Spyre Therapeutics completes IBD proof-of-concept with SPY003 data
Spyre Therapeutics has reported 12-week induction results from Part A of its SKYLINE Phase 2 trial showing that SPY003, its extended half-life anti-IL-23 antibody, met its primary endpoint in moderately-to-severely active ulcerative colitis. The Waltham, Massachusetts-based company said the data complete proof-of-concept for all three mechanisms underpinning its pairwise combination strategy, following earlier positive readouts for SPY001 (anti-α4β7) and SPY002 (anti-TL1A).
SPY003 produced a statistically significant 10.0-point reduction from baseline in Robart's Histopathology Index score at Week 12 (p<0.0001), which the company says is among the largest improvements recorded in UC trials to date. Secondary endpoints showed a clinical remission rate of 20% by modified Mayo Score and an endoscopic improvement rate of 30%. The mean change in modified Mayo Score was minus 3.5 points. The trial population included 41% of participants who had already been exposed to advanced therapies, a group typically harder to treat, with a mean disease duration of 7.1 years.
Safety profile and combination rationale
The safety data were broadly reassuring. Of 44 participants evaluated, 19 experienced at least one treatment-emergent adverse event, and three serious adverse events were reported, all judged by the investigators to be unrelated to the drug. No drug-related serious adverse events occurred, and no participants discontinued because of an adverse event. The most frequently reported events were arthralgia, nasopharyngitis, and urinary tract infection, each in two patients. Spyre said the profile is consistent with the established IL-23 class.
Deanna Nguyen, SVP of Clinical Development and SKYLINE study lead, said the results, "combined with a well-tolerated safety profile and extended pharmacokinetics in alignment with the rest of our portfolio, position SPY003 as a potentially best-in-class combination component for patients with moderately-to-severely active UC."
The company now moves to SKYLINE Part B, a randomised, placebo-controlled assessment of monotherapy at two dose levels and three high-dose pairwise combination arms: SPY120 (SPY001 plus SPY002), SPY130 (SPY001 plus SPY003), and SPY230 (SPY002 plus SPY003). Topline induction data from Part B are expected in 2027.
Market context and competitive landscape
The IL-23 class is already crowded in inflammatory bowel disease. Approved agents targeting the IL-23 p19 subunit, including risankizumab (AbbVie), mirikizumab (Eli Lilly), and guselkumab (Johnson & Johnson), have established a high clinical bar in UC and Crohn's disease. Spyre's thesis is that an optimised antibody with extended half-life will permit less frequent dosing and slot more cleanly into multi-mechanism combinations, rather than simply competing as a standalone agent.
The broader combination-therapy hypothesis in IBD is drawing significant industry attention. The rationale is that no single pathway fully controls disease in a meaningful proportion of patients, and that combining agents with distinct mechanisms of action could meaningfully shift remission rates. Several companies and academic consortia are running dual-mechanism combination studies, though head-to-head data comparing combination regimens remain sparse.
For Spyre, the near-term catalysts are substantial. A readout from the SKYWAY trial of SPY072 in psoriatic arthritis and axial spondyloarthritis is expected in the fourth quarter of 2026, followed by the SKYLINE Part B induction data in 2027 and the SKYLIGHT trial of SPY072 in hidradenitis suppurativa in late 2027 or early 2028. Investors will be watching the Part B data most closely: whether pairwise combinations of individually promising monotherapies actually deliver additive or synergistic clinical benefit in a controlled setting remains to be demonstrated.