzymes that efficiently degrade cystine AEB5100 Program: Novel Human Enzyme Solution for Cystinuria Cramer SL et al, 2017 Nature Medicine 23:120-7 Creating Novel Cystine Degrading Activity1 ¥ total cysteine (µM) normalized to creatinine (mM) * p<0.005 ** p<0.0

  30. Slide 30: AEB5100 Program: Prevention of Kidney Stone Formation in Cystinuria Mouse Model

    AEB5100 Program: Prevention of Kidney Stone Formation in Cystinuria Mouse Model Agnello, et al American Society of Nephrology #TH-P0815 Volume of Kidney Stones Slc3a1 mice received restricted fluid intake Urine Cystine 0 1 2 3 4 -1 (Weeks) Reduced Fluid Intake (65% of water) Normal Fluid Intake (age

  31. Slide 31: Leveraging Aeglea's Next Generation Human Enzyme Platform

    Leveraging Aeglea’s Next Generation Human Enzyme Platform Therapeutic Approach Pegylated enhanced human enzyme Enzymatic control of high levels of a metabolite considered important in disease pathogenesis Unmet Medical Need Very high - no effective therapy Early mortality and serious complications w

  32. Slide 32: Strong Momentum with Near-Term Catalysts

    Strong Momentum with Near-Term Catalysts Pegzilarginase: ARG1-D Statistically significant arginine reduction at 20-doses vs baseline (p<0.001) Phase 1/2 & OLE (20-dose) efficacy data: 79% clinical responder rate First patient dosed in pivotal Phase 3 PEACE trial Breakthrough Therapy Designation (BTD

  33. Slide 33: A Disruptive Platform Producing Next-Generation Human Enzyme Solutions

    Homocystinuria Metabolism Nephrology Cystinuria Pegzilarginase Pivotal Phase 3 ACN00177 AEB5100 Arginase 1 Deficiency A Disruptive Platform Producing Next-Generation Human Enzyme Solutions Lead assets in three areas of high unmet medical need Looking beyond the conventional, redefining the potential

  34. Slide 34: Financial Summary

    Financial Summary Includes $1.5M of restricted cash $ Millions Three Months Ended 12/31/2019 Twelve Months Ended 12/31/2019 R&D Expense $17.6 $64.6 G&A Expense $4.3 $15.7 Net Loss $21.5 $78.3 Cash, cash equivalents and marketable securities at March 31, 2020: $50.5 million1 (no debt) Shares outstand

  35. Slide 35: = aeglea”

    = aeglea” BIOTHERAPEUTICS ©Aeglea BioTherapeutics, Inc. | EXTERNAL

  36. Slide 36: Overall Clinical Responder Rate of 79% After 20 Doses

    Overall Clinical Responder Rate of 79% After 20 Doses MCID for 6MWT = 9%; MCID for GMFM Part D is 2.4, 3.3, and 1.5 for GMFCS Levels I, II and III, respectively; MCID for GMFM Part E is 4.0, 2.8, and 1.8 for GMFCS Levels I, II and III, respectively. Maximum values for GMFM-D and GMFM-E are 39 and 72

  37. Slide 37: 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

  38. Slide 38: Designing Enzyme Therapeutics – Pegzilarginase

    Designing Enzyme Therapeutics – Pegzilarginase Improved Catalytic Activity & Serum Stability Reduced Circulating Arginine levels Pegzilarginase Substituted Metal Cofactor (Mn2+ replaced with Co2+ ) Serum Stability 37 ± 3 4.8 ± 0.8 Pegzilarginase PEGylated native human arginase 1 T 1/2 (hr) 40 30 20

  39. Slide 39: Pegzilarginase: Clinical Benefit Associated With Extra-Hepatic Enhancement of Arginase 1 Activity

    Pegzilarginase: Clinical Benefit Associated With Extra-Hepatic Enhancement of Arginase 1 Enzyme Activity Adapted from Sakiyama et al (1984) “A successful trial of enzyme replacement therapy in a case of Argininemia” J Exp Med. Red blood cell exchange improved clinical presentation Improved clinical

  40. Slide 40: Increasing dosing duration markedly increases the percentage of responders

    Increasing dosing duration markedly increases the percentage of responders for all three selected mobility assessments: 6MWT, GMFM-D and GMFM-E After 20 doses 6MWT: responder (n=7) mean change distance walked 66 meters GMFM-D: responder (n= 5) mean MCID 1.84x, range 1.21x to 3.33x GMFM-E: responder

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