Background: The development of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) has improved rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patient care by providing additional therapeutic options for achieving disease remission or low disease activity. However, there is continued unmet need for safe and effective agents with improved convenience. TNF-like protein 1A (TL1A) is a pro-inflammatory and pro-fibrotic cytokine that is upregulated in patients with rheumatic diseases. Spyre Therapeutics is developing SPY072, a half-life extended antibody targeting TL1A, as a potential treatment for patients with RA, PsA, and axSpA.

Objectives: Compare the biological activity of anti-TL1A in mouse models of rheumatoid arthritis (CIA) and psoriasis (IMQ) to positive controls adalimumab (anti-TNF antibody; CIA and IMQ) and an anti-IL-23 antibody (IMQ).

Methods: In the CIA model, DBA/1 mice (n=10/group) were injected subcutaneously with a bovine type II collagen emulsion in Freund’s complete adjuvant on study days 0 and 21. Test article dosing began at the first sign of symptoms (day 28). Anti-TL1A and anti-TNF (adalimumab) antibodies were injected intraperitoneally twice weekly at 25 mg/kg and 5 mg/kg. Arthritis score and hind paw thickness were measured on day 21 and twice per week starting on day 28 until the end of the study (day 49). At study conclusion, right hind paw imaging was performed via micro-computed tomography (micro-CT). The left hind paw was placed in formalin for histopathology scoring. In the IMQ psoriasis model, female C57BL/6 transgenic mice (n=8/group) expressing human TL1A and human IL-23 (hTL1A/hIL23A/hIL12B, Biocytogen) had their dorsal side shaved with an electric razor and remaining hair removed with a depilatory cream on study day -2. On study days 0 to 7, IMQ cream was applied to the dorsal skin twice per day except once on day 7, the final day of the study. Healthy control mice had petrolatum applied to the dorsal skin. Anti-TL1A, anti-IL-23 and anti-TNF (adalimumab) were dosed intravenously on study days -1, 2 and 5 at 25 mg/kg or 5 mg/kg. A Psoriasis Area and Severity Index (PASI) score was measured daily based upon skin erythema, scaling, and thickness. At study conclusion, skin tissue was collected and placed in formalin for subsequent histopathology scoring.

Results: In the mouse CIA model, treatment with 25 mg/kg and 5 mg/kg anti-TL1A resulted in improved disease activity score and hind paw thickness relative to vehicle control starting at the first post-dose measurement (day 32) and persisting until the end of the study. The magnitude of improvement relative to vehicle control in disease activity score (p<0.001) and hind paw thickness (p<0.001) was comparable between anti-TL1A and anti-TNF treatment at both doses. Micro-CT images of the hind paw showed reductions in bone deformity in both the anti-TL1A and anti-TNF treatment groups. Histopathology showed a significant reduction in cell infiltration, pannus severity, cartilage lesion severity and bone resorption severity for anti-TL1A and anti-TNF relative to vehicle control (p<0.001). In the IMQ model, anti-TL1A, anti-IL-23 and anti-TNF all significantly reduced PASI scores relative to the vehicle control starting on study day 2 and lasting until the end of the study (p<0.001). Anti-TL1A showed slightly improved PASI scores during the final 3 study days compared to anti-IL-23 and anti-TNF at both doses (p<0.01). All three treatments showed an equivalent dose-dependent reduction in histopathology score relative to the vehicle control (p<0.001).

Conclusions: Anti-TL1A and anti-TNF antibody treatments showed comparable efficacy in the mouse CIA model at both doses tested. Anti-TL1A showed efficacy that was equivalent to or slightly better than anti-IL-23 and anti-TNF in the mouse IMQ psoriasis model. Taken together, the data suggest that anti-TL1A therapy has the potential to improve joint (RA, PsA) and skin (PsA) symptoms associated with rheumatic diseases. These data support the ongoing clinical trial of SPY072 in patients with rheumatic disease (SKYWAY-RD, NCT07148414).

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Matthew Siegel Spyre Therapeutics, Spyre Therapeutics, Emily Lewis Spyre, Spyre, David Giles Spyre, Spyre, Justin LaFountaine Spyre, Spyre, Joshua Friedman Spyre, Spyre, Andy Spencer Spyre, Spyre.