CN-105 Improves Functional Outcome After Intracranial Hemorrhage

ABSTRACT Intracerebral hemorrhageICHis a devastating form of cerebrovascular disease with no FDAapproved treatmentsIt is generally accepted that ICH induced neuroinflammatory responses mediate development of cerebral edemaintracranial hypertensionand secondary neuronal injuryOne promising strategy for ICH neuroinflammatory modulation is through the downstream effects of apolipoprotein EapoEPrevious studies from our lab and others have demonstrated that endogenous apoE modifies neuroinflammatory responses by downregulating glial activation and release of pro inflammatory mediators making it a compelling target for therapeutic developmentHoweverthe therapeutic potential of the intact apoE protein is limitedas it does not cross the blood brain barrierTo address this limitation AegisCN developed CNaamino acid peptide that mimics the polar face of the apoE helical domain involved in receptor interactionsIn well established preclinical models of ICHCNimproves shortand long term neurobehavioral and histological outcomesdecreases cerebral edemaand increases neuronal survivalOur preclinical work with CNhas led to the successful completion of an IND and translation to early clinical studiesCNdemonstrated an excellent clinical safety profile in Phasehealthy volunteer single and multiple dose escalation safety and PK studies andas recommended by the FDAwe have initiated a multisite open label safety study in patients with ICHCNandapos s efficacy in preclinical ICH models is firmly establishedas are its neurorestorative and anti inflammatory effects in other preclinical models of acute brain injuryHoweverthis knowledge alone is insufficient for therapeutic translationTo bridge this gapthe objective of this application is to define the effects of genderageand chronic hypertension on long term neurobehavioral outcomes in preclinical ICH relevant paradigms and to identify surrogate imaging and biochemical markers of CNtarget engagement and efficacyWe will complete the following milestonesEstablish a greater thantreatment effect of CNvsvehicle treatment on vestibulomotor deficitrotorod latencyat Dayin a rat model of ICH with comorbid hypertensionEstablish treatment effects on vestibulomotor function as a function of age and gender to inform clinical translationCompletion of these milestones will facilitate translation into an adaptive randomized clinical trial for patients with acute ICH through PhaseSTTR funding NARRATIVE Each yearapproximatelypatients in the US suffer from intracerebral hemorrhageICHa common form of cerebrovascular disease with high mortality and poor long term cognitive and physical recoveryThere are no FDA approved pharmacologic treatments improving functional outcomes in ICHOne promising therapeutic strategy is modulation of ICH induced neuroinflammation responsible for secondary neuronal lossWe have identified CNa proprietary neuroprotective peptidewhich improves long term histological and functional outcomes in well established preclinical models of ICH as well as demonstrating an excellent clinical safety profile with reproducible pharmacokinetics and brain penetration in Phasehealthy volunteer studiesThe primary goal of this proposal is to define the critical parameters necessary to advance CNinto a fully informed adaptive Phaseb randomizedcontrolled clinical trial for acute ICH treatment