SPY003 / Spyre Therap - LARVOL DELTA

ANTI-Α4Β7 INTEGRIN, ANTI-TL1A, AND ANTI-IL-23 ARE EFFICACIOUS IN TNBS-INDUCED COLITIS USING HUMANIZED MICE, AND COMBINATIONS FURTHER IMPROVE EFFICACY (UEGW 2026) - P2 | "Anti-α4β7, anti-TL1A, and anti-IL-23 showed comparable efficacy in a mouse model of colitis using transgenic mice expressing the human orthologs of each targeted protein. Combination of anti-α4β7 and anti-TL1A resulted in directional improvement across most disease readouts relative to individual antibody treatments, suggesting that therapies targeting multiple disease-relevant pathways may improve efficacy in IBD. Overall, these results support and provide biologic rationale for the ongoing Phase 2 SKYLINE-UC clinical trial (NCT07012395) of SPY001, SPY002, SPY003, and their combinations."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CXCL5 • IL23A • IL6

EFFICACY AND SAFETY OF HALF-LIFE EXTENDED ANTIBODIES SPY001, SPY002, AND SPY003 FOR INDUCTION TREATMENT OF MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS (UEGW 2026) - "SPY001 and SPY002 demonstrated statistically and clinically significant changes from baseline in RHI score (with p<0.0001), along with robust rates of clinical remission, endoscopic improvement, and changes from baseline in mMS. Both were well tolerated. SPY001, SPY002, and SPY003 are being tested as monotherapies at two dosing levels and as pairwise combinations in Part B with a placebo-controlled factorial design."

Clinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

SKYLINE-UC: The First Platform Study in Ulcerative Colitis Assessing Efficacy and Safety of Three Long-Acting Antibodies Administered as Single Agents and in Combinations (ACG 2026) - "The Phase 2 study SKYLINE-UC aims to assess the efficacy and safety of SPY001, SPY002, and SPY003 as single agents and in pairwise combinations (SPY120, SPY130, SPY230) in ulcerative colitis through a patient-centric study design that shares placebo and monotherapy data to minimize placebo exposure and overall enrollment. Evaluating three combinations in a platform study is estimated to reduce sample size by 45% compared to investigating the same hypotheses in separate studies. Part A data are anticipated to be available in 2026; Part B data are anticipated to be available in 2027. SKYLINE-UC is an innovative platform study that will evaluate 6 interventions, including 3 single agents and 3 pairwise combinations."

Clinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

Spyre Announces Potential Best-in-Class SPY003 (anti-IL-23) Part A Induction Results from SKYLINE Trial, Completing Proof-of-Concept for All Three Components of its IBD Combinations (GlobeNewswire) - "Initial 12-week findings from SKYLINE Part A demonstrated that SPY003 met all key objectives. The study population consisted of 41% advanced therapy-exposed participants with a mean disease duration of 7.1 years, a mean baseline RHI score of 17.2 ± 8.3 (SD), a mean modified Mayo Score of 6.9 ± 1.2 (SD), and 59% of whom had a baseline endoscopy score of 3. SPY003 achieved the primary endpoint, demonstrating a statistically significant 10.0-point reduction in RHI score (p<0.0001), robust rates of clinical remission and endoscopic improvement, and a meaningful change in mMS. The 10.0-point reduction in RHI observed in participants receiving SPY003 is in line with the 9.2- and 10.7-point reductions observed in participants receiving SPY001 and SPY002, respectively, and all are among the largest improvements observed in UC trials to date."

P2 data • Ulcerative Colitis

SKYLINE Phase 2 Platform Trial in IBD (GlobeNewswire) - "Part A: Open-label assessment of the safety and preliminary efficacy of a single dose level of each investigational monotherapy. Enrollment for Part A has completed...topline data expected for SPY003 in September 2026....Part B: Randomized and placebo-controlled assessment of the safety and efficacy of monotherapies and combinations, designed to provide dose-ranging data on monotherapies, proof-of-concept, and contribution of components for combinations, with induction data expected in 2027."

