Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Investor Presentation (January 2025)
58 slides from Spyre Therapeutics's investor presentation, Jan 13, 2025
Slide 1: Corporate overview January 2025
Exhibit 99.2 Corporate overview January 2025
Slide 2: Disclosures
Disclosures The information contained in this presentation has been prepared by Spyre Therapeutics, Inc. and its affiliates (“Spyre” or the “Company”) and contains information pertaining to the business and operations of the Company. The information contained in this presentation: (a) is provided as
Slide 3: Engineering for new heights in the treatment of IBD & beyond
Engineering for new heights in the treatment of IBD & beyond Our strategy Our pipeline 1 POTENTIAL SC Q3M-Q6M DOSING* INDICATION TARGET PROGRAM PRECLIN. PHASE 1 PHASE 2 PHASE 3 α4β7 SPY001 2Q25: SPY002 Ph1 data 2H25: SPY003 Ph1 data Next-generation TL1A SPY002 Mid-2025: Ph2 initiation monotherapies
Slide 4: Multiple opportunities for value creation with next-gen monotherapies and combinations
Multiple opportunities for value creation with next-gen monotherapies and paradigm-changing combinations Next-generation monotherapies Paradigm-changing IBD combinations Monoclonal antibody candidates engineered Fixed-dose-combinations designed to enable for optimized potency, selectivity, and PK su
Slide 5: Next-generation monotherapies
Next-generation monotherapies
Slide 6: Next-generation antibodies engineered to match or exceed potency of first-generation molecules
Our next-generation antibodies are engineered to match or exceed the potency of first-generation molecules … SPY001 (α4β7) in vitro potency SPY002 (TL1A) in vitro potency SPY003 (IL-23) in vitro potency SPY001 SPY002 SPY003 Risankizumab Vedolizumab Tulisokibart 60 100 50 100 80 40 60 30 40 50 20 20
Slide 7: YTE backbone significantly extends half-life
… and share a YTE backbone that significantly extends half-life … SPY001 (α4β7) Human PK SPY002 (TL1A) NHP PK SPY003 (IL-23) NHP PK SPY001 t = >90 days SPY002 t = ~24 days SPY003 t = ~30 days 1/2 1/2 1/2 Risankizumab t = ~9 days Vedolizumab t = ~25 days Tulisokibart t = ~12 days 1/2 1/2 1/2 1000 100
Slide 8: Projected unified and less frequent dosing across portfolio
… supporting projected unified and less frequent dosing across our portfolio SPY001 (α4β7) Human PK Simulation SPY002 (TL1A) Human PK Simulation SPY003 (IL-23) Human PK Simulation SPY002 SPY001 SPY003 Vedolizumab Tulisokibart Risankizumab Potential unified Q3M-Q6M SC maintenance dosing Versus Q2W-Q8
Slide 9: Phase 1 data from all molecules expected by 2H 2025
Phase 1 data from all molecules are expected by 2H 2025 2024 2025 SPY001 (α4β7) ü Interim data – Nov2024 Phase 1 üFPI – June 2024 SPY002 (TL1A) Interim data – 2Q 2025 Phase 1 ü FPI – Q4 2024 SPY003 (IL-23) Interim data – 2H 2025 Phase 1 FPI – Q1 2025 Anticipated milestones as of January 13, 2025 sub
Slide 10: Paradigm-changing combinations
Paradigm-changing combinations
Slide 11: MOAs rationally chosen based on attractive risk-benefit profiles
Our MOAs were rationally chosen based on attractive risk-benefit profiles Induction clinical remission rates (pbo-adjusted) by MOA 100 1 1 2 2030 IBD SALES : 2030 IBD SALES : Acquired for : Ulcerative colitis Crohn’s disease ~$8B ~$7B 80 ~$12B Stronger efficacy in Stronger efficacy in Encouraging ef
Slide 12: Spyre MOAs address diverse pathophysiology of IBD
Spyre MOAs address the diverse pathophysiology of IBD by targeting distinct pathways Blockade of α4β7 prevents circulating immune cells Neutralization of TL1A suppresses inflammation and Neutralization of IL-23 inhibits cascade of from entering inflamed gut tissues reduces fibrosis by inhibiting fib
Slide 13: JNJ's VEGA study demonstrated power of combination therapy in IBD
