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and research and development programs; expectations regarding the use of proceeds and the time periods over which the Company's capital resources will be sufficient to fund its anticipated operations; the market and potential opportunities for
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reliance on forward- looking statements. Industry Information This presentation also contains or references certain industry data that is based upon information from independent industry publications, market research, and surveys and other publicly
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no representation or warranty as to the origin, validity, accuracy, completeness, currency or reliability of the information in this presentation. 2
Targeting new heights in the treatment of IBD THREE-PILLAR STRATEGY
PARALLEL LEAD PROGRAMS AGAINST HIGH VALUE TARGETS OPPORTUNITY FOR BEST-IN-CLASS TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL LONG-ACTING ANTIBODIES SUBCUTANEOUS (SC) Q8-12W DOSING Phase 1 interim data 4 7 SPY001 expected YE24 Phase 1
interim data TL1A SPY002 expected 1H25 IL-23 SPY003 RATIONAL THERAPEUTIC COMBINATIONS Novel MOA SPY004 4 7 + IL-23 SPY130 4 7 + TL1A SPY120 PRECISION IMMUNOLOGY TL1A + IL-23 SPY230
Potential best-in-class lead programs SPY001 ( 4 7) SPY002
(TL1A) COMBINATIONS IDENTICAL EPITOPE TARGETING DUAL MONOMER AND TRIMER ONLY KNOWN PORTFOLIO WITH AS VEDOLIZUMAB BINDER 4 7, TL1A, AND IL-23 COMPARABLE POTENCY AND PICOMOLAR POTENCY AGAINST
POTENTIAL TO ADDRESS SELECTIVITY AS VEDOLIZUMAB MONOMERS AND TRIMERS ORTHOGONAL BIOLOGY SC EXTENDED HALF-LIFE mAb TO SC EXTENDED HALF-LIFE mAb TO TARGETING UNIFIED SC Q8-12W ENABLE Q8-12W REGIMEN ENABLE Q8-12W REGIMEN DOSING
INTERIM HV PK DATA INTERIM HV PK DATA INITIATION EXPECTED EXPECTED YE 2024 EXPECTED 1H 2025 AFTER PH1 DATA 4 DESIGN ATTRIBUTES
Despite advances, new approaches are needed to break the efficacy
ceiling and improve convenience of biologics UNMET NEED 80 ~1.7 million individuals are currently diagnosed with 1 IBD in the U.S. SPYRE TARGET There remain substantial unmet needs in IBD 60 management, including: 40 Inadequate response or loss of 2
SOC TODAY response to existing therapies vedolizumab mirikizumab Side effects and safety concerns vedolizumab ustekinumab 20 associated with long-term medication use golimumab infliximab adalimumab Adherence to frequent and/or inconvenient dosing
regimens 0 0 2 4 6 8 10 12 14 MAINTENANCE DOSING FREQUENCY (WEEKS) 1 2 Source: Crohn's and Colitis Foundation. Summary data for select agents that randomize patients post response to induction; data from labels, company reports. Vedolizumab
approved in US as Q8W IV - Q2W SC approval pending following CRL in 2019. TL1A maintenance data not available. Orals not shown (pbo-adj maintenance remission rates): Jaks - tofacitinib (27%), upadacitinib (30% 15mg, 40% 30mg); S1Ps: ozanimod
(19%); etrasimod (25% - P3 treat-through design). 5 UC MAINTENANCE REMISSION RATES (%)
Our strategy is built on three validated approaches to address unmet
needs in IBD BEST-IN-CLASS ANTIBODY RATIONAL THERAPEUTIC PRECISION IMMUNOLOGY ENGINEERING COMBINATIONS APPROACHES GENETIC AND BIOMARKER SELECTION HALF-LIFE EXTENSION TECHNOLOGIES COMBINATION TARGETING TO ENHANCE TO IDENTIFY MOST LIKELY 1 2 TO
IMPROVE CONVENIENCE REMISSION RATES 3 RESPONDERS 1 2 Sources: Several half-life extended antibodies are in clinical development, with at least two commercially approved (Evusheld, Beyfortus), Rosario, M, et. al. (2017); JNJ VEGA Phase 2 study
demonstrated approximately additive efficacy with a TNF and IL-23 combination (~47% clinical remission at week 12) versus monotherapies (25% and 24% remission rates, respectively, Feagan, B. G. et al. Lancet 3 Gastroenterol. Hepatol. 8,