P2 data • Ulcerative Colitis

SKYLINE-UC: A Study of Long-acting Antibodies Alone and in Combinations for Moderate to Severe Ulcerative Colitis (clinicaltrials.gov) - P2 | N=645 | Recruiting | Sponsor: Spyre Therapeutics, Inc. | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial primary completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

SKYLINE-UC: The First Platform Study in Ulcerative Colitis Assessing Efficacy and Safety of Three Long-Acting Antibodies Administered as Single Agents and in Combinations (AOCC-IMKASID 2026) - "The Phase 2 study SKYLINE-UC aims to assess the efficacy and safety of SPY001, SPY002, and SPY003 as single agents and in pairwise combinations (SPY120, SPY130, SPY230) in ulcerative colitis through a patient-centric study design that shares placebo and monotherapy data to minimize placebo exposure and overall enrollment. SKYLINE-UC is an innovative platform study that will evaluate 6 interventions, including 3 single agents and 3 pairwise combinations. The study is designed to provide proof-of-concept for each investigational monotherapy and combination compared to placebo, dose-ranging data on each mono-therapy, and preliminary assessment of potential additive and/or synergistic benefits of combinations. Keywords: Ulcerative Colitis, Platform Trial, Combination Therapy, Half-life Extension, Proof Of Concept"

Clinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

Interim Phase 1 Results for SPY003, a Novel Half-Life Extended Monoclonal Antibody Targeting IL-23, Suggest Potential for Q3M or Q6M Maintenance Dosing for Inflammatory Bowel Disease (AOCC-IMKASID 2026) - "SPY003 is an investigational fully humanized IgG1 monoclonal antibody that specifically binds IL-23(p19) at an epitope similar to risankizumab, incorporating a YTE Fc modification to increase FcRn binding affinity and extend half-life. SPY003 was well tolerated in SAD, MD, and Eb Phase 1 cohorts. Interim PK confirmed half-life extension, supporting potential quarterly or twice annual maintenance dosing. PD analysis following single doses of SPY003 confirmed target-dependent PD effects."

Clinical • First-in-human • P1 data • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

SKYLINE-LTE: Long-term Safety and Efficacy of Multiple Long-acting Antibodies Alone and in Combinations for IBD (clinicaltrials.gov) - P2 | N=645 | Enrolling by invitation | Sponsor: Spyre Therapeutics, Inc.

New P2 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

SPY123-202: Long-term Safety and Efficacy of Multiple Long-acting Antibodies Alone and in Combination for Inflammatory Bowel Disease (clinicaltrialsregister.eu) - P1/2 | N=102 | Not yet recruiting | Sponsor: Spyre Therapeutics Inc.

New P1/2 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Development Pipeline Overview and Update (The Manila Times) - "SKYLINE Phase 2 Platform Trial in IBD...topline data expected for SPY002 and SPY003 in mid-2026 and the third quarter of 2026, respectively....Part B: Randomized and placebo-controlled assessment of the safety and efficacy of monotherapies and combinations, designed to provide dose-ranging data on monotherapies, proof-of-concept, and contribution of components for combinations, with induction data expected in 2027....SKYLINE is currently enrolling participants into Part B of the trial."

P2 data • Trial status • Ulcerative Colitis

SKYLINE-UC: A Study of Long-acting Antibodies Alone and in Combinations for Moderate to Severe Ulcerative Colitis (clinicaltrials.gov) - P2 | N=645 | Recruiting | Sponsor: Spyre Therapeutics, Inc.

Trial initiation date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Additionally, Spyre announced today that recruitment for Part A of SKYLINE is now closed and enrollment is open for Part B… (GlobeNewswire) - "...which includes three monotherapy cohorts (SPY001, SPY002, and SPY003) and three combination cohorts (SPY120, SPY130, and SPY230) into which participants may be randomized versus a shared placebo. Proof-of-concept induction data for the remaining cohorts of Part A are now expected mid-2026 (SPY002) and Q3 2026 (SPY003). Part B induction data (all cohorts) remain on track for 2027."

