SPY003 Meets Primary Endpoint in Phase 2 Trial for Ulcerative Colitis

Spyre Therapeutics has reported positive 12-week induction results from Part A of the Phase 2 SKYLINE trial evaluating SPY003, an investigational anti-IL-23 antibody, in patients with moderately-to-severely active ulcerative colitis (UC). According to the press release, this readout completes proof-of-concept for all 3 components of Spyre's inflammatory bowel disease (IBD) combination pipeline, following earlier positive Part A results for SPY001 (anti-α4β7) and SPY002 (anti-TL1A).

“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,” Deanna Nguyen, MD, senior vice president of clinical development and SKYLINE study lead, said in a statement. “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.”

How SPY003 Targets IL-23 in Ulcerative Colitis

SPY003 is an extended half-life investigational antibody targeting IL-23, a cytokine implicated in chronic inflammation in IBD. By blocking IL-23 signaling, the antibody is designed to reduce the downstream immune activity that drives tissue damage in UC, a mechanism shared with other approved and investigational agents in the anti-IL-23 class.

SKYLINE-UC Trial Design and Patient Population

SKYLINE-UC is a 2-part induction and maintenance platform trial assessing SPY001, SPY002, SPY003, and pairwise combinations of the 3 agents in patients with moderately-to-severely active UC. Part A is an open-label evaluation of a single dose level of each monotherapy, and Part B, which is actively enrolling, is a randomized, placebo-controlled assessment of 2 dose levels of each monotherapy along with 3 combination arms.

Among the 44 participants who received SPY003 through the July 27, 2026, data cutoff, 41% had prior exposure to advanced therapy, and mean disease duration was 7.1 years. The population had a mean baseline Robarts Histopathology Index (RHI) score of 17.2 (± 8.3), a mean baseline modified Mayo Score of 6.9 (± 1.2), and 59% had a baseline endoscopy subscore of 3.

SPY003 Efficacy Results in Ulcerative Colitis

SPY003 met its primary endpoint, achieving a 10.0-point reduction in RHI score from baseline at week 12 (P < .0001). Secondary endpoints included a clinical remission rate of 20% by modified Mayo Score and an endoscopic improvement rate of 30%; the modified Mayo Score itself decreased by 3.5 points.

The 10.0-point RHI reduction with SPY003 was consistent with the 9.2-point and 10.7-point reductions previously reported for SPY001 and SPY002, respectively. According to Spyre, all 3 results are among the largest RHI improvements observed in UC trials to date.

SPY003 Safety and Tolerability Data

SPY003 was well tolerated, with a safety profile consistent with the anti-IL-23 class. Of the 44 participants, 19 (43%) had a treatment-emergent adverse event (TEAE) during induction, and 3 serious adverse events (SAEs), none deemed drug-related, were reported: hospitalization for a UC flare, hemorrhoid thrombosis, and acute cholecystitis. The most common adverse events, each occurring in 2 patients, were arthralgia, nasopharyngitis, and urinary tract infection. No patients discontinued treatment due to an adverse event, and no deaths occurred.

SPY001 and SPY002 were previously reported as well tolerated in Part A, each with safety profiles consistent with their respective drug classes and no drug-related SAEs.

Next Steps: SKYLINE Part B and Spyre's IBD Pipeline

With clinical proof-of-concept now established for all 3 mechanisms, SKYLINE Part B will evaluate 2 dose levels of each monotherapy alongside 3 high-dose combination arms (SPY120, SPY130, and SPY230). Spyre expects topline induction data from Part B in 2027.

The company also has readouts expected for SPY072 in psoriatic arthritis and axial spondyloarthritis (SKYWAY trial) in the fourth quarter of 2026, and for SPY072 plus an IL-17A/F agent in hidradenitis suppurativa (SKYLIGHT trial) in late 2027 or early 2028.

References

1. 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. News release. Spyre Therapeutics, Inc. September 8, 2026. https://ir.spyre.com/news-releases/news-release-details/spyre-announces-potential-best-class-spy003-anti-il-23-part

2. A Study of Long-Acting Antibodies Alone and in Combinations for Moderate to Severe Ulcerative Colitis (SKYLINE-UC). ClinicalTrials.gov identifier: NCT07012395. Updated 2026. https://clinicaltrials.gov/study/NCT07012395