JNJ’s VEGA study demonstrated the power of combination therapy in IBD VEGA combination study (N=71/arm) – Ulcerative colitis ~Additive absolute W12 MMS clinical remission rates Δ+22% 47% 22% 25% 24% 25% Anti-TNF Anti-IL23 Combination (Golimumab) (Guselkumab) BLACK BOX WARNING PROBABLE BLACK BOX Sour
Slide 14: Spyre combinations are rational alternatives to combos with clinical precedent
Spyre combinations are rational alternatives to combos with clinical precedent Clinical trial Precedent combination Spyre combinations & rationale 1 Spyre component exchange EXPLORER Crohn’s – Endoscopic remission % • Exchange TNF for another TNF 35% superfamily targeting agent 30% 27% • TL1A effica
Slide 15: Potential best-in-indication Q3M & Q6M dosing profile for IBD
Spyre monotherapies and combinations have potential best-in-indication Q3M & Q6M dosing profile for IBD 1 Expected Annual Maintenance Dosing Category Benchmark Annual injections SPY001 2 - 4x SC Q3M-Q6M SPY002 2 - 4x SC Q3M-Q6M SPY003 2 - 4x SC Q3M-Q6M Portfolio SPY120/130/230 2 - 4x SC Q3M-Q6M α4β7
Slide 16: Portfolio enables profiles with potential superior efficacy and convenience
Spyre’s portfolio uniquely enables product profiles with potential superior efficacy and convenience ILLUSTRATIVE 80 60 Potential to break the efficacy ceiling with 40 SPY120 SPY130 SPY230 combinations JNJ’4804 TNF+IL-23 combo Potential for best-in- 1 (VEGA ) class efficacy with SPY001 SPY002 SPY003
Slide 17: Planned platform trial enables multiple placebo-controlled readouts
Spyre’s planned platform trial enables multiple placebo- controlled readouts of monotherapies and combinations Pending regulatory feedback Design elements Illustrative schematic Design SPY001 (α4β7) • Master protocol platform trial SPY002 (TL1A) • Double blind, placebo-controlled SPY003 (IL-23) Popu
Slide 18: Comparison to other trials highlights advantage of designing portfolio from ground up
Comparison to other trials highlights potential advantage of designing a portfolio from the ground up w/ unified dosing 1 rd 2 Planned platform trial Example 3 party platform trial Induction (12W) Maintenance (through 24W) Trial arm Induction (12W) Maintenance (through 26W) Trial arm Placebo Q3M Q4W
Slide 19: Platform design attractive with 6 ways to win at up to 40% lower cost
Platform design is attractive to patients and investigators with 6 ways to win at up to 40% lower cost 6 High enthusiasm 6 ways to win Operational efficiency With 3 combination arms and Including 3 optimized monotherapies & Up to 40% lower cost vs. low placebo randomization rate 3 paradigm-changing
Slide 20: Optimized coformulations preferred approach for inhibiting multiple targets
Optimized coformulations are the preferred approach for inhibiting multiple targets in IBD Allows for dose optimization Coformulations allow opportunity for adjustment of antibody ratios to achieve of each component desired concentration of each mAb Coformulations retain extension of monoclonal half
Slide 21: Survey showed strong preference for long-acting, safe combinations
>100 surveyed gastros showed a strong preference for long- acting, safe combinations with efficacy +10pp over monos Relative preference share of hypothetical IBD market entrants ~7x Hypothetical Q3M Spyre combo ~3x Hypothetical monthly TNF Hypothetical combo TNF-like agent Efficacy ~25% ~35% ~35% MM
Slide 22: TL1A indication expansion
TL1A indication expansion
Slide 23: TL1A has scientific rationale across multiple diseases
TL1A has scientific rationale across multiple diseases 1 TL1A exacerbates inflammation TL1A has been implicated in a wide range of human diseases and fibrosis based on genetic, proteomic, and/or preclinical data Not exhaustive • Ulcerative colitis (UC) Gastroenterology • Crohn’s disease (CD) • Rheum
