WALTHAM, Mass. — August 25, 2026

Spyre Therapeutics, Inc. announced topline results from the rheumatoid arthritis (RA) sub-study of the Phase 2 SKYWAY trial, evaluating SPY072, an investigational long-acting TL1A antibody. Both SPY072 dose groups demonstrated statistically significant or nominally significant improvements versus placebo across selected efficacy measures, including DAS28-CRP, ACR20 and ACR50, while the treatment was generally well tolerated. However, the magnitude of benefit did not meet Spyre’s internal threshold for prioritizing SPY072 monotherapy development in RA. The company said the findings nevertheless provide proof-of-mechanism for TL1A inhibition in RA and strengthen its broader strategy of evaluating TL1A antibodies across autoimmune diseases and as components of combination therapies. The results also reinforce the importance of the SKYWAY basket trial as Spyre continues to assess SPY072 across multiple inflammatory rheumatic diseases.

SPY072 Shows Activity Across Key RA Measures

In the SKYWAY-RA sub-study, 143 patients were randomized across high-dose SPY072, low-dose SPY072 and placebo groups. At Week 12, the low-dose group produced a DAS28-CRP change from baseline of -1.9, compared with -1.3 for placebo, reaching statistical significance. ACR20 response rates were 63% with high-dose SPY072, 58% with low-dose SPY072 and 43% with placebo, while ACR50 responses were 31%, 38% and 19%, respectively. The company also reported that both SPY072 doses achieved target drug concentrations and produced complete and durable suppression of free TL1A through Week 12, indicating complete target engagement. Results were generally comparable between patients who were advanced-therapy-naïve and those previously exposed to advanced therapies. Despite these biological and clinical signals, Spyre concluded that the overall magnitude of efficacy was insufficient to prioritize SPY072 as an RA monotherapy. This distinction is important because positive individual endpoints do not necessarily translate into a development program meeting a company’s predefined efficacy threshold.

Safety Profile Remains Consistent With TL1A Class

The safety profile of SPY072 remained generally favorable in the Phase 2 RA evaluation, supporting continued investigation of the molecule in other autoimmune settings. Treatment-emergent adverse events occurred in 27% of SPY072-treated participants compared with 36% for placebo, and events were generally mild or moderate. One serious treatment-emergent adverse event occurred in each treatment arm, with neither considered drug-related. One death was reported in the placebo group. Infections and infestations were the most common adverse events, occurring in 14% of SPY072-treated participants and 15% of placebo-treated participants. Spyre said the safety findings were consistent with the broader TL1A class. While the RA efficacy outcome limits the immediate case for monotherapy development in this indication, the combination of target engagement, selected efficacy signals and tolerability provides supporting information for the company’s wider immunology and inflammation (I&I) development strategy.

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Spyre Shifts Focus to Other Autoimmune Opportunities

Following the RA results, Spyre is maintaining focus on SPY072 in other inflammatory diseases and combination approaches. Topline results from the SKYWAY program in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are expected in the fourth quarter of 2026. The company has also initiated the SKYLIGHT trial, evaluating SPY072 in combination with an IL-17A/F inhibitor in hidradenitis suppurativa (HS), with results expected in late 2027 or early 2028. Additional upcoming milestones include the SKYLINE Part A study of SPY003 in ulcerative colitis, expected in September 2026. The RA findings therefore represent a prioritization decision rather than a termination of the SPY072 program. Spyre continues to position its extended-half-life TL1A antibodies as potential treatments across autoimmune diseases and as combination components alongside validated inflammatory pathways. The company’s broader pipeline includes investigational antibodies targeting α4β7, TL1A, IL-23 and IL-17A/F, alongside rational combination programs.

Source: Spyre Therapeutics,press relese