Abstract
Management of patients with small bowel Crohn’s disease (SBCD) remains challenging due to limited efficacy from current therapeutic options. AZD7798 is a first-in-class monoclonal antibody for CD that depletes CCR9+ lymphocytes, with potential for targeted treatment of SBCD given the critical role that CCR9 plays in lymphocyte homing to the small bowel. Monitoring CCR9+ cell depletion and repletion in the blood is straightforward, but difficult in the small bowel due to accessibility for biopsy. Here we use positron emission tomography (PET) with a novel CCR9-specific PET tracer, [11C]vercirnon, to assess the ability of AZD7798 to deplete CCR9+ cells in the intestines of healthy volunteers and patients with SBCD.
We performed an open-label phase 1b study to evaluate the effects of single and repeat intravenous doses of AZD7798 on intestinal [11C]vercirnon uptake in healthy volunteers and patients with SBCD (NCT06053424). Additional endpoints were safety and pharmacodynamics in blood (CCR9 cell depletion). PET imaging using [11C]vercirnon was performed prior to AZD7798 dosing and at 2 follow-up timepoints, approximately 2 and 6 weeks post dosing.
A total of 6 healthy (aged 25-64 years, 4 female) and 6 SBCD participants (aged 24-59 years, 4 female) completed the study. There were no major adverse tolerability or safety findings following single or repeat doses of AZD7798. Mild cytokine release syndrome (CTCAE Grade 1) was observed after first doses, but not after second doses in the repeat dose cohort. There were no serious adverse events or treatment discontinuations due to adverse events.
In 4 out of 6 SBCD participants, PET imaging showed a quantitative reduction in [11C]vercirnon uptake of up to 21.6% (median 11.5%) in the intestines at 6 weeks following single (n = 3 out of 4) and repeat (n = 1 out of 2) IV doses of AZD7798 (Figure 1). Rapid, profound and sustained CCR9+ cell depletion was observed in blood in all healthy and SBCD participants (Figure 2).
The use of a CCR9-specific PET tracer has enabled repeatable, non-invasive quantification of CCR9 expression in the gut. Preliminary evidence of intestinal CCR9+ cell depletion in patients with SBCD following single and repeat doses of AZD7798 was provided. The study demonstrates the value of molecular imaging for understanding treatment effect in the target tissue in vivo. An ongoing PET imaging study will assess the effects of AZD7798 on CCR9+ cell depletion/repletion in the gut following multiple doses, alongside Phase 2 studies evaluating the clinical efficacy of AZD7798 in moderate-to-severe Crohn’s disease.
