COLON-TARGETED CYCLOSPORINE IN THE IL10 KNOCK OUT MODEL OF CROHN'S COLITIS
Authors: I S Coulter, V Aversa, C T Taylor, P Fallon
Journal: Gut (2013)

<h3>Introduction</h3> Cyclosporine A (CyA) is a powerful immunosuppressive agent and has been used off label for steroid-dependent or steroid-refractory ulcerative colitis. However, systemic exposure results in a number of side effects. A novel advanced oral drug delivery system, SmPill<sup>®</sup>, has been developed to permit targeted release of CyA directly into the colon tissue with limited systemic exposure. <h3>Aims/Background</h3> The objective was to compare SmPill<sup>®</sup>-CyA activity in the IL10 knock-out mouse model of Crohn9s colitis against the marketed Neoral<sup>®</sup> (po) and Sandimmun<sup>®</sup> (ip). <h3>Method</h3> Mice were treated for 42 days, received the equivalent of 15 mg/kg/day CyA as well as untreated and SmPill<sup>®</sup> placebo. A secondary objective was to measure systemic pro-inflammatory cytokine activity in isolated spleen cells. <h3>Results</h3> General Mouse Health: The SmPill<sup>®</sup>-CyA group were significantly heavier than mice in all other groups on Day 42. The SmPill<sup>®</sup>-CyA group had the lowest Disease Activity Index scores relative to the other groups. Colon Tissue Inflammatory Biomarkers: The untreated mice had the highest Serum Amyloid A levels (SAA), with the lowest levels seen with those treated with SmPill<sup>®</sup>-CyA (p&lt;0.001) followed by Sandimmun<sup>®</sup> (i.p) (p&lt;0.01) treated mice. Sandimmun (i.p) and SmPill<sup>®</sup>-CyA groups had significantly lower (P&lt;0.01) histology scores relative to Neoral<sup>®</sup>. Neoral<sup>®</sup> (po) had the greatest relative score. The highest levels of Myeloperoxidase (MPO) activity were seen in the untreated and placebo mice. There was statistically lower MPO activity in both the SmPill<sup>®</sup>-CyA and Sandimmune<sup>®</sup> (i.p.) groups relative to untreated mice (p&lt;0.05). Similarly to a reduction in MPO activity, the SmPill<sup>®</sup>-CyA groups also had reduced IL-1α, IL-17 and TNFα pro-inflammatory cytokine levels (p&lt;0.05) in colon tissue at Day 42. Systemic Tissue Inflammatory Biomarkers: In a measure of systemic CyA activity, the activity of a number of pro-inflammatory cytokines in activated isolated spleen cells was measured. The Sandimmune<sup>®</sup> (i.p) treated mice had significantly reduced production of TNF-α (p&lt;0.01) and IL-17 (p&lt;0.05) relative to cells from the untreated and placebo treated mice. In mice treated with SmPill<sup>®</sup>-CyA the reduction in TNF-α and IL-17 release by cells was non-significant. The pro-inflammatory cytokine expression levels for Neoral<sup>®</sup> was between that of Sandimmune<sup>®</sup> and SmPill<sup>®</sup>-CyA. <h3>Conclusion</h3> The above study demonstrated that SmPill<sup>®</sup>-CyA conferred preferential local colonic efficacy with limited systemic activity, in effect, harnessing the local efficacy of CyA and reducing systemic side effect risks. A SmPill<sup>®</sup>-CyA formulation, CyCol<sup>®</sup>, has progressed through human Phase I (PK) study in Canada and Phase IIb study in Ireland and the UK. A multi-centre Phase IIb study is being planned.