P1001 Efficacy and safety of an oral tyrosine kinase 2 inhibitor VTX958 in moderately to severely active Crohn’s disease: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract Background Tyrosine kinase 2 inhibitors (TYK2i) are a novel class of therapies for immune-mediated inflammatory disorders, including Crohn’s disease (CD). A phase 2, multicentre, randomised, double-blind, placebo-controlled trial assessed the efficacy and safety of the oral selective TYK2i VTX958 in CD. Methods Adults (N=109) with moderately-to-severely active CD (CD Activity Index [CDAI] 220-450; Simple Endoscopic Score for CD [SES-CD] ≥6 [≥4 for isolated ileal CD]) and inadequate/loss of response or intolerance to conventional or biologic therapies were randomised 1:1:1 to 12-weeks twice daily treatment with placebo or VTX958 (225mg or 300mg). The primary endpoint was CDAI change from baseline at week 12. Additional secondary endpoints are described in the Table. Changes from baseline in C-reactive protein (CRP) and faecal calprotectin (FCP) concentrations at week 12 were exploratory endpoints. Results Mean CDAI change from baseline at week 12 was -113.6, -134.1, and -104.3 for VTX958 300mg, 225mg, and placebo, respectively (p>0.05; see Table). Conversely, significantly greater SES-CD reductions from baseline at week 12 were observed for VTX958 300mg (-2.7) and 225mg (-3.5) compared to placebo (2.1; p=0.0005 and p<0.0001, respectively), and significantly greater proportions of patients achieved endoscopic response with VTX958 300mg (32.4%) and 225mg (24.3%) treatment compared to placebo (5.7%; p=0.007 and p=0.026, respectively). Although secondary clinical endpoints alone were not significantly different between VTX958 and placebo (Table), combined endoscopic response and clinical remission and clinical-biomarker response rates were significantly higher for VTX958 300mg compared to placebo (18.9% vs 2.9%, p=0.041, and 43.2% vs 14.3%, p=0.011, respectively). Greater reductions in CRP and FCP concentrations compared to placebo were observed with both VTX958 doses. Most adverse events (AE) were mild-to-moderate and comparable across treatment groups. No serious infections, thromboembolic, major adverse cardiovascular events, or deaths occurred in the VTX958 groups. Overall rates of skin reactions were also similar between treatment groups. Rash and acne occurred at a higher rate in the VTX958 groups compared to placebo, most of which were mild, except for one moderate AE of acne in the VTX958 225mg group. Conclusion Twelve weeks treatment with VTX958 was well-tolerated in patients with CD. Although the primary endpoint of CDAI change from baseline was not met, higher rates for most objective outcomes were observed with VTX958 300mg, including endoscopic response and combined clinical remission and endoscopic response. Additional data are needed to determine the long-term safety and efficacy of VTX958 in CD.

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