Slide 24: RA is a foothold to the >$30B rheumatology market
Rheumatoid arthritis (RA) is a foothold to the >$30B rheumatology market WW Sales by indication (2028E) No novel MOAs have been introduced in RA since U.S. Dollars 2012 despite the potential for multi-$B peak sales MOA entry year and global peak sales IBD 1998 2005 2006 2011 2012 2025 Rheumatology >
Slide 25: Significant unmet need remains in RA
Significant unmet need remains in RA despite multiple approved MOAs 60 Support for SPY002 TPP TNF CD80/86 CD20 IL-6 50 § Novel MOAs are still needed to treat RA, particularly for refractory patients who cycle through all MOAs 40 “ … We need more new medicines with new mechanisms of action, as we kno
Slide 26: Published studies support anti-TL1A as potential RA treatment
Multiple published studies support anti-TL1A as a potential treatment option in RA TL1A is elevated in RA patients relative to healthy TL1A administration exacerbates arthritis in murine models 1, 2, 3 2,4 controls & increases with disease severity and administration of anti-TL1A reduces arthritis T
Slide 27: Spyre anti-TL1A meets or exceeds etanercept efficacy in rat RA models
Spyre anti-TL1A antibody meets or exceeds the efficacy of etanercept (anti-TNF) in rat models of RA Superior efficacy vs. anti-TNF in semi-preventative model Comparable efficacy vs. anti-TNF in therapeutic model Healthy Healthy 8 8 Vehicle Vehicle Isotype control Isotype control 6 6 Etanercept Etane
Slide 28: RA Ph2 initiation mid-2025 with topline data expected 2H26
Spyre anticipates RA Ph2 initiation in mid-2025 with topline data expected 2H26 2024 2025 2026 SPY002-072 (TL1A) Phase 1 (Healthy volunteers) FPI 4Q24 SPY002-091 (TL1A) Phase 1 (Healthy volunteers) FPI Interim data & molecule selection 4Q24 2Q25 SPY002 (TL1A) FPI Topline results Phase 2 (RA patients
Slide 29: Corporate Team and cash runway
Corporate Team and cash runway
Slide 30: Leadership
Leadership Scott Burrows Brian Connolly Melissa Cooper Paul Fehlner Joshua Friedman Janet Gunzner-Toste Chief Financial Officer Chief Technical Officer SVP, People SVP, Chief Intellectual SVP, Clinical Development SVP, Operations Property Counsel MiRa Huyghe Heidy King-Jones Justin LaFountaine Deann
Slide 31: Board of Directors
Board of Directors Peter Harwin Michael Henderson Tomas Kiselak Jeffrey Albers Mark McKenna Sandra Milligan Laurie Stelzer Cameron Turtle 31
Slide 32: Catalyst rich 2025 planned
Catalyst rich 2025 planned with expected Ph1 readouts on TL1A and IL-23 programs and multiple Ph2 initiations 2025 2026 q UC Platform Ph2 Initiationq UC Ph2 data SPY001 (α4β7) q UC Ph2 data q Ph1 data (2Q)q RA Ph2 Initiation SPY002 (TL1A) q RA Ph2 data q Ph1 Initiation (1Q)q Ph1 dataq UC Ph2 data SP
Slide 33: Cash and shares outstanding
Cash and shares outstanding 1 $603M preliminary cash as of December 31, 2024 Number of shares (M) Expected runway into 2H 2028 Common stock • Shares outstanding 60.3 • Series A preferred stock 13.8 Common stock equivalents • Series B preferred stock 0.7 Common stock and common • Total outstanding 74
Slide 34: Thank you
Thank you
Slide 35: SPY001 Appendix: Next-generation anti-α4β7 antibody
SPY001 Appendix Next-generation anti-α4β7 antibody
Slide 36: SPY001 engineered with next-generation antibody properties
SPY001 is engineered to have next-generation antibody properties Identical epitope target as vedolizumab with comparable potency and selectivity in vitro >90-day human half-life supports both Q3M and Q6M SC maintenance dosing regimens IND-enabling tox studies completed with NOAEL at the highest dose
Slide 37: SPY001 potency & selectivity match vedolizumab in vitro
