Spyre Therapeutics, Inc. · NASDAQ:SYRE
Spyre Therapeutics — Aeglea BioTherapeutics — Investor Presentation (September 2023)
56 slides from Spyre Therapeutics's investor presentation, Sep 8, 2023
Slide 1: Corporate Overview September 2023
CORPORATE OVERVIEW September 2023 Exhibit 99.1
Slide 2: Disclosures
Disclosures The information contained in this presentation has been prepared by Aeglea Biotherapeutics, Inc. and its affiliates, including Spyre Therapeutics, Inc. (“Spyre” or the “Company”) and contains information pertaining to the business and operations of the Company. The information contained
Slide 3: Aeglea-Spyre Transaction highlights
Aeglea-Spyre Transaction highlights Structure: The acquisition of Spyre was structured as a stock-for-stock transaction whereby all of Spyre’s outstanding equity interests were exchanged for a combination of shares of Aeglea common stock and a newly created non-voting Series A convertible preferred
Slide 4: Capitalization
Capitalization As of 6/20/2023* Shares of common stock outstanding 2.6 million Pre-funded warrants 1.2 million Merger consideration Shares of common 0.5 million Shares of preferred 0.4 million Preferred conversion ratio 1:40 Total pre-financing common equivalent 18.9 million Concurrent financing Sha
Slide 5: Spyre aims to transform the treatment of IBD
TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL a4b7 Same MOA as vedolizumab SPY001 TL1A Same MOA as PRA023 SPY002 IL-23 SPY003 Novel MOA SPY004 a4b7 + IL-23 SPY130 a4b7 + TL1A SPY120 TL1A + IL-23 SPY230 Spyre aims to transform the treatment of IBD Opportunity for best-in-class Long-acting antibodies
Slide 6: Inflammatory bowel disease is a growing $21B market
Sources: Global Data, Evaluate Pharma, UpToDate, SVB Leerink. Inflammatory bowel disease is a growing $21B market in which biologics are the preferred modality ~1.7M IBD patients diagnosed in the US. $29.1B Crohn's disease 2021 Global IBD Market $21.1B IBD represents a multi-billion dollar market op
Slide 7: Inflammatory bowel disease is a growing $21B market
Sources: Global Data, Evaluate Pharma, UpToDate, SVB Leerink. Inflammatory bowel disease is a growing $21B market in which biologics are the preferred modality ~1.7M IBD patients diagnosed in the US. $29.1B Crohn's disease 2021 Global IBD Market $21.1B IBD represents a multi-billion dollar market op
Slide 8: New approaches are needed to break the efficacy ceiling
Despite advances, new approaches are needed to break the efficacy ceiling and improve convenience of biologics 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 followin
Slide 9: Spyre's strategy to address unmet needs in IBD
Spyre’s strategy to address unmet needs in IBD 1 2 3 Best-in-class mAb engineering With half-life extension technology Rational therapeutic combinations Precision patient selection Three strategic pillars in an effort to create the preeminent IBD company
Slide 10: Spyre mAbs introduce significant improvements over 1st generation mAbs
Spyre mAbs introduce significant improvements over 1st generation mAbs Epitopes maintained Validated pharmacology Equivalent or better potency Potential for IP into 2040s Novel dosing profile Improved manufacturability Coverage of diverse back-up series High concentration SQ Ability to formulate at
Slide 11: Rapidly developing combination products
Spyre is rapidly developing combination products given clinical evidence of substantial efficacy enhancement 1 2 3 CLINICAL PRECEDENT JNJ VEGA Ph2a study Clinical remission at 12 weeks Anti-TNFα Anti-IL-23 Δ% Source: Feagan, B. G. et al. Lancet Gastroenterol. Hepatol. 8, 307–320 (2023) Strong single
Slide 12: Genetically-driven patient selection