307-320 (2023); Prometheus Biosciences demonstrated a ~13% increase in clinical remission rates in CDx+ patients versus all-comers, Prometheus corporate materials 6
Spyre is building a potentially best-in-class IBD pipeline with
next-generation mAbs and rational combinations 1 STRATEGY TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL Phase 1 interim data Potentially 4 7 SPY001 expected YE24 best-in-class mAbs Phase 1 interim data TL1A SPY002 expected 1H25 IL-23
SPY003 Novel MOA SPY004 Rational 4 7 + IL-23 SPY130 combinations 4 7 + TL1A SPY120 TL1A + IL-23 SPY230 1 Spyre exercised its option to license worldwide rights from Paragon Therapeutics, Inc. for SPY001. Spyre continues to hold
an option to license similar rights from Paragon for all other programs. SPY003 license will be restricted to IBD, all other program licenses will be indication agnostic. 7
SPY001 LONG-ACTING 4 7 ANTIBODY
SPY001 is designed to be a long-acting anti- 4 7 IDENTICAL
EPITOPE TARGET AS VEDOLIZUMAB COMPARABLE POTENCY AND SELECTIVITY AS VEDOLIZUMAB SUB-CUTANEOUS, EXTENDED HALF-LIFE mAb PREDICTED TO ENABLE Q8-12W DOSING 9
SPY001 potency & selectivity matches vedolizumab 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 adhesion bind
the same 4 Subunit epitope ( 4 1) 7 Subunit POTENT & SELECTIVE BINDING TO 4 7 1 Antibody 4 7 4 1 E 7 2 2 SPY001 K <1 nM NB NB D 2 2 Vedolizumab K <1 nM NB NB D 1 Dissociation
constant (K ) measured by surface plasmon resonance (SPR) D 2 NB = no binding by a particular antibody to a test molecule Source: Data on file. 10
SPY001 has exhibited ~2x the half-life of vedolizumab in NHPs
DEMONSTRATED EXTENDED HALF-LIFE IN Tg276 MICE DEMONSTRATED EXTENDED HALF-LIFE IN NHPs SPY001 t : ~10 Days SPY001 t : ~17 Days 1/2 1/2 Vedo t : ~3 Days Vedo t : ~10 Days 1/2 1/2 Source: Data on file. 11
SPY001 Phase 1 clinical trial design SINGLE-ASCENDING DOSE
MULTIPLE-ASCENDING DOSE SAD 4 IV MAD 2 SC SAD 3 SC SAD 2 SC MAD 1 SC SAD 1 SC Expected interim YE2024 readout to include 2-3 SAD cohorts and is sufficient to answer key objectives with PK modeling Single-ascending dose cohorts Multiple-ascending
dose cohorts Healthy volunteers Healthy volunteers N=8/cohort (3:1 randomization) N=8/cohort (3:1 randomization) Two doses 12
We aim to demonstrate the following for SPY001 in the expected interim
Phase 1 readout HALF-LIFE ENABLES Q8-12W SC MAINTENANCE DOSING BASED ON PK MODELING 1 POTENTIAL TO ADDRESS VEDO'S SLOW ONSET OF ACTION WITH HIGHER INDUCTION EXPOSURES 2 ESTABLISH SPY-001 HAS FAVORABLE SAFETY PROFILE AND IS WELL-TOLERATED 3
MINIMAL TO NO IMPACT ON ADA RATES VS VEDOLIZUMAB 4 13
Expected Phase 1 interim PK data informs dose and schedule modeling for
target maintenance profile SPY001 HUMAN HALF-LIFE PREDICTIONS MAINTENANCE PK SIMULATIONS Q12W SPY001 Dosing Simulation based on 50d half-life 1 SPY001 SC Q12W VEDO IV Q8W Half-life (days) Q8W based on PK Q12W based on PK modeling modeling 43-56 days
Humans ~35 ~40 1 Predicted range 17 NHPs SPY001 C trough exceeds vedo by ~1.5x 6 ug/mL Humans 25 C associated trough with maximal 2 efficacy NHPs 10 1 2 Source: Human YTE mAb half-life is on average 3.1x of NHP half-life; Rosario, M, et. al. (2017);
Feagan, et. al. (2013) 14 VEDO SPY001
A half-life of 43-56 days in a 300mg SC format is expected to offer a
superior product profile for patients MAINTENANCE DOSING PROFILE SPY001 SC 300 MG 4-6 POTENTIAL FOR SEASONAL DOSING CITRATE FREE INJECTIONS PER YEAR VEDOLIZUMAB SC 108 MG 26 20 MM CITRATE INJECTIONS PER YEAR 15
Expected interim PK data will also inform our ability to test induction
exposure-response relationship in Phase 2 UPSIDE: GREATER REMISSION VIA HIGHER EXPOSURE INDUCTION PK SIMULATIONS SPY001 INDUCTION SIMULATION BASED ON 50-DAY HALF-LIFE GEMINI I: WEEK 6 CLINICAL REMISSION RATES IN UC (%) 2 SPY001: ALL modeled patients
