Developing the required biomarkers that define IL-23R target engagement and effect on downstream signaling for late stage drug development and early clinical proof-of-concept

Abstract Developing the required biomarkers that define ILR target engagement and effect on downstream signaling for late stage drug development and early clinical proof of conceptInflammatory bowel diseaseIBDaffects aboutof the world s populationDue to its early onset and lack of an adequate curethis disease requires lifelong treatmentIBD affects the gastrointestinalGItract and manifests as two subtypesCrohn s diseaseCDand ulcerative colitisUCIn recent yearsanti TNF biological agents have transformed the treatment of IBDbut these are not ideal drugsrequiring administration by injectionand in some instances hospitalization for intravenous infusionThese agents have numerous side effectsincluding increased infection ratesadditionallyanywhere fromof patients either lose responsethrough the production of neutralizing antibodiesor become intolerante gsite reactionsLong half lives of injected antibodieswhich can result in TNF blockade over sustained periodscan exacerbate these issues and make it hard to control drug exposure to minimize safety issuesAlthough current anti TNF drugs possess similar modes of actionswitching from one agent to another is an established treatment approach for patients who become unresponsive or intolerantStelaraustekinumabtargets both the ILand ILpathways and is efficacious in Phase III Crohn s disease clinical trials in TNF resistant patientsHoweverthere is some concern about cardiovascular safety eventsas illustrated by the removal from the market of briakinumabwhich also targets ILand ILduein partto increased cardiovascular riskILis produced locally in the intestine and plays a fundamental role controlling intestinal mucosal inflammationHenceselectively modulating the ILpathway locally in diseased tissue is the preferred strategySuch an approach would provide high concentrations of drug in diseased tissue and block ILfunction locally in the intestineDuring the Phase I SBIRwe developed a potentnMorally stable antagonistPNof the ILreceptorILRthat is efficacious when orally delivered in a TNBS induced model of colitisPNprevented body weight lossreduced the colon weight tolength ratioandmost importantlyimproved colon macroscopic pathologyPNwas predominantly restricted to GI tissue with minimal systemic exposureThe overall objective of this Phase II SBIR proposal is to develop methods for characterizing in vivo target engagementincluding pharmacokinetic and pharmacodynamic methods to characterize the binding of PNto ILR in various compartments and how binding affects downstream biomarkers and efficacyThese biomarkers will be used to aid compound and dose selectionsand to provide early stage clinical proof of conceptThe specific objectives are toDevelop the required target engagement methods to enable quantification of binding of PNto ILR bearing cellsIdentify the required pharmacodynamics biomarkers that would reflect the downstream biological changes upon target engagementandCorrelate target engagement and pharmacodynamics biomarkers with efficacy readouts in TNBS models of colitis in ratsThis PhaseSBIR program is supported by a team that has a track record in the oral delivery of constrained peptidesa proven capacity in translating early stage research to clinical outcomesa group of scientific and clinical advisors with significant experience in IBDand the appropriate research environmentIn this Phase II SBIR proposalwe describe the development of the appropriate biomarkers that will establish early proof of concept and the effective human dose range through an assessment of target engagement and pharmacologic activity in early stage human trialsThese are important steps towards our ultimate objective of demonstrating clinical benefit in late stage clinical trialsThese biomarkers will permit the assessment of mechanism specific and disease related parameters in bloodfecaland or colon biopsy samples