Spyre leverages genetically-driven patient selection to match disease drivers with therapeutic targets 1 2 3 CLINICAL PRECEDENT TL1A studies UC clinical remission at 12 weeks Δ Δ PRA023 RVT-3101 TL1A a4b7 IL-23 Genetic companion diagnostic (CDx) leveraging large-scale human genomic datasets
Slide 13: Building a potentially best-in-class IBD pipeline
Spyre is building a potentially best-in-class IBD pipeline with next-generation mAbs and rational combinations STRATEGY TARGET PROGRAM1 DISCOVERY IND-ENABLING CLINICAL Best-in-class mAbs (Extended half-life) a4b7 Same MOA as vedolizumab SPY001 TL1A Same MOA as PRA023 SPY002 IL-23 SPY003 Novel MOA SP
Slide 14: Building a potentially best-in-class IBD pipeline
Spyre is building a potentially best-in-class IBD pipeline with next-generation mAbs and rational combinations STRATEGY TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL Best-in-class mAbs (Extended half-life) a4b7 Same MOA as vedolizumab SPY001 TL1A Same MOA as PRA023 SPY002 IL-23 SPY003 Novel MOA SPY
Slide 15: Vedolizumab is a mega-blockbuster product in IBD
Vedolizumab is a mega-blockbuster product in IBD Vedolizumab estimated $5.4B revenues WW in FY22.1 Projected to sell $7.5-9.0B at peak WW.1 1. Takeda JPM 2023 presentation. Note that Takeda’s FY22 is April 2022-March 2023. Sales forecast in figure: EvaluatePharma consensus “Biologic of choice for UC
Slide 16: Vedolizumab specifically binds a4b7 integrin
Vedolizumab specifically binds a4b7 integrin, selectively blocking gut lymphocyte trafficking. Leading maintenance efficacy data in UC replicated in two P3 studies; efficacy on par with upadacitinib 15mg dose; superior head-to-head vs adalimumab (Humira) in UC. Clean safety profile since approval in
Slide 17: SPY001 is designed to be a best-in-class anti-a4b7 mAb
SPY001 is designed to be a best-in-class anti-⍺4β7 mAb *Entyvio SC US BLA resubmitted April 2023 following CRL in 2019. Highly potent Proven epitope Selective No ⍺4β1 binding, no VCAM-1 adhesion blocking Favorable safety profile High maintenance efficacy Convenient SC dosing Q8W or Q12W+ Convenient
Slide 18: Spyre mAbs introduce significant improvements over 1st generation mAbs: SPY001
Spyre mAbs introduce significant improvements over 1st generation mAbs SPY001 Epitope maintained Validated pharmacology Equivalent potency Potential for IP into 2040s Diverse coverage of lead and backup series High concentration SC Ability to formulate at >150 mg/mL with low viscosity Citrate-free f
Slide 19: SPY001 is as potent and selective as vedolizumab
SPY001 is as potent and selective as vedolizumab in preclinical studies SPY001 binds the same ⍺4b7 epitope as vedolizumab. SPY001 is comparable to vedolizumab in potency… …and avoids unwanted interactions with a4b1. a4 Subunit b7 Subunit SPY001 Epitope Blocking MADCAM-1 Adhesion Blocking VCAM-1 Adhe
Slide 20: SPY001 binds to memory T-helper cells as well as vedolizumab
SPY001 binds to memory T-helper cells as well as vedolizumab 1. Soler, et. al. (2009) Vedolizumab EC50 (nM) SPY001 EC50 (nM) Donor 1 0.22 0.21 Donor 2 0.27 0.30 Donor 3 0.24 0.22 PBMCs from three human donors were isolated and stained with either vedolizumab or SPY001, as well as a basic immunopheno
Slide 21: SPY001 has a 17-day half-life in NHPs
SPY001 has exhibited a 17-day half-life in NHPs, nearly 2x the half-life of vedolizumab observed in multiple studies β-elimination half-life of SPY001 observed at ~17 days, 70% longer than observed for vedolizumab. Spyre vedolizumab data matches half-life observed in Takeda studies.1,2 NOTE: 1BLA 12
Slide 22: SPY001 NHP half-life suggests improvement over Entyvio
SPY001 NHP half-life and increased dose suggest potential for significant improvement over Entyvio Source: Rosario, M, et. al. (2017). 300 mg Q12W based on PK modeling SPY001 predicted human half-life and dosing interval, days NHP half-life, days ~35 43-56 Predicted half-life range YTE modification