SPY001 potency & selectivity match vedolizumab in vitro SPY001 & vedolizumab epitope Potent and selective inhibition of cellular adhesion SPY001 and SPY001 and vedolizumab potently inhibit No inhibition of unwanted VCAM-1- vedolizumab MAdCAM-1-mediated (gut) cellular adhesion mediated (CNS) cellular
Slide 38: SPY001 Phase 1 trial ongoing, interim data
SPY001 Phase 1 trial is ongoing - interim data includes up to 4 months of follow up (10/30/24 data cutoff) Multiple ascending dose follow up Trial design elements Single ascending dose follow up Design ~4 months ~2 months 300 mg SC 300 mg SC • Double-blind, pbo-controlled, first-in-human trial • Nes
Slide 39: SPY001 well tolerated with favorable safety profile
Interim data show SPY001 was well tolerated with a favorable safety profile SAD MAD 100 mg 300 mg 600 mg 1000 mg 1000 mg Pooled 300 mg 600 mg Pooled N (%) N= 8 8 8 8 8 40 8 8 16 At least one 1 (13%) 3 (38%) 2 (25%) 3 (38%) 0 9 (23%) 2 (25%) 3 (38%) 5 (31%) TEAE At least one 0 0 0 0 0 0 0 0 0 TESAE A
Slide 40: Interim data demonstrated >90-day half-life
Interim data demonstrated >90-day half-life, which exceeded 1 expectations (~4-fold vs. published vedo half-life ) SPY001 simulated concentration-time profile Human half-life SPY001 300mg SC Vedolizumab 300mg SC Median +/- IQR SPY001 >90 days ~4-fold VEDO ~25 days 1 Note: Human PK data in this prese
Slide 41: SPY001 exhibits dose-proportional pharmacokinetics
SPY001 exhibits dose-proportional pharmacokinetics SAD mean PK profiles MAD mean PK profiles t > 100 days 1/2 t = 91 days 1/2 1 Dose proportionality observed between 300 - 1000 mg Initial MAD PK consistent with SAD PK 1 Note: Cohorts with sufficient follow up for dose proportionality assessment. 41
Slide 42: Modeled Phase 2 induction exposures exceeded vedolizumab
Modeled Phase 2 induction exposures exceeded those of vedolizumab with all patients anticipated in quartile 4 Potential upside: Greater remission w/ higher exposure Phase 2 Induction human PK simulations Targeting all patients with W6 1 Vedolizumab Week 14 Deep Remission Rates in UC (%) concentratio
Slide 43: Population PK modeling supports Q3M and Q6M maintenance dosing
Population PK modeling for SPY001 supports potential for both Q3M and Q6M maintenance dosing regimens Maintenance human PK simulations Maintenance Induction 2-4x SC maintenance injections per year SPY001 Q3M SC SPY001 Q6M SC Vedolizumab Q2W SC Data on file, simulations represent median +/- interquar
Slide 44: SPY001 saturated α4β7 receptors through ~12 weeks
SPY001 saturated α4β7 receptors through ~12-weeks of follow-up after a single dose % MAdCAM-1 Bound on CD4+ Memory T cells Notes: Data shown are Mean +/- SD for each cohort at each visit; pooled placebo. (n): Placebo (2-6), SPY001 300 mg SC (5-6), SPY001 600 mg SC (6), SPY001 1000 mg SC (6). Data ha
Slide 45: SPY001 Phase 1 interim results summary
SPY001 Phase 1 interim results summary (10/30/24 cutoff) SPY001 was well tolerated Favorable safety profile across all dose levels Half-life of >90 days, far Potential for as little as twice-yearly maintenance dosing in a single exceeding expectations SC injection compared to 26 yearly SC injections
Slide 46: SPY002 Appendix: Next-generation anti-TL1A antibody
SPY002 Appendix Next-generation anti-TL1A antibody
Slide 47: SPY002 candidates engineered to achieve optimal profile
SPY002 candidates are engineered to achieve an optimal profile Advanced two candidates into Ph1 with novel epitopes that optimize potency and binding profiles in vitro Half-life extension through validated Fc modification to potentially enable Q3M-Q6M SC dosing IND-enabling tox studies completed wit
Slide 48: Each SPY002 candidate targets a distinct epitope
