S1054 TUSCANY-2: A Dose-Ranging Phase IIb Study Evaluating Efficacy and Safety of RO7790121, an Antibody Against Tumor Necrosis Factor-Like Ligand 1A (Anti-TL1A) in Adults With Moderately to Severely Active Ulcerative Colitis

Introduction: RO7790121 (previously PF-06480605, RVT-3101), an anti-TL1A antibody, was effective in a previous open-label phase IIa study for the treatment of active ulcerative colitis (UC). We report results from TUSCANY-2, a phase IIb, randomized, dose-ranging study evaluating efficacy, safety and changes in fecal calprotectin (FCP) levels in patients with moderately to severely active UC receiving subcutaneous (SC) RO7790121. Methods: In this treat-through study, patients aged 18–75 years with moderately to severely active UC (total Mayo Score [tMS] 6–12, endoscopic subscore ≥2) who had failed ≥1 prior conventional or advanced treatment were randomized to receive RO7790121 SC 50 mg, 150 mg, 450 mg, or matched placebo (PBO) monthly during the 12-week induction period, and RO7790121 SC 50, 150 or 450 mg monthly during the 40-week maintenance period. The primary efficacy endpoint was clinical remission at week 14 by tMS. Secondary endpoints included clinical remission by modified Mayo Score (mMS; aligned with FDA guidance) at weeks 14 and 56, clinical remission by tMS at week 56, endoscopic improvement at weeks 14 and 56, and change from baseline in FCP levels during induction. Safety was assessed throughout the study. Results: A total of 245 patients received ≥1 dose of RO7790121; 228 patients completed induction and 224 entered maintenance. At week 14, a greater proportion of patients across all treatment doses achieved remission vs PBO by both tMS (P >0.05) and mMS (nominal P < 0.05), sustained through week 56 (Table 1). Patients receiving any dose of RO7790121 showed greater endoscopic improvement vs PBO at weeks 14 and 56 (Table 1). Substantial decreases in FCP were observed between baseline and week 12 across all RO7790121 doses vs PBO (Figure 1). Overall, 47.8% (117/245) of patients during induction experienced ≥1 treatment-emergent adverse event (TEAE), the most common (reported in ≥5% patients overall) were anemia (5.3%) and headache (5.3%). Ten patients experienced serious adverse events in the induction period; 4 PBO, 3 50 mg and 3 450 mg (2 treatment related: 1 PBO, 1 450 mg). There were no treatment discontinuations due to TEAEs. Conclusion: Treatment with RO7790121 resulted in clinical and endoscopic improvements at week 14, which were sustained through week 56, including early decreases in FCP vs PBO. A continuing phase III study will further evaluate these findings. Clinical trial identification: NCT04090411.Figure 1.: Mean Fecal Calprotectin Fold Change (μg/g) at Weeks 0, 4, 8 and 12. *Nominal P value <0.05 in each arm CI, confidence interval. Table 1. - Summary of Efficacy Outcomes at Week 14 and Week 56 Induction, week 14 PBO (n=43) 50 mg (n=47) 150 mg (n=60) 450 mg (n=88) Clinical remission by tMS,* % (90% CI) 11.6 (5.8–22.9) 25.5 (15.4–37.2) 23.3 (15.0–34.0) 23.9 (16.6–32.1) Clinical remission by mMS,† % (90% CI) 11.6 (5.8–22.9) 29.8 (19.9–42.3) 35.0 (25.1–45.2) 31.8 (23.7–40.8) Endoscopic improvement,‡ % (90% CI) 18.6 (9.6–30.2) 40.4 (28.3–53.5) 38.3 (27.8–48.6) 40.9 (32.1–50.0) Maintenance, week 56 § N/A ‖ 50 mg (n=42) 150 mg (n=26) 450 mg (n=28) Clinical remission by tMS,* % (90% CI) 31.0 (19.4–43.3) 34.6 (20.9–52.6) 39.3 (23.8–56.5) Clinical remission by mMS,† % (90% CI) 31.0 (19.4–43.3) 38.5 (23.3–56.4) 35.7 (20.9–52.7) Endoscopic improvement,‡ % (90% CI) 38.1 (25.6–52.0) 39.3¶ (23.8–56.5) 50.0 (33.3–66.7) Data cut-off: 3 March, 2023. n=number of participants in the analysis set with observed data or NRI, excluding a total of 7 participants with missing data due to medical or operational complications resulting from COVID-19.*Primary endpoint: defined as tMS ≤2 with no individual subscore >1.†Secondary endpoint: defined per FDA definition with an mMS 0–2 (endoscopic subscore=0 or 1, ≥1 point decrease from baseline to achieve a stool frequency subscore=0 or 1, and rectal bleeding subscore=0). ‡Defined as endoscopic subscore=0 or 1.§Analyses were conducted for all dose groups; however, maintenance efficacy results are presented only for patients receiving the same dose during the induction and maintenance periods. Efficacy data from patients who received a lower dose in maintenance vs induction demonstrated sustained efficacy (data not shown).‖As PBO was not administered during the maintenance period, no data for week 56 are shown.¶For the endoscopic improvement endpoint at week 56 with the 150 mg dose, data were available for n=28 patients.CI, confidence interval; COVID-19, coronavirus disease 2019; FDA, Food and Drug Administration; mMS, modified Mayo Score; N/A, non-applicable; NRI, non-responder imputation; PBO, placebo; tMS, total Mayo Score.

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