Slide 23: SPY001 specifically formulated to maximize dosing
SPY001 is specifically formulated to maximize dosing without sacrificing patient comfort Note: Vedolizumab SC approved in EU. US BLA resubmitted April 2023 following CRL in 2019. Vedolizumab SC 108 mg 20 mM Citrate SPY001 SC 300 mg Citrate Free 26 injections per year Potential injection site pain Se
Slide 24: Vedolizumab appears underdosed in induction
1. Rosario, M., et. al. (2017). 2. Vedolizumab FDA Clinical Pharmacology Review. Figure sources: Multi-MOA benchmark data from adalimumab label (TNFα), ustekinumab label (IL-12/23), mirikizumab LUCENT-1 study (IL-23), PRA023 P2b (TL1A), and vedolizumab VARSITY study (⍺4b7). Vedolizumab exposure-resp
Slide 25: Low exposures of vedolizumab sufficient to maintain remission
Once induction is achieved, very low exposures of vedolizumab are sufficient to maintain remission Source: Feagan, et. al. (2013). Minimal difference in maintenance of clinical remission between vedolizumab IV Q4W (44.8%) or Q8W (41.8%). Ctrough ≥ 6 µg/mL is a conservative target to maintain long-te
Slide 26: SPY001 potentially best-in-class anti-a4b7 mAb
SPY001 is a potentially best-in-class anti-a4b7 mAb with near-term de-risking studies anticipated SPY001 Preferred target in large market Clinically validated pharmacology Designed for differentiation Promising early data PROGRAM SUMMARY UPCOMING CATALYSTS Vedolizumab is the preferred biologic in UC
Slide 27: Key value inflection in ~18 months
Key value inflection in ~18 months with Phase 1 PK data anticipated to validate SPY001 as “long-acting Vedo” Source: FactSet 30-d average market caps after event date. 1 Morphic Phase 2a single arm UC data; Prometheus RCT (UC) and single arm (CD) Phase 2.; Prometheus ultimately acquired for $10.8B a
Slide 28: SPY001 product profile vs Entyvio and MORF-057
A conservative SPY001 product profile was tested against Takeda’s Entyvio and Morphic’s MORF-057 Agent SPY001 Entyvio IV Entyvio SC MORF-057 MOA a4b7 monoclonal antibody a4b7 monoclonal antibody a4b7 monoclonal antibody a4b7 antagonist small molecule Indication Treatment of moderately to severely ac
Slide 29: A quarterly injectable would be the preferred profile
Assuming equivalent efficacy and safety, a quarterly injectable would be the preferred profile “Oral agents typically have an advantage except in this case … one shot every three months will have the advantage” U.S. KOL “Infrequent injections are more beneficial than orals, patients will forget to t
Slide 30: Building a potentially best-in-class IBD pipeline
Spyre is building a potentially best-in-class IBD pipeline with next-generation mAbs and rational combinations STRATEGY TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL Best-in-class mAbs (Extended half-life) a4b7 Same MOA as vedolizumab SPY001 TL1A Same MOA as PRA023 SPY002 IL-23 SPY003 Novel MOA SPY
Slide 31: TL1A has emerged as a promising target in UC and CD
TL1A has emerged as one of the most promising targets in both UC and CD TL1A is involved in chronic inflammation and fibrosis pathways and is genetically associated with IBD. Clinical results from first-generation anti-TL1A antibodies suggest potential for highest induction efficacy across target cl
Slide 32: SPY002 designed to be a best-in-class anti-TL1A mAb
SPY002 is designed to be a best-in-class anti-TL1A mAb PRA023 RVT-3101 SPY002 Complete TL1A blockade Monomers and trimers Highly potent Kd below 150 pM Infrequent SC dosing Q8W or Q12W+ Convenient formulation High concentration High remission rates Favorable safety profile Immunogenicity <20% ADA1 1
Slide 33: Spyre mAbs introduce significant improvements: SPY002
Spyre mAbs introduce significant improvements over the 1st generation mAbs PRA023 clinically validates pharmacology and therapeutic effect of MOA Novel into 2040s SPY002 exploits biology that has been validated by PRA023 and is designed to be best-in-class High concentration SC Ability to formulate