Each SPY002 development candidate targets a distinct epitope and exhibits unique binding properties Single TL1A subunit epitope Superior or comparable potency in multiple assays Each SPY002 candidate targets a distinct Superior or comparable inhibition of TF-1 Superior or comparable inhibition of IF
Slide 49: SPY002 candidates exhibit increased half-life in NHP
SPY002 candidates exhibit increased half-life in NHP compared to first-generation anti-TL1As SPY002 DC1: >2-3x Increased Half-life in NHPs SPY002 DC2: >2-3x Increased Half-life in NHPs SPY002 t : ~24 days SPY002 t : ~24 days 1/2 1/2 Tulisokibart t : ~12 days Tulisokibart t : ~12 days 1/2 1/2 RO77901
Slide 50: SPY002 Phase 1 initiated in 4Q 2024
SPY002 Phase 1 initiated in 4Q 2024 Expected Ph1 study design Phase 1 milestones ü q IND clearance ü q Phase 1 initiation in 4Q 2024 SAD 5 q Interim FIH data expected 2Q 2025 SAD 4 SAD 3 q Safety and tolerability SAD 2 q Pharmacokinetics SAD 1 q Pharmacodynamics (sTL1A) q ADA Single-ascending and mu
Slide 51: Phase 1 interim PK to confirm potential of Q3M-Q6M dosing
Phase 1 interim PK to confirm the potential of Q3M-Q6M maintenance dosing, as predicted by NHP data SPY002 human half-life targets Human PK simulations Q3M based on Q6M based on Half-life (days) PK modeling PK modeling SPY002 Tulisokibart 1 Humans ~45 ~65 24 NHPs 2 Humans 19 Q2-4W SC 3 NHPs 12 1 2
Slide 52: Tulisokibart and RO7790121 dose responses support improved maintenance efficacy
Tulisokibart and RO7790121 dose responses support opportunity for improved efficacy in maintenance Clinical remission (mMayo) Endoscopic improvement W50 or W56 250 mg 48% 48% Q4W TULISOKIBART 100 mg 32% 36% ARTEMIS-UC Q4W Greater maintenance efficacy with higher doses 250 mg 56% 68% TULISOKIBART Q4W
Slide 53: SPY003 Appendix: Next-generation anti-IL-23 antibody
SPY003 Appendix Next-generation anti-IL-23 antibody
Slide 54: SPY003 engineered with next-generation antibody properties
SPY003 is engineered to have next-generation antibody properties Similar epitope target as risankizumab with comparable potency and selectivity in vitro Half-life extension through validated Fc modification to potentially enable Q3M-Q6M SC maintenance dosing IND-enabling tox studies completed with N
Slide 55: SPY003 targets similar epitope as risankizumab with comparable potency
SPY003 targets a similar epitope as risankizumab with comparable potency in vitro Similar epitope to risankizumab Comparable potency in multiple assays SPY003 and risankizumab bind the SPY003 and risankizumab potently SPY003 and risankizumab potently same p19 subunit of IL-23 inhibit pSTAT signaling
Slide 56: SPY003 exhibits >3x the half-life of risankizumab in NHPs
SPY003 exhibits >3x the half-life of risankizumab in NHPs NHP PK profiles of SPY003 and risankizumab Half-life 1000 ~30 days SPY003 100 ~3-fold vs. risankizumab 10 ~9 days Risankizumab 1 0 14 28 42 56 70 84 98 Days Source: Data on file. Group size was n = 4 in the NHP studies with n = 4 and n = 3 at
Slide 57: SPY003 Phase 1 initiation expected in 1Q 2025
SPY003 Phase 1 initiation expected in 1Q 2025 Expected Ph1 study design Phase 1 milestones q Phase 1 initiation expected 1Q 2025 q Interim FIH data expected 2H 2025 SAD 5 q Safety and tolerability SAD 4 SAD 3 q Pharmacokinetics SAD 2 q ADA SAD 1 Single-ascending and multiple-ascending dose cohorts •
Slide 58: Phase 1 interim PK to confirm potential of Q3M-Q6M dosing
Phase 1 interim PK to confirm the potential of Q3M-Q6M maintenance dosing, as predicted by NHP data SPY003 human half-life targets Human PK simulations SPY003 Q3M based on Q6M based on Half-life (days) Risankizumab PK modeling PK modeling 1 Humans ~45 ~60 30 NHPs 2 Humans 28 Q8W OBI 3 NHPs 9 1 2 3
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