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
Phase 2 SKYLINE Part A results establish SPY003 proof-of-concept and support advancing Spyre’s three-antibody IBD combination strategy toward 2027 data.
Rhea-AI Summary
Spyre Therapeutics (SYRE) reported positive 12‑week Part A induction results from the Phase 2 SKYLINE trial of SPY003, its extended half-life anti‑IL‑23 antibody for moderately‑to‑severely active ulcerative colitis.
SPY003 met the primary endpoint with a statistically significant 10.0‑point reduction in Robart’s Histopathology Index (RHI) at Week 12 (p<0.0001), alongside secondary outcomes of 20% clinical remission and 30% endoscopic improvement and a 3.5‑point mean decline in modified Mayo Score. The safety profile was consistent with the IL‑23 class: 43% of patients experienced treatment‑emergent AEs, 11% had severe AEs, 2% had drug‑related AEs, and there were no drug‑related serious AEs, discontinuations, or deaths.
With prior positive data for SPY001 (anti‑α4β7) and SPY002 (anti‑TL1A), Spyre now has clinical proof‑of‑concept for all three inflammatory bowel disease components, supporting enrollment of SKYLINE Part B combination cohorts, with topline induction data expected in 2027.
Positive
- Primary endpoint met with 10.0‑point RHI reduction at Week 12 (p<0.0001)
- Secondary endpoints: 20% clinical remission and 30% endoscopic improvement at Week 12
- Symptom burden improved with a 3.5‑point mean reduction in modified Mayo Score
- Safety: 0 drug‑related serious AEs, 0 discontinuations, 0 deaths in 44 patients through Week 12
- Portfolio de-risking: Proof-of-concept achieved for SPY001, SPY002 and SPY003 monotherapies
- Pipeline visibility: SKYLINE Part B enrolling with topline induction data expected in 2027
Negative
- Adverse events in 43% of SPY003 patients, with 11% experiencing severe AEs
- Three serious adverse events reported in SPY003-treated patients, though all deemed not drug-related
- Clinical timelines for key SKYLINE Part B combination readout extend to 2027
News Explained
The release reports that SPY003’s single-dose, open-label Part A produced proof-of-concept, while Part B is still enrolling as a randomized, placebo-controlled test of two monotherapy dose levels and three high-dose combinations, moving the program into combination testing rather than a completed combination readout.
Key Figures
- RHI reduction
- 10.0 points
- Week 12 primary endpoint for SPY003
- P-value
- p<0.0001
- Week 12 RHI reduction
- Clinical remission rate
- 20%
- Week 12 SPY003 result
- Endoscopic improvement rate
- 30%
- Week 12 SPY003 result
- Modified Mayo Score change
- -3.5
- Week 12 SPY003 result
- Study population
- 44 subjects
- SPY003 through Week 12
- Subjects with any adverse event
- 19 (43%)
- SPY003 induction treatment period
- Serious adverse events
- 3 (7%)
- SPY003 through Week 12; none drug-related
Historical Context
-
Reported positive SPY001 and SPY002 Part A induction data with significant histologic endpoints.
24h Move is the share-price change in the day after each event; other market factors may also have contributed.
Key Terms
robart’s histopathology index medical
modified mayo score medical
pharmacokinetics medical
treatment-emergent adverse events medical
AI-generated analysis. How Rhea-AI works. Not financial advice.
SPY003 met its primary endpoint with a statistically significant reduction of 10.0 points (p<0.0001) from baseline at Week 12 in Robart’s Histopathology Index (RHI) score
Secondary endpoints included clinical remission by modified Mayo Score of
SPY003 was well tolerated with a safety profile consistent with the IL-23 class
SKYLINE Part A has demonstrated potential best-in-class results for SPY001 (anti-α4β7), SPY002 (anti-TL1A), and SPY003 (anti-IL-23); SKYLINE Part B evaluating pairwise combinations of these components is enrolling with topline induction data expected in 2027
WALTHAM, Mass., Sept. 08, 2026 (GLOBE NEWSWIRE) -- Spyre Therapeutics, Inc. (NASDAQ: SYRE), a clinical-stage biotechnology company committed to developing next-generation therapies that elevate the standard in immunology by delivering more complete disease control, greater durability, and a simpler treatment experience for patients, today announced positive 12-week induction data from Part A of the Phase 2 SKYLINE trial of SPY003, a potential best-in-class anti-IL-23 being investigated for the treatment of moderately-to-severely active ulcerative colitis (UC). With these results, Spyre has now reported positive Part A data for all three mechanisms in its IBD portfolio (α4β7, TL1A, and IL-23), achieving clinical proof-of-concept for each component of the pairwise combinations being evaluated in Part B of the SKYLINE trial.