Slide 34: Evaluating trimeric and monomeric/trimeric TL1A blockade
Figure sources: Prometheus PRA023 P2 ARTEMIS-UC data release, December 7, 2022. Roivant RVT-3101 Release Deck, January 4, 2023. Spyre is evaluating both trimeric and monomeric/trimeric TL1A blockade for SPY002 RVT-3101 Monomers & trimers Trimers only UC induction clinical remission rates Pbo-adjuste
Slide 35: De novo TL1A lead clones are highly potent
De novo TL1A lead clones are highly potent and characteristically diverse Example Spyre clones observed to be more potent than leading competitors …with diverse profiles of monomer binding and/or DcR3 sparing Spyre has multiple lead clones that have demonstrated superior potency as compared to PRA02
Slide 36: SPY002 potentially best-in-class anti-TL1A mAb
SPY002 is a potentially best-in-class anti-TL1A mAb with near-term de-risking studies anticipated SPY002 Attractive target in a large market Clinically validated pharmacology Designed for differentiation Promising early data PROGRAM SUMMARY UPCOMING CATALYSTS Existing investigational products have d
Slide 37: TL1A: Potential I&I indication expansion
TL1A: Potential I&I indication expansion with dual anti-fibrotic and anti-inflammatory mechanism IBD SSc-ILD Expansion I&I indications
Slide 38: Building a potentially best-in-class IBD pipeline
Spyre is building a potentially best-in-class IBD pipeline with next-generation mAbs and rational combinations STRATEGY TARGET PROGRAM DISCOVERY IND-ENABLING CLINICAL Best-in-class mAbs (Extended half-life) a4b7 Same MOA as vedolizumab SPY001 TL1A Same MOA as PRA023 SPY002 IL-23 SPY003 Novel MOA SPY
Slide 39: Spyre portfolio addresses diverse pathophysiology of IBD
Spyre portfolio addresses the diverse pathophysiology of IBD Spyre is a pioneer in developing best-in-class mAbs against three top targets to enable superior combinations for IBD Blockade of α4β7 prevents circulating T cells from entering inflammatory gut tissues Neutralization of TL1A suppresses in
Slide 40: JNJ's VEGA study demonstrated power of combination therapy
JNJ's VEGA study demonstrated power of combination therapy despite relative weakness of components Golimumab (TNFα) Guselkumab (IL-23) Combination N= 72 71 71 Maintenance remission* 28% 31% 48% Safety Poor (class effect) Well tolerated Mixed Despite non-optimal components, JNJ combination (JNJ-78934
Slide 41: Spyre could create optimal combinations in IBD
Program UC Induction UC Maintenance Safety Dosing JNJ-4804 TNFα + IL-23 TNFα black-box safety warning Broad immunosuppression Q4W SPY120 a4b7 + TL1A Gut-selective α4β7 backbone + Encouraging TL1A safety profile Q8-12W SPY130 a4b7 + IL-23 Gut-selective α4β7 backbone + 2nd safest class in IBD Q8-12W S
Slide 42: Rapidly advance combination programs in parallel with monotherapies
We plan to rapidly advance combination programs in parallel with monotherapies in Phase 2 Preliminary; pending regulatory feedback Phase 1 Phase 2 Phase 3 SAD 1 SAD 2 SAD 3 MAD 1 MAD 2 UC SPY001 low dose SPY001 high dose SPY001 low dose + IL-23 SPY001 high dose + IL-23 PBO UC SPY001 (α4β7) SPY003 (I
Slide 43: Developing best-in-class combinations
Spyre is developing potentially best-in-class combinations to maximize efficacy for patients with IBD Established combination precedent Ideal building blocks Rapid proof-of concept PROGRAM SUMMARY UPCOMING CATALYSTS JNJ VEGA study demonstrated unprecedented efficacy despite sub-optimal combination c
Slide 44: Precision immunology
Precision immunology We aim to develop companion diagnostics to augment our therapeutic combinations and monotherapies We believe the future of IBD includes combination therapies and precision approaches to break the therapeutic ceiling IL-23 TL1A a4b7 TL1A a4b7 IL-23 IL-23 + a4b7 TL1A + a4b7 IBD pa