above SPY001 SC vedo Q4 trough concentration VEDO IV (per label) Q4 37% 35.7 Q3 22% 25.0-35.7 Q2 13% 17.1-25.0 Q1 7% 17.1 Vedo Quartile 4: 36 g/mL 17% W6 PBO 6% +20% Higher anti- 4 7 mAb exposure may Weeks lead to more
rapid remission 1 Source: Vedolizumab exposure-response data from Rosario, M., et. al. (2017); Vedolizumab FDA Clinical Pharmacology Review 16 1 Vedolizumab trough concentration quartiles ( g/ml) Concentration ( g/mL)
SPY001 is designed for fully SC induction dosing with upside efficacy
potential INDUCTION DOSING PROFILE PATIENT-ADMINISTERED SC SPY001 INDUCTION UPSIDE POTENTIAL FOR ENHANCED EFFICACY DOSING W0 W2 W6 REQUIRES PHYSICIAN ADMINISTRATION / OFFICE VISIT IV VEDOLIZUMAB INDUCTION POTENTIALLY UNDER-DOSED DOSING W0 W2 W6
SPY001 is designed to match vedolizumab's favorable safety
profile and low rate of ADAs 1 2,3 VEDO IS WELL TOLERATED WITH LOW IMMUNOGENICITY ADA RATES ARE SIMILAR FOR YTE AND WT ANTIBODIES 3 4 Vedolizumab Placebo 100 YTE (Half-life extension) 0.85 0.70 WT Infection rates per patient-year per patient-year 80
0.07 0.06 Serious infection rates per patient-year per patient-year 60 52% 45% Adverse reaction rates (N=1434) (N=297) 40 0.4% 0.3% 25.0% Malignancy rates (N=1434) (N=297) 20.0% 20 4% 3% Infusion reactions 3.6% (N=1434) (N=297) 0.4% 0 Nirsevimab
Palivizumab Motavizumab-YTE Motavizumab 6% (MEDI-8897; YTE) (non-YTE) N = 16 N = 16 Immunogenicity rates N/A (N=1434) N = 483 N = 251 1 2 3 Source: Entyvio prescribing information; Rocca, A, et al. Int J of Mol Sci, 2021; Domachowske NEJM 2022
SPY001 summary PK MODELLING SUPPORTS COMPARABLE IN VITRO DEVELOPING
PATIENT Q8-12W SC DOSING; UPSIDE PERFORMANCE TO SELECTION APPROACHES TO POTENTIAL FOR GREATER VEDOLIZUMAB IDENTIFY RESPONDERS INDUCTION EFFICACY INTERIM PHASE 1 PK DATA EXPECTED YE2024 19
SPY002 POTENTIAL BEST-IN-CLASS TL1A ANTIBODY
SPY002 is designed to achieve an optimal anti-TL1A product profile DUAL
MONOMER AND TRIMER BINDING PICOMOLAR POTENCY AGAINST MONOMERS & TRIMERS FULLY SC, EXTENDED HALF-LIFE mAb PREDICTED TO ENABLE Q8-12W DOSING 21
Extensive discovery campaign pursued to identify an uncompromising TL1A
antibody Heavily resourced campaign employing multiple strategies and formats enabled discovery of desirable TL1A clones 1000+ CLONES Format 3 Format 4 Format 1 Format 2 MONOMER AND TRIMER BINDER Set A Set G Strategy 1 Set B Set H Strategy 2
PICOMOLAR POTENCY Set C Set E Strategy 3 EXTENDED HALF-LIFE Set D Set F Set I Strategy 4 POTENTIAL BEST-IN-CLASS TL1A 22
SPY002 clones are unique in binding both monomers and trimers with
picomolar potency 1 1 SUPERIOR MONOMER AND TRIMER BINDING SUPERIOR TF-1 APOPTOSIS INHIBITION RVT-3101 NO MONOMER BINDING TEV-48574 TEV-48574 MK-7240 RVT-3101 SELECT SPYRE CLONES MK-7240 SELECT SPYRE CLONES Greater trimer binding (M) 1 Source:
Nonclinical data on file. Compared to TEV-48574, RVT-3101, MK-7240 23 Greater monomer binding (M)
SPY002 is a potential best-in-class TL1A mAb SPY002 MK-7240 RVT-3101
TEV-48574 Complete TL1A blockade Monomer and trimer Picomolar trimer potency Half-life extension Q8-12W dosing Source: Company materials 24
SPY002 is potentially the most advanced unencumbered TL1A in
development April 16, 2023 Oct 3, 2023 Announcement dates: Oct 23, 2023 $10.8B 50-50 $7.1B acquisition licensing deal acquisition Global rights $0.5B upfront +$1B in milestones +$150M near-term milestone North America, Japan, Asia rights U.S. and
Japan rights Source: Company press releases 25
SPY002 summary ONLY KNOWN EXTENDED DEVELOPING PATIENT LEAD CLONES ARE
MONOMER AND HALF-LIFE TL1A ANTIBODY IN SELECTION APPROACHES TO TRIMER BINDERS WITH POTENCY DEVELOPMENT IDENTIFY RESPONDERS DESIGNED TO BE SUPERIOR TO SELECT ANTIBODIES INTERIM PHASE 1 PK DATA EXPECTED 1H2025 26
THERAPEUTIC COMBINATIONS
Spyre is unique in its portfolio approach evaluating multiple