Spyre Scales Back Development of SPY072 as Monotherapy for Rheumatoid Arthritis

Spyre Therapeutics’ anti-TL1A antibody SPY072 produced results below expectations in a phase 2 trial for rheumatoid arthritis, prompting the company to lower the priority of developing it as a monotherapy for the indication.

According to Fierce Biotech on the 26th (local time), at week 12 of the phase 2 trial, DAS28-CRP (28-joint disease activity score) decreased by 1.5 points and 1.9 points in the high- and low-dose SPY072 groups, respectively. The control group’s score fell by 1.3 points, leaving the reduction versus placebo well short of the targeted 1 point; only the low-dose group reached statistical significance.

Spyre CEO Cameron Turtle said at a Goldman Sachs event in June that the placebo-adjusted reduction in DAS28-CRP among patients with rheumatoid arthritis who had failed TNF inhibitors was about 1 point. Guggenheim Securities analysts cited the same figure in an investor note last week, expressing similar expectations.

The proportions of patients who improved, as measured by ACR20, ACR50 and ACR70, also fell short of expectations. ACR20 response rates were 63% and 58% with high- and low-dose SPY072, respectively, compared with 43% in the placebo group, but the results did not meet the placebo-adjusted improvement targets set by Turtle and Guggenheim—about 30, 20 and 10 percentage points, respectively. ACR50 improved by 19 percentage points versus placebo with the low dose, and ACR70 improved by 11 percentage points with the high dose, but the opposite dose groups fell short of expectations.

Following the results, Spyre shares fell 12.4% to $93.99 in premarket trading on the 26th, from the previous close of $107.36.

Spyre said the results did not meet its criteria for prioritizing SPY072 monotherapy in rheumatoid arthritis, but it viewed them as demonstrating the mechanism of action of TL1A inhibition in the indication. The company also pointed to SPY072’s favorable tolerability and the potential use of TL1A drugs in other autoimmune diseases and in combination therapies.

Phase 2 results for SPY072 monotherapy in psoriatic arthritis and axial spondyloarthritis are expected in the fourth quarter of this year. Results from a recently initiated combination trial with UCB’s Bimzelx are expected in late 2027 or early 2028.

Spyre is pursuing expansion of TL1A inhibitors into indications beyond ulcerative colitis (UC) and Crohn’s disease. The company is also testing another TL1A inhibitor, SPY002, as a monotherapy and in various combination regimens for UC. Merck, Roche and Sanofi have also selected UC and Crohn’s disease as lead indications for their TL1A drug candidates and are conducting phase 3 trials in intestinal diseases.

Evidence demonstrating the efficacy of the TL1A mechanism of action in rheumatic diseases remains limited. Merck began a phase 2b trial last year in several rheumatic indications targeted by Spyre, while Roche included rheumatoid arthritis and eczema trials in its phase 2 program.