Slide 45: Genetic CDx can identify responders to TL1A
Prometheus and Roivant demonstrated POC that a genetic CDx can identify responders to TL1A RVT-3101 TL1A Δ UC clinical remission at 12 weeks Source: Company materials PRA023 TL1A Δ UC clinical remission at 12 weeks CDx partner CDx partner Spyre aims to develop genetic companion diagnostics across a
Slide 46: Spyre Therapeutics Corporate
A SPYRE THERAPEUTICS Corporate
Slide 47: Leadership and BOD
Leadership and BOD () Management team Board of Directors Cameron Turtle Scott Burrows —_ Heidy Kite Janes: jan Friedman Ritgeell J.Cox HunterC. Smith |vana Magovéevié-Liebisch Alison Lawton ‘man Janet Gunraner- Toate Andy Spencer —_ Justin LaFountaine Peter Harwin Tomas Kiselak Michael Henderson Boa
Slide 48: Cash and anticipated milestones
Cash and anticipated milestones SPY001 (SC, extended half-life a4b7) 2Q – IND/CTN YE – POC PK in HVs Full PK in HVs Phase 2 initiation SPY002 (SC, extended half-life TL1A) 1H – R&D Day 2H – IND/CTN PK in HVs SPY003 (SC, extended half-life IL-23) 1H – R&D Day IND/CTN SPY004 (SC, extended half-life no
Slide 49: I&I companies have maintained value in market downturns
I&I companies with compelling science have maintained value even in market downturns NOTE: “Today” market cap as of April 17, 2023 SOURCE: FactSet. Company S-1s. IPO Raise Market Cap ($M) Min IPO Today Max Stage at IPO Lead program status at fundraising Prometheus Biosciences $219 Lead anti-TL1A pro
Slide 50: Comparable acquisitions illustrate potential exits
Acquirer Target Deal economics (year) Status of lead asset We believe Spyre programs could be at comparable stage by 2025 2026 2027 $1.85B (2021) Proof-of-mechanism in P1a (HVs); potential for UC & autoimmune indications. SPY001 SPY003 SPY002 SPY004 $1.435B total (2021) $1.1B upfront $350M milestone
Slide 51: Thank you
Thank you
Slide 52: Spyre antibodies were developed by our partners at Paragon
Spyre antibodies were developed by our partners at Paragon was founded in 2021 by Fairmount. Professionals with deep expertise in antibody engineering and drug development from across the industry. by facilities and scientists at FairJourney Biologics and contract research organizations across the g
Slide 53: Diverse expertise in antibody discovery and engineering
Diverse expertise in antibody discovery and engineering enables potentially best-in-class therapeutics Established workflows and CRO relationships enable fast and reliable antibody discovery to generate novel drug candidates with best-in-class properties Cross-species immunization Hybridoma approach
Slide 54: Paragon engineers antibodies across five key properties
Paragon aims to engineer best-in-class antibodies by optimizing across five key properties Potency Formulatability More drug and less pain Pharmacokinetics Longer half-life for fewer shots 2 1 3 4 5 Targeting the best epitope and maximizing in vitro responses Manufacturability Plug-and-play manufact
Slide 55: Spyre mAbs employ proven half-life extension technology
Spyre mAbs employ proven half-life extension technology Spyre mAbs designed to be recycled back into circulation more readily Drug exists at much higher levels for longer duration of effect Fewer injections decrease patient burden and can improve compliance and penetration Blood Stream pH 5.5 pH 7 A
Slide 56: YTE technology prolongs half-life without increasing immunogenicity
YTE technology shown to significantly prolong half-life and without increasing immunogenicity Source: 1) Rocca, A, et al. Int J of Mol Sci, 2021; 2) Domachowske NEJM 2022 YTE mAbs have extended half-lives in NHPs and humans ADA rates are similar for YTE and non-YTE antibodies1,2 YTE Non-YTE Extent o
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