P2 data • Trial status • Ulcerative Colitis

SPY003-207-101: A Study of SPY003-207 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=59 | Active, not recruiting | Sponsor: Spyre Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human

SKYLINE-UC: The First Platform Study in Ulcerative Colitis Assessing Efficacy and Safety of Three Long-Acting Antibodies Administered as Single Agents and in Combinations (ECCO-IBD 2026) - "The aim of this study is to assess the efficacy & safety of SPY001, SPY002, and SPY003 as single agents & in pairwise combinations (SPY120 [SPY001 & SPY002], SPY130 [SPY001 & SPY003], SPY230 [SPY002 & SPY003]) in UC through a patient-centric study design that enables sharing of data from placebo and monotherapy treatment arms, thereby minimizing the number of participants assigned to placebo and enrolled overall. Conclusion SKYLINE-UC is an innovative platform study that will evaluate 6 interventions, including 3 single agents and 3 pairwise combinations. The study is designed to provide proof of concept for each investigational monotherapy and combination compared to placebo, dose-ranging data on each monotherapy, and a preliminary assessment of the additive and/or synergistic benefit of combinations."

Clinical • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

Interim Phase 1 Results for SPY003, a Novel Half-life Extended Monoclonal Antibody Targeting IL-23, Suggest a Potential for Q3M or Q6M Maintenance Dosing for Inflammatory Bowel Disease (ECCO-IBD 2026) - "SPY003 is an investigational fully humanized IgG1 monoclonal antibody that specifically binds to IL-23(p19) at an epitope similar to risankizumab. PD analysis following single doses of SPY003 confirmed target-dependent PD effects. These results support advancement of SPY003 into clinical trials in IBD as a monotherapy and as a component of combination treatments."

Clinical • First-in-human • P1 data • Crohn's disease • Immunology • Inflammation • Inflammatory Bowel Disease • IL23A

Rational Combinations – the Company plans to investigate combinations of our proprietary antibodies in nonclinical studies and clinical trials in order to evaluate whether combinations can potentially lead to best-in-class efficacy in IBD, with less frequent dosing. (GlobeNewswire) - "The Company expects to include each of its rational combinations in Part B of the SKYLINE trial."

New trial • Preclinical • Trial status • Inflammatory Bowel Disease • Ulcerative Colitis

The Company has two ongoing Phase 2 clinical trials with proof-of-concept data readouts beginning in 2026 (GlobeNewswire) - "Enrollment on track in Phase 2 SKYWAY basket trial evaluating TL1A inhibition in rheumatoid arthritis ('RA'), psoriatic arthritis ('PsA'), and axial spondyloarthritis ('axSpA'), with fourth quarter readouts expected in each sub-study...SKYLINE Phase 2 Platform Trial in IBD...Part A: Open-label assessment of the safety and preliminary efficacy of a single dose level of each investigational monotherapy, with induction data expected beginning in the second quarter of 2026; Part B: Randomized and placebo-controlled assessment of the safety and efficacy of investigational monotherapies (two dose levels) and combinations, with induction data expected in 2027...SKYLINE is currently enrolling subjects into Part A of the trial, with Part B expected to begin enrolling after all arms in Part A complete enrollment."

P2 data • Trial status • Ankylosing Spondylitis • Psoriatic Arthritis • Rheumatoid Arthritis • Ulcerative Colitis

Spyre Therapeutics Announces Presentations at the 21st ECCO Congress Supporting Differentiated Profile of SPY003 and Novel Animal Studies Demonstrating Superiority of Combination Approach (GlobeNewswire) - "...'Follow-up data out to 20 weeks from our Phase 1 study of SPY003...showed SPY003 was well tolerated, had a differentiated PK profile supporting quarterly or twice-yearly dosing, and demonstrated targeted biological activity via a reduction in downstream cytokines. In addition, we are presenting details of our innovative SKYLINE platform trial evaluating long-acting antibodies as monotherapies and in rational combinations, as well as preclinical data demonstrating that dual targeting of TL1A and IL-23 can provide superior efficacy compared to either agent alone'."

