SKYWAY Phase 2 showed efficacy signals but did not meet development criteria

Spyre Therapeutics (SYRE) has obtained 12-week results from the SKYWAY Phase 2 trial of SPY072, an anti-TL1A monoclonal antibody, in rheumatoid arthritis but has decided to deprioritize monotherapy development. SPY072 is a long-acting antibody under development without a brand name, designed to block the inflammatory cytokine TL1A produced by the TNFSF15 gene. The change in DAS28-CRP was -1.5 points for the high dose, -1.9 points for the low dose, and -1.3 points for the placebo, with only the low dose achieving statistical significance compared to placebo. Despite full target engagement, the placebo-adjusted improvements were 0.2 points and 0.6 points, respectively, failing to meet the company's 1.0-point threshold, which was a key factor in the decision to discontinue.

Dose consistency in response rates was lacking

The ACR20 response rates were 63% for the high dose, 58% for the low dose, and 43% for the placebo, with the high dose showing nominal significance but not the expected 30-point improvement over placebo. ACR50 rates were 31%, 38%, and 19%, with the low dose achieving nominal significance, and ACR70 rates were 13%, 4%, and 2%, with the high dose showing an 11-point difference. Different endpoints improved at different doses, failing to demonstrate a clear dose-response relationship or reproducible clinical competitiveness. Adverse events occurred in 27% of SPY072-treated patients and 36% of placebo-treated patients, with no drug-related serious adverse events, indicating that the failure was due to efficacy rather than safety.

Existing standard-of-care and TL1A competitors set high benchmarks

Rheumatoid arthritis treatment is structured around methotrexate, with TNF-alpha inhibitors like Humira’s adalimumab and JAK inhibitors like Rinvoq’s upadacitinib as key competitors. The U.S. FDA approved Humira for rheumatoid arthritis in 2002 and Rinvoq’s JAK1 inhibitor in August 2019. SPY072 has not yet entered any FDA, EMA, or PMDA approval or advisory committee review stages as a Phase 2 candidate. Competing anti-TL1A agents include Merck & Co. (MRK)’s tilsotimod in Phase 2b for rheumatoid arthritis and Roche Holding (RHHBY)’s apimisib in Phase 2. These results highlight that the size and consistency of efficacy, rather than TL1A inhibition alone, are central to competitive differentiation.

Resources will shift to other indications and combination therapy

Spyre plans to release Phase 2 results for SPY072 in psoriatic arthritis and ankylosing spondylitis in Q4 2026. The SKYLIGHT Phase 2 trial combining SPY072 with UCB (UCB.BR)’s Bimzelx (bimekizumab) targets pyoderma gangrenosum rather than rheumatoid arthritis, with bimekizumab inhibiting both IL-17A and IL-17F. Topline data from this combination trial are expected by late 2027 or early 2028, meaning short-term value recovery will depend on follow-up SKYWAY data and the ulcerative colitis pipeline. With the loss of monotherapy opportunity in the $28.5 billion rheumatoid arthritis market in 2025, pipeline diversification has become central to value protection.