The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease.

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all P values <0.001). These observations correlated with dose responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2, and modulation of inflammatory genes in the colon. This demonstrates that a relatively low oral dose of a potent and selective RIPK2 inhibitor can modulate signaling in the intestinal immune system and significantly improve disease associated intestinal inflammation.NEW & NOTEWORTHY The RIPK2 kinase at the apex of microbiome immunosensing is an attractive target for pharmacological intervention. A low oral dose of a RIPK2 inhibitor leads to significantly improved intestinal inflammation in the murine TRUC model of colitis. A selective and potent inhibitor of the RIPK2 kinase may represent a new class of therapeutics that target microbiome-driven signaling for the treatment of IBD.

Bayesian sample size determination for a Phase III clinical trial with diluted treatment effect.

When Phase III treatment effect is diluted from what was observed from Phase II results, we propose to determine the Bayesian sample size for a Phase III clinical trial based on the normal, uniform, and truncated normal prior distributions of the treatment effects on an interval, which starts from an acceptable treatment effect to the observed treatment effect from Phase II. After incorporating the prior information of the treatment effects, the Bayesian sample size is the number of patients of the Phase III trial for a given Bayesian Predictive Power (BPP) or Bayesian Historical Predictive Power (BHPP). After that, the numerical simulations are carried out to determine the Bayesian sample size for the Phase III clinical trial. In particular, there exists a hook phenomenon for the BHPP when the number of patients of the Phase II trial equals 70 assuming the normal, uniform, or truncated normal treatment effect. Moreover, we add some sensitivity analysis of the Bayesian sample size about the parameters in the simulations. Finally, we determine the Bayesian sample size (number of events or deaths) of the Phase III trial for a fixed power, Bayesian Historical Power (BHP), and BHPP in the axitinib example.

Evaluation of the effect of the specific CCR1 antagonist CP-481715 on the clinical and cellular responses observed following epicutaneous nickel challenge in human subjects.

BACKGROUND: The CC-chemokine receptor-1 (CCR1) is thought to be involved in recruitment of inflammatory cells in allergic contact dermatitis (ACD). CP-481715 is a specific antagonist of CCR1. OBJECTIVES: To determine the inhibitory effects of CP-418 715 in ACD by evaluating the clinical signs and cellular infiltration in skin biopsies following epicutaneous nickel challenge in allergic subjects. SUBJECTS/METHODS: In this phase 1/2 study, 40 subjects were randomized to 5 days of treatment in four parallel groups (placebo three times daily (TID), placebo once daily (QD), 1000 mg CP-418 715 TID, and 3000 mg CP-418 715 QD). Twenty-four hours after the first drug administration, nickel sulfate patches were applied on subjects' backs and removed 48 hours later. RESULTS: Pretreatment with 1000 mg CP-481715 TID resulted in significant reductions in visual scores of the nickel reactions (P = 0.01). Instrumentally measured erythema tended to decrease in the CP-481715 mg TID group (P = 0.06). No differences were noted between the 3000 mg CP-481715 mg QD group and pooled placebo. No significant differences were found for immunohistological cell counts. CP-418 715 was generally safe and well tolerated. CONCLUSIONS: Blocking of CCR1 only partly inhibited clinical manifestations of ACD. Several chemokine receptors are likely relevant for the cellular influx observed in ACD lesions.