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ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R42AI155107-02
Agency Tracking Number: R42AI155107
Amount: $1,988,078.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA19-270
Timeline
Solicitation Year: 2019
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-07-19
Award End Date (Contract End Date): 2023-06-30
Small Business Information
201A E FRANKLIN ST STE 104
Chapel Hill, NC 27514-3621
United States
DUNS: 080971466
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ROBERT TARRAN
 (919) 219-1113
 robert_tarran@med.unc.edu
Business Contact
 ROBERT TARRAN
Phone: (919) 219-1113
Email: eldecpharmaceuticals@gmail.com
Research Institution
 UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
 
ROOM 102 CARRINGTON HALL
CHAPEL HILL, NC 27599
United States

 Nonprofit College or University
Abstract

Abstract
Hospital acquired pneumonia (HAP) is most common cause of mortality in intensive care units and the 2nd most common nosocomial infection in the US. P. aeruginosa, S. aureus (including MRSA) and other ESKAPE pathogens are common causes of HAP. The rise in antibiotic-resistant bacteria, including MRSA, further complicates the challenges of delivering effective treatments in this patient population. New approaches beyond traditional antibiotics are urgently need to improve outcomes in HAP patients. The innate immune protein Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is secreted into the lung lumen, where it can bind to and regulate ion channels. Orai1 is a ubiquitously-expressed plasma membrane Ca2+ channel, whose activation is required for the onset of inflammation. We have identified SPLUNC1’s Orai1-inhibitory domain, termed the a6 region: SPLUNC1 and a6 negatively regulate Orai1 to moderate Ca2+ signaling and reduce inflammation. However, both SPLUNC1 and the a6 peptide are rapidly degraded by neutrophil elastase, limiting their effectiveness in reducing Ca2+ signaling and inflammation in pneumonia, which is characterized by neutrophilia. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reconstitutes SPLUNC1/a6’s ability to inhibit Orai1, yet is significantly more resistant to degradation by neutrophil elastase than a6. In murine pneumonia models with P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung neutrophilia by 90%, decreased lung bacterial infection by 3-5 log10 CFUs, reduced sepsis, and increased survival. These definitive experiments demonstrate that rebalancing the lung’s inflammatory response via ELD607 enhances the lungs’ natural ability to clear pathogens, in the absence of antibiotics. This capacity is predicted to make concurrently-administered antibiotics more effective, providing an important new therapeutic strategy to help address the emergence of antibiotic-resistant strains of bacteria. The ability of ELD607 to inhibit Orai1 and increase bacterial clearance represents a revolutionary approach to improving HAP outcomes. Robust validation of ELD607 in Phase I will enable Eldec Pharma to request a pre-IND meeting with the FDA, in order to perform IND-enabling studies in Phase II and to make the subsequent transition to clinical development. Phase 1 Aim 1. To confirm that ELD607 replicates the Orai1-tropism observed with SPLUNC1/a6. Aim 2. To replicate ELD607’s ability to clear other ESKAPE pathogens. Phase 2 Aim 3 To produce GLP grade ELD607 to support downstream development activities. Aim 4. To determine the optimal dosing regimen of ELD607 in a murine model. Aim 5. To validate the ELD607 dosing regimen in a Rhesus macaque model of HAP.PUBLIC HEALTH RELEVANCE: Public Health Hospital acquired pneumonia is a type of pneumonia that occurs 2 days or more after a patient is hospitalized. It is the primary cause of mortality in intensive care units. We have developed a novel non-antibiotic treatment that helps the lungs immune system to get rid of bacteria.

* Information listed above is at the time of submission. *

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