P-271 The Biomarker Profile of PTG-200, an Oral Peptide Antagonist of IL-23 Receptor, Correlates with Efficacy in Preclinical Models of IBD

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Abstract

Background:

Emerging clinical data from several monoclonal antibodies, ustekinumab (which targets IL-12/IL-23) and MEDI2070, BI655066 and LY3074828 (which target IL-23), strongly support IL-23 as a therapeutic target for the treatment of inflammatory bowel disease (IBD). To effectively treat IBD, we are developing a potentially potent and orally stable peptide, PTG-200, that would act locally in the GI tissues and functionally block the IL-23 pathway by selectively antagonizing the IL-23 receptor (IL-23R). In this study, we evaluated the effects of orally delivered PTG-200 in an animal model of acute colitis. As there is interest in using pharmacodynamics (PD) biomarkers for early stage drug development, we sought to profile mechanism-specific and disease-related efficacy biomarkers as well as target engagement biomarkers in 2 different colitis models.

Methods:

Acute colitis was induced in Sprague-Dawley rats by a single intra-rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) followed by efficacy analysis at day 8, or by ad libitum access to 5% DSS dissolved in drinking water every day until analysis at day 6. Candidate biomarkers were identified using enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), or immunohistochemistry (IHC) analysis of colon samples obtained from colitic rats orally treated with PTG-200 at 3 dose levels.

Results:

In the TNBS-induced colitis model, oral treatment with PTG-200 resulted in significant dose-dependent improvement in animal body weight, reduction in the colon weight to length ratio, and normalization of the macroscopic and histopathological changes in the colon. To characterize the efficacy biomarkers underlying the protective effects of PTG-200, we examined the levels of cytokines known to be regulated by IL-23R and disease-related markers in the distal colons of TNBS-treated rats. Protein levels of IL-17A and IL-22 were significantly attenuated in PTG-200-treated animals. The levels of myeloperoxidase (MPO), an indicator of neutrophil infiltration and of the innate immune response, were also significantly reduced. In the same model, IHC staining showed that the levels of phosphorylated signal transducer and activator of transcription 3 (Stat3) in the colons returned to control levels and correlated to dose titration in PTG-200-treated animals. The beneficial effects observed with oral PTG-200 were comparable to those from a high dose of neutralizing anti-IL-23p19 antibody following intraperitoneal administration. Additional support for the engagement of IL-23R resulted from oral treatment with PTG-200 in a DSS-induced rat model of IBD, which led to significant reduction in the protein and/or mRNA levels of IL-23-directed cytokines IL-17A, IL-17F and IL-22.

Conclusions:

In this study, we demonstrated that blockade of IL-23R-mediated signaling by oral treatment with PTG-200 significantly improved disease outcomes in a TNBS-induced rat model for IBD. More importantly, we showed that PD biomarkers correlate with PTG-200 treatment effects in preclinical models of IBD. This highlights the potential value of these biomarkers in translating preclinical efficacy to early clinical proof-of-concept for anti-IL-23R therapy.

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