“SPY003 demonstrated a highly statistically significant 10-point reduction in RHI and meaningful clinical remission and endoscopic outcomes in line with the anti-IL-23 class,” said Deanna Nguyen, M.D., SVP of Clinical Development and SKYLINE study lead. “Combined with a well-tolerated safety profile and extended pharmacokinetics in alignment with the rest of our portfolio, these results position SPY003 as a potentially best-in-class combination component for patients with moderately-to-severely active UC.”
“With today’s SPY003 data building upon impressive SPY001 and SPY002 results, we have now delivered three potential best-in-class IBD readouts within a span of five months, demonstrating the quality and efficiency of our development organization and strategy,” said Cameron Turtle, DPhil, Chief Executive Officer of Spyre. “We engineered optimized antibodies against the best targets in IBD based on our thesis that better components will lead to better combinations. Each molecule has now demonstrated compelling monotherapy efficacy and safety data, and the combination cohorts are actively enrolling. We believe that these combinations have the potential to deliver an efficacy, safety, and dosing profile that meaningfully surpasses today’s standard of care, and we are excited to unveil those data in 2027.”
Efficacy: POC Established Across All Three Combination Components
SKYLINE is a two-part induction and maintenance platform trial of SPY001, SPY002, SPY003, as well as pairwise combinations thereof (six investigational agents total) in patients with moderately-to-severely active ulcerative colitis. Part A is an open-label assessment of the safety and efficacy of a single dose level of each investigational monotherapy, and Part B is a randomized and placebo-controlled assessment of the safety and efficacy of investigational monotherapies (two dose levels) and combinations.
SPY003 is an extended half-life investigational antibody targeting IL-23, a cytokine implicated in chronic inflammation in IBD. Initial 12-week findings from SKYLINE Part A demonstrated that SPY003 met all key objectives. The study population consisted of
| Endpoint (Week 12) | SPY003 | |
| Change in RHI from baseline Primary endpoint | -10.0 (p<0.0001) | |
| Clinical remission rate | ||
| Endoscopic improvement rate | ||
| Change in modified Mayo Score | -3.5 | |
Safety: Well-Tolerated Profiles Across All Three Monotherapies Support Combination Development
As previously reported, SPY001 and SPY002 were each well tolerated in Part A, with safety profiles consistent with their respective classes, and no drug-related serious adverse events.
SPY003 was well tolerated with a safety profile consistent with the IL-23 class. There were 19 subjects with treatment-emergent adverse events (TEAEs) during the induction treatment period. Three serious adverse events (SAEs) were reported, deemed not drug-related. The most common adverse events (AEs) (occurring in ≥ 2 patients) were arthralgia (n=2), nasopharyngitis (n=2), and urinary tract infection (n=2).
| SPY003 | |
| Subjects with any AE (n, %) | 19 ( |
| Severe (Grade ≥ 3) AE | 5 ( |
| Drug-related AE | 1 ( |
| AE leading to drug discontinuation | 0 |
| SAE | 3 ( |
| Drug-related SAE | 0 |
| AEs of special interest | 0 |
| Death | 0 |
1Ulcerative colitis flare, intervertebral disc protrusion, anaemia, urinary tract infection, and acute cholecystitis, each in one subject; all deemed not drug-related.
2Pruritus (Grade 1) that resolved without intervention or treatment interruption.
3Hospitalization for ulcerative colitis flare, hemorrhoid thrombosis, and acute cholecystitis, each in one subject; all deemed not drug-related.
Data pertain to SPY003 (N=44) through Week 12 and data cut-off of July 27, 2026.
Next steps
Clinical proof-of-concept across all three IBD programs strengthens the biological rationale for Spyre’s combination strategy and sets the stage for Part B of the SKYLINE trial, which is actively enrolling. Part B includes two dose levels of each monotherapy as well as three high-dose combination arms (SPY120, SPY130, and SPY230), which the Company believes have the potential to deliver best-in-disease efficacy, safety, and treatment experience. Topline induction data from Part B are expected in 2027.
The Company remains at the forefront of evaluating potential first- and best-in-class monotherapies and combinations in immunology and inflammation, with multiple expected topline readouts over the next 12-18 months:
| Trial | Indication | Asset(s) | Expected timing |
| SKYWAY | PsA, axSpA | SPY072 | 4Q 2026 |
| SKYLINE Part B | UC | SPY001, SPY002, SPY003, SPY120, SPY130, SPY230 | 2027 |
| SKYLIGHT | HS | SPY072 + IL-17A/F | Late 2027 or early 2028 |
About Spyre Therapeutics
Spyre Therapeutics is a clinical-stage biotechnology company committed to developing next-generation therapies that elevate the standard in immunology by delivering more complete disease control, greater durability, and a simpler treatment experience for patients. Spyre's pipeline includes investigational extended half-life antibodies targeting α4β7, TL1A, IL-23, and IL-17A/F as well as rational combination programs.
