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IND enabling development of LGM2605 as adjuvant treatment for asthma

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42AI132012-02
Agency Tracking Number: R42AI132012
Amount: $1,000,000.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-07-25
Award End Date (Contract End Date): 2022-06-30
Small Business Information
3160 CHESTNUT ST STE 200, Philadelphia, PA, 19104-2853
DUNS: 078829605
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (610) 299-7482
Business Contact
Phone: (215) 206-2754
Research Institution
 1850 Research Park Drive, Suite 300
DAVIS, CA, 95618-6153
 Nonprofit college or university
Project summary IND enabling development of LGMas adjuvant treatment for asthma Glucocorticoid resistance is a major treatment problem in asthmaOur recent studies in micenon human primates and severe asthma patientsalong with reports by others suggest that glucocorticoid receptorGRexpression was impaired by psychosocial stressin association with enhanced NF kB activation and glucocorticoid non responsiveness of immune cellsThis Phase II STTR proposal was developed jointly between LignaMedDrSieleckiUPennDrChristofidou Solomidou and UC DavisDrHaczkubased on our results generated by the Phase I STTR projectOur study strongly suggested that LGMa racemic synthetic form of a novelnaturalnon toxicanti inflammatory component of flaxseedsecoisolariciresinol diglucosideSDGmay be effective to treat severe asthma exacerbation induced by inhalation of ozoneLGMis a racemate which has proven free radical scavenging activities in vitro and in vivo and it induces activation of nuclear factor erythroidrelated factorNRFa major anti oxidant transcription regulator and inhibitor of NF kBAs part of assembling an IND package we will complete a pivotal proof of concept study using rhesus macaquesbecause of their phylogenetic proximity to humans with a high degree of immune crossreactivity and a predisposition to spontaneously develop both asthma and psychosocial stressOur exciting preliminary results from stressed asthmatic macaques treated with LignaMed s LGMdemonstrated a significant suppression of airway inflammation and it abolished airway hyperresponsivenessAHRin response to ozone exposureWe hypothesize that LGMalleviates asthma symptoms by interfering with activation of immune and airway structuralepithelial and smooth musclecells and improving glucocorticoid responsiveness through activation of NRFgene expression and downstream anti oxidant pathwaysAimAssess the mechanism of action and dose dependent effects of LGMtreatment on regulation of the GRNF kB and NRFexpression and glucocorticoid responsiveness in vitroAimAScale up and definition of release specifications of the single isomer of LGMBPharmacokinetic evaluation of the single isomer of LGMin nonhuman primatesrhesus macaquesAimStudy the dose dependent effects of single isomer LGMon preventing AHRimmune cell activation and improving glucocorticoid responsiveness in ozoneexposed rhesus macaquesOur translational approach using rhesus macaquesin vivo clinical testingand cells from severe asthma patientsin vitro mechanistic studies on cell types relevant to asthmawill establish how LGMaffects glucocorticoid responsiveness and will lay the groundwork for subsequent human clinical trials NARRATIVEIn collaboration with UC Davis and the University of Pennsylvania LignaMed LLC is developing LGMas an adjuvant treatment of severe asthmaa condition associated with heightened airway inflammation and nonresponsiveness to mainstream corticosteroid treatmentOur Phase I STTR study demonstrated effectiveness of LGMin reducing airway hyperreactivity and airway inflammation in asthmatic rhesus macaquesIn this Phase II project we will use this macaque model for a pivotal proof of concept studyIn additionwe will investigate the mechanism of action of this compound in peripheral blood mononuclear cells from severe asthma patients and in human airway smooth muscle cells by hypothesizing that LGMinhibits NF kB and improves glucocorticoid responsiveness through stimulating NRFrelated pathwaysThese studies will determine the optimal dosing regimenestablish the role of the oxidative molecular changes in glucocorticoid responsiveness and will inform future clinical trials of LGMas an asthma treatment

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

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