UEGW 2018: Clinical trials in IBD – late-breaking abstracts

Among the late-breaking clinical trial abstracts at UEG Week were new data for ustekinumab in UC, a new formulation for subcutaneous administration of vedolizumab, and early clinical data for a gut-selective JAK inhibitor.

Among the late-breaking clinical trial abstracts at UEG Week were new data for ustekinumab in UC, a new formulation for subcutaneous administration of vedolizumab, and early clinical data for a gut-selective JAK inhibitor.

Professor Bruce Sands from Mount Sinai in New York presented results from the Phase 3 UNIFI study which show that a single intravenous infusion of ustekinumab at a dose of 130mg or ~6mg/kg can induce clinical remission and mucosal healing at Week 8 in patients with moderate to severe UC. A total of 961 patients were included and randomised to either a fixed dose or weight-based dose of ustekinumab or placebo. The primary endpoint of clinical remission was achieved by 15.6% and 15.5% of patients in the two ustekinumab arms, respectively, versus 5.3% in the placebo arm (p<0.001 for both). In patients who had previously failed biologic therapy, remission rates in the ustekinumab arms were 11.6% and 12.7% in the fixed-dose and weight-based dose, respectively, compared with 19.9% and 18.6% in patients who had not failed on biologic therapy. The two ustekinumab arms also had significantly higher rates of endoscopic healing and clinical response, as well as greater improvements in IBDQ scores from baseline. Eight weeks after the injection, mucosal healing rates, defined as combined endoscopic and histologic healing, were 20.3% in the ustekinumab 130mg arm and 18.4% in the ustekinumab ~6mg/kg arm, versus 8.9% in the placebo arm. Ustekinumab was well tolerated and adverse events were consistent with the safety profile observed in previous studies.

Professor William Sandborn (USA) discusses the results from the VISIBLE-I study which looked at the use of subcutaneous vedolizumab.

The gut-selective α₄β₇ integrin antibody vedolizumab has been developed in a subcutaneous formulation for improved patient convenience. Professor William Sandborn from San Diego presented the phase 3 VISIBLE 1 study in which 216 patients with moderate to severe UC were randomised to receive vedolizumab induction followed by subcutaneous (n=106) or intravenous (n=54) vedolizumab or placebo (n=56). At 52 weeks, 46% of patients in the subcutaneous arm and 43% in the intravenous arm had achieved the primary endpoint of clinical remission, defined as a Mayo score ≤2 and no subscore >1, versus 14.3% in the placebo arm (p<0.001). Significantly higher proportions of patients in the two vedolizumab arms also had mucosal healing, durable clinical response and remission, and steroid-free remission. Remission rates were higher among anti-TNF naïve patients compared with patients who had failed on anti-TNF therapy in all treatment arms. Anti-vedolizumab antibodies were detected in 6% of patients in both vedolizumab arms, and 10% of patients in the subcutaneous arm experienced a mild to moderate injection site reactions. The efficacy results seen in this study were consistent with those seen in the pivotal GEMINI 1 study¹ and the investigators concluded that vedolizumab administered subcutaneously is effective and well tolerated.

A further study with vedolizumab, presented by Dr Julia Liu from the University of Arkansas, indicates that a feature of the inflammasome, a protein complex which is responsible for activating innate immunity,² can be used as a predictive biomarker in CD. As caspase-1 is activated by the inflammasome this mediates a process known as pyroptosis, which involves intestinal epithelial cell death from innate immune activation³ and which is a surrogate marker of mucosal barrier defects.⁴ In a multicentre study involving 78 CD patients at five US centres, Dr Liu and her co-investigators found that the degree of pyroptosis in pre-treatment ileal biopsies was significantly predictive of the clinical response to vedolizumab: pyroptosis was detected in 16.8 ± 11.8 cells/1,000 intestinal epithelial cells in responders compared with 24.5 ± 11.6 cells/1,000 intestinal epithelial cells in non-responders (p=0.007). Further work is in progress to evaluate the prognostic role of ileal pyroptosis in UC patients and for predicting response to anti-TNF therapy.

Professor Julian Panés from Barcelona presented the results of a phase 1b study of a gut-selective oral pan-JAK inhibitor known as TD-1473. In this four-week study, 40 patients with refractory UC received the study drug at doses of 20mg, 80mg or 270mg or placebo. In addition to the primary endpoints safety and plasma pharmacokinetics, the study protocol also included clinical response and mucosal healing as exploratory endpoints. TD-1473 was well tolerated at the doses investigated with therapeutic tissue concentrations and low systemic exposure; the exploratory analyses showed trends towards higher rates of clinical response and mucosal healing versus placebo, as well as greater improvements in endoscopy and rectal bleeding subscores. TK-1473 is currently being investigated in a phase 2 study in CD and phase 2b/3 studies in UC.

References

1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699-710.
2. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417-26.
3. Fink SL, Cookson BT. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 2006;8:1812-25.
4. Liu JJ, Davis EM, Wine E, et al. Epithelial cell extrusion leads to breaches in the intestinal epithelium. Inflamm Bowel Dis 2013;19:912-21.