SBIR-STTR Award

Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease with no FDA- approved treatments. It is generally accepted that ICH-induced neuroinflammatory responses mediate development of cerebral edema, intracranial hypertension, and secondary neuronal injury. One promising strategy for ICH neuroinflammatory modulation is through the downstream effects of apolipoprotein E (apoE). Previous 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 development. However, the therapeutic potential of the intact apoE protein is limited, as it does not cross the blood-brain barrier. To address this limitation AegisCN developed CN-105, a 5-amino acid peptide that mimics the polar face of the apoE helical domain involved in receptor interactions. In well-established preclinical models of ICH, CN-105 improves short- and long-term neurobehavioral and histological outcomes, decreases cerebral edema, and increases neuronal survival. Our preclinical work with CN-105 has led to the successful completion of an IND and translation to early clinical studies. CN-105 demonstrated an excellent clinical safety profile in Phase 1 healthy volunteer single and multiple dose escalation safety and PK studies and, as recommended by the FDA, we have initiated a multisite open label safety study in patients with ICH. CN-105's efficacy in preclinical ICH models is firmly established, as are its neurorestorative and anti-inflammatory effects in other preclinical models of acute brain injury. However, this knowledge alone is insufficient for therapeutic translation. To bridge this gap, the objective of this application is to define the effects of gender, age, and chronic hypertension on long-term neurobehavioral outcomes in preclinical ICH-relevant paradigms and to identify surrogate imaging and biochemical markers of CN-105 target engagement and efficacy. We will complete the following milestones: 1: Establish a greater than 20% treatment effect of CN-105- vs. vehicle-treatment on vestibulomotor deficit (rotorod latency) at Day 7 in a rat model of ICH with comorbid hypertension; 2: Establish treatment effects on vestibulomotor function as a function of age and gender to inform clinical translation. Completion of these milestones will facilitate translation into an adaptive randomized clinical trial for patients with acute ICH through Phase 2 STTR funding.

Public Health Relevance Statement:
NARRATIVE Each year, approximately 100,000 patients in the US suffer from intracerebral hemorrhage (ICH), a common form of cerebrovascular disease with high mortality and poor long-term cognitive and physical recovery. There are no FDA-approved pharmacologic treatments improving functional outcomes in ICH. One promising therapeutic strategy is modulation of ICH-induced neuroinflammation responsible for secondary neuronal loss. We have identified CN-105, a proprietary neuroprotective peptide, which 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 Phase 1 healthy volunteer studies. The primary goal of this proposal is to define the critical parameters necessary to advance CN-105 into a fully informed adaptive Phase 2b randomized, controlled clinical trial for acute ICH treatment.

Project Terms:
Acute; Acute Brain Injuries; Address; Affect; Age; aged; American Heart Association; Amino Acids; Animals; Antiinflammatory Effect; Apolipoprotein E; attenuation; Autologous; base; Biochemical Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebrovascular Disorders; Chronic; Clinical; Clinical Research; clinical translation; Clinical Trials; Clinical Trials Design; clinically relevant; Cognitive; collagenase; Communities; Comorbidity; design; Development; Dose; Drug Kinetics; E protein; Face; FDA approved; Female; functional outcomes; Funding; Future; Gender; glial activation; Goals; Guidelines; healthy volunteer; Hematoma; Histologic; Human; Hypertension; imaging biomarker; improved; improved outcome; In Vitro; in vivo; Inbred SHR Rats; Inflammation Mediators; Injections; Injury; Intracranial Hemorrhages; Intracranial Hypertension; Investigation; Knowledge; Lipoprotein Receptor; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; mimetics; Modeling; mortality; multidisciplinary; Mus; neurobehavioral; neurobehavioral test; neuroinflammation; neurological recovery; neuron loss; Neuronal Injury; neuronal survival; neurorestoration; open label; Orphan Drugs; Outcome; Patients; Penetration; Peptides; peptidomimetics; Pharmacological Treatment; Phase; pre-clinical; Pre-Clinical Model; Proteins; Publishing; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Rattus; receptor; Recovery; Recovery of Function; Reporting; Reproducibility; response; Safety; safety study; Serum; Small Business Technology Transfer Research; Surrogate Markers; targeted biomarker; targeted treatment; Therapeutic; therapeutic development; Toxic effect; Translations; treatment effect; Treatment Efficacy; United States National Institutes of Health; Work

Annually, approximately 100,000 patients in the USA suffer from intracerebral hemorrhage (ICH), which isassociated with high mortality rates and poor long-term cognitive and physical recovery. At present, nopharmacological therapies have been demonstrated to improve functional outcomes after ICH. However, wehave successfully demonstrated that CN-105, a pentapeptide derived from the receptor binding surface of theapolipoprotein E (apoE), is a highly promising therapy for improving recovery after ICH. CN-105 was rationallydesigned to mimic the LRP-1 receptor binding face of the apoE holoprotein, which binds the cell surface lowdensity lipoprotein-related (LRP1) receptor, reducing microglial activation, neuroinflammation, and neuronalexcitotoxicity. We demonstrated that CN-105 has excellent CNS penetration, is well tolerated, and retains theanti-inflammatory and neuroprotective effects of endogenous apoE holoprotein.In the Phase 1 of this STTR, we demonstrated CN-105's preclinical efficacy across species, sex, age, andhypertensive comorbidity, as evidence to support efficacy phase clinical trials. Our preclinical work with CN-105has led to the successful completion of an IND and translation to a Phase 1 single- and multiple-escalating dosestudy (NCT02670824), where CN-105 demonstrated excellent clinical safety profile and linear pharmacokinetics.Based on the successful completion of the Phase 1 trial and after consultation with and funding from the FDA,we completed and recently published the CN-105 in participants from the Acute supraTentorialintraCerebral Hemorrhage (CATCH) trial, a multisite open-label safety study in patients with acute ICH(NCT03168581)1, which demonstrated early efficacy, and completed a parallel randomized placebo-controlledclinical trial in patients with ICH in Singapore (S-CATCH; NCT03711903).Together the CATCH and S-CATCH trials will allow insight into target engagement and therapeutic efficacy ofCN-105 via analyses of serologic proteins and radiographic surrogates. Given the orphan drug status of CN-105, our preliminary data are critical to rationally inform the development of a larger and definitive ICH study. Inthe current proposal, we will design an adaptive Phase 2b/3 clinical trial to evaluate CN-105 efficacy, incollaboration with StrokeNet and the Duke Clinical Research Institute (DCRI) (Milestone 1). To form the basisfor trial adaptation, we will utilize radiographic and serologic data already collected in the completed CATCH andS-CATCH trials to characterize an algorithm for screening treatment response to CN-105 (Milestone 2).

Public Health Relevance Statement:
Narrative Intracerebral hemorrhage (ICH) is a devastating stroke sub-type with no proven therapy. Based on strong supportive evidence and recent clinical trials, CN-105, a 5-amino acid peptide derived from the receptor binding surface of the apolipoprotein E (apoE), appears to be poised for translation as an acute ICH therapeutic. This project will build on prior our Phase 1 STTR by coupling use of blood proteins and brain imaging to improve patient selection for planning an Phase 3 clinical trial of CN-105 in acute ICH.

Project Terms:
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