Spyre Therapeutics' (Nasdaq: SYRE) extended half-life anti-TL1A antibody SPY072 produced statistically significant reductions in disease activity in rheumatoid arthritis compared to placebo, but the magnitude of effect fell short of the company's internal threshold for advancing the drug as a monotherapy in that indication, as reported by the Waltham, Massachusetts-based company.
The results come from the RA sub-study of the SKYWAY Phase II basket trial, which enrolled 143 patients with moderately to severely active RA who had inadequate responses to conventional or advanced therapies. SPY072 low dose achieved a statistically significant improvement on the primary endpoint — change from baseline in Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) — at Week 12 (-1.9 versus -1.3 for placebo, p<0.05). The high dose produced a nominally significant ACR20 response rate of 63% versus 43% for placebo, and the low dose showed a nominally significant ACR50 rate of 38% versus 19%. Both doses achieved complete and durable suppression of free TL1A through Week 12, confirming full target engagement. The adverse event rate was lower in the SPY072 arms (27%) than placebo (36%), with no drug-related serious events.
SPY072 neutralizes TL1A, a TNF superfamily cytokine that drives T-cell-mediated inflammation across multiple tissues. Spyre designed SPY072 with half-life extension technology to enable quarterly or twice-yearly subcutaneous dosing — a profile that distinguishes it from approved RA biologics, which generally require more frequent administration.
The company said the data establish proof-of-mechanism for TL1A inhibition in RA, but that the degree of benefit does not justify prioritizing SPY072 as a standalone RA monotherapy. Spyre had previously flagged the RA readout as a key proof-of-concept milestone, and Phase I data reported in June 2025 had demonstrated a half-life of approximately 75 days — more than three times that of first-generation anti-TL1A antibodies — supporting the rationale for the Phase II program.