P1 data • Preclinical • Inflammatory Bowel Disease

Spyre Therapeutics Poised for Transformational 2026 With Six Expected Proof-of-Concept Readouts Beginning in Q2 (GlobeNewswire) - "SKYLINE (NCT07012395) is a Phase 2 platform trial of SPY001 (anti-α4β7), SPY002 (anti-TL1A), SPY003 (anti-IL-23), and pairwise combinations thereof (six investigational long-acting agents in total) in patients with moderately to severely active ulcerative colitis...Enrollment in Part A has exceeded expectations with SPY001 enrollment completed ahead of schedule. Readouts for Part A are now expected to begin in Q2....SKYWAY (NCT07148414) is a Phase 2 basket trial of SPY072 (anti-TL1A) in patients with moderate to severely active RA, PsA, or axSpA. Enrollment is on track, and all indications are expected to readout in 4Q 2026."

Enrollment status • P2 data • Ankylosing Spondylitis • Psoriatic Arthritis • Rheumatoid Arthritis • Ulcerative Colitis

Spyre Therapeutics Announces Positive Interim Phase 1 Results for SPY003, Its Novel, Half-Life Extended anti-IL-23 Antibody (GlobeNewswire) - "SPY003 was well tolerated at all dose levels, with a favorable safety profile consistent with the anti-IL-23 class. There were two Grade 2 or above treatment-emergent adverse events (TEAEs), both deemed not treatment-related, and no serious adverse events were observed in the study....SPY003 expected to advance to the ongoing Part A of the SKYLINE Ph2 platform trial. SKYLINE and SKYWAY trials are expected to provide 6 proof-of-concept readouts in 2026."

P1 data • P2 data • Trial status • Inflammatory Bowel Disease • Psoriatic Arthritis • Rheumatoid Arthritis • Spondylarthritis

COMBINED INHIBITION OF INTEGRIN Β7 AND TL1A, INTEGRIN Β7 AND IL-23, OR TL1A AND IL-23 ARE SUPERIOR TO THEIR CONSTITUENT MONOTHERAPIES IN MOUSE TNBS-INDUCED COLITIS (UEGW 2025) - "Towards this end, Spyre Therapeutics is developing half-life extended antibody drug candidates that can be administered in combination, inhibiting the clinically validated IBD targets α4β7 integrin (SPY001), TL1A (SPY002), and IL-23 (SPY003). Combination therapy with anti-β7 + anti-TL1A, anti-β7 + anti-IL-23 or anti-TL1A + anti-IL-23 resulted in efficacy superior to their constituent monotherapies in the murine TNBS model of colitis. These data support and provide biologic rationale for the advancement of antibody combinations into human clinical trials for inflammatory bowel disease."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • IL23A

SKYLINE-UC Phase 2 Platform Trial (GlobeNewswire) - "In May 2025, the Company initiated a Phase 2 induction and maintenance platform trial of SPY001, SPY002, SPY003, as well as pairwise combinations thereof (six active investigational agents in total) in patients with moderately to severely active UC. The trial consists of two parts: Part A: Open-label assessment of the safety and preliminary efficacy of a single dose level of each investigational monotherapy, with induction data expected in 2026; Part B: Randomized and placebo-controlled assessment of the safety and efficacy of investigational monotherapies (two dose levels) and combinations, with induction data expected in 2027....SKYLINE-UC is currently enrolling subjects into the SPY001 arm of Part A."

P2 data • Trial status • Ulcerative Colitis

SKYLINE-UC: A Study of Long-acting Antibodies Alone and in Combinations for Moderate to Severe Ulcerative Colitis (clinicaltrials.gov) - P2 | N=645 | Recruiting | Sponsor: Spyre Therapeutics, Inc. | N=35 ➔ 645 | Trial completion date: Jun 2027 ➔ Mar 2028

Enrollment change • Trial completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Spyre Therapeutics Announces Positive Interim Phase 1 Results for Two Next-Generation TL1A Antibody Programs, and Provides Clinical Development Updates Expected to Deliver 9 Phase 2 Readouts (PRNewswire) - "Building on these encouraging Phase 1 results, Spyre is advancing SPY002 into the SKYLINE-UC platform trial – initiated in May 2025 – for ulcerative colitis. SKYLINE-UC is expected to include SPY001 (anti-α4β7), SPY002 (anti-TL1A), SPY003 (anti-IL-23), and combinations thereof under an efficient single master protocol...Part A: Induction data are expected in 2026; Part B: Induction data are expected in 2027."

P2 data • Trial status • Ulcerative Colitis