For more information, visit Spyre's website at www.spyre.com.
Forward-Looking Statements
Certain statements in this press release, other than purely historical information, may constitute "forward-looking statements" within the meaning of the federal securities laws, including for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements regarding: Spyre’s ability to achieve the expected benefits or opportunities with respect to its product candidates, including its ability to develop next-generation therapies that elevate the standard in immunology by delivering more complete disease control, greater durability, and a simpler treatment experience for patients; the potential best-in-class results for SPY001, SPY002 and SPY003; the potential for SPY003 to be a best-in-class IL-23 and combination component for patients with moderately-to-severely active UC; the potential for better components leading to better combinations; the potential for Spyre’s combinations to deliver an efficacy, safety, and dosing profile that meaningfully surpasses today’s standard of care; the potential for Spyre’s three high-dose combination arms to deliver best-in-disease efficacy, safety, and treatment experiences; Spyre’s ongoing and future clinical development activities, including Spyre’s plans for data readouts for the ongoing SKYLINE, SKYWAY and SKYLIGHT trials and timing thereof. The words "opportunity," "potential," "milestones," "pipeline," "strategy," "anticipate," "believe," "could," "estimate," "expect," "may," "might," "plan," "possible," "predict," "should," "will," "would," and similar expressions (including the negatives of these terms) may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements are based on current expectations and beliefs and involve a number of risks and uncertainties, many of which are beyond Spyre’s control, and other assumptions that may cause actual results or performance to be materially different from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to, uncertainties and risks arising from regulatory feedback, including potential disagreement by regulatory authorities with the Company’s interpretation of data and the Company’s clinical trials for its product candidates; the potential for interim data not being delivered within expected time frames or final data not being consistent with or different than the topline or interim data reported for our programs; the potential impact of Trump Administration policies and changes in law on our business; and those uncertainties and factors described in Spyre's most recent Annual Report on Form 10-K, as supplemented and updated by subsequent Quarterly Reports on Form 10-Q and any other filings that Spyre has made or may make with the SEC from time to time. You should not place undue reliance on forward-looking statements in this press release, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. Spyre does not undertake or accept any duty to make any updates or revisions to any forward-looking statements.
For Investors:
Eric McIntyre, Spyre Therapeutics
SVP of Finance and Investor Relations
Eric.mcintyre@spyre.com
For Media:
Josie Butler, 1AB
josie@1abmedia.com
FAQ
What was the design of the SKYLINE Part A study for SPY003?
SKYLINE is a two-part platform trial in moderately‑to‑severely active ulcerative colitis. Part A is an open‑label assessment of a single dose level of each investigational monotherapy (SPY001, SPY002, SPY003) to evaluate safety and efficacy over a 12‑week induction period.
What baseline characteristics did patients in the SPY003 Part A cohort have?
In the SPY003 cohort, 41% of participants were advanced therapy‑exposed, with a mean disease duration of 7.1 years. The mean baseline RHI score was 17.2 ± 8.3, the mean modified Mayo Score was 6.9 ± 1.2, and 59% of patients had a baseline endoscopy score of 3.
How do SPY003’s histologic results compare with SPY001 and SPY002 in SKYLINE Part A?
The 10.0‑point RHI reduction observed with SPY003 is described as being in line with the 9.2‑point and 10.7‑point reductions reported for SPY001 and SPY002, respectively, and all three are characterized as among the largest improvements seen in ulcerative colitis trials to date.
What specific adverse events were most common with SPY003?
Among SPY003-treated patients, the most common adverse events (occurring in ≥ 2 patients) were arthralgia (2 patients), nasopharyngitis (2 patients), and urinary tract infection (2 patients). There was one Grade 1 pruritus event deemed drug‑related, which resolved without intervention or treatment interruption.
What are the next clinical steps for Spyre’s IBD combination strategy?
Part B of SKYLINE is actively enrolling and includes two dose levels of each monotherapy plus three high‑dose combination arms (SPY120, SPY130, SPY230). Spyre expects topline induction data in 2027 and states that these combinations may offer best‑in‑disease efficacy, safety, and treatment experience.
What other upcoming clinical readouts does Spyre highlight?
Spyre lists multiple expected topline readouts over the next 12–18 months, including: SKYWAY in psoriatic arthritis and axial spondyloarthritis with SPY072 in 4Q 2026; SKYLINE Part B in ulcerative colitis with SPY001, SPY002, SPY003 and combinations in 2027; and SKYLIGHT in hidradenitis suppurativa with SPY072 plus IL‑17A/F in late 2027 or early 2028.