The Medicines for Malaria Venture (MMV) recently published a ?roadmap? for the types of medicines that are needed to support the long-term goal of malaria eradication. The roadmap consists of a wish list of target candidateprofiles(TCP)andmedicines(targetproductprofiles,i.e.,TPP).Withthemostrecentrevisiontothe anti-malarialtargetcandidatesandproductprofilestheMMVhighlightedtheneedforidentifyingnewmedicines for chemo-protection and chemo-prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2)(Burrows,JNetal.,2017,MalariaJournal,16:26).Accordingtotheirupdatedroadmapnewdrugsare needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver-stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil.TheMMVenvisionsthataninjectablesustained-releaseformulationcouldbedevelopedasalong- actingpreventativeprovidingupto3to4monthsofprotection. As a potent and selective inhibitor of the parasite?s cytochrome bc1 complex, ELQ-300 targets Plasmodium falciparuminthebloodandliverstagesandevenkillsparasitesdevelopinginthemidgutofthemosquitovector. WithsupportfromtheNIHandUSDODwehavebeensuccessfulindevelopinganoralformulationofprodrug ELQ-331 for use in humans for weekly prophylaxis against malaria, work that was performed in collaboration withSRIInternational.InthepresentapplicationweseekNIHsupportforacomprehensiveassessmentofELQ- 300 prodrugs for intramuscular injection to effect the sustained-release of drug from an oil depot (or other extendedreleasematrix)intothehostbloodstreamatlevelsabovetheminimumeffectiveconcentrationneeded to block liver stage infection by infectious sporozoites. In collaboration with SRI International we will leverage our knowledge of ELQ-300 prodrug chemistry, crystallinity, stability, and solvent/vehicle solubility with their expertise in formulation design and optimization to identify the optimal ELQ-300 prodrug design that is paired with an optimal depot formulation to provide long-term protection of animals from sporozoite infection. Four different prodrug chemistries will be evaluated and compared, varying R-group chain length to optimize the physiochemicalpropertiesofthedrugandtoenhancesolubilityinvehiclesandmixturesthatareapprovedfor humanuse.Theoverallgoalistodevelopalong-actingsustainedreleaseformulationofanELQ-300prodrug forchemo-protectionagainstmalaria.

Public Health Relevance

ELQ-300 is a selectively potent inhibitor of the Qi site of Plasmodium falciparum cytochrome bc1 with activity againstalllifecyclestagesoftheparasiteincludingliver,bloodandvectorstages.Inthisapplicationwefocus on the design of an ELQ-300 prodrug for enhanced performance as a long-acting sustained-release depot formulationforintramusculardeliveryandlong-termchemo-protectionagainstmalaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI141412-01A1
Application #
9816269
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
O'Neil, Michael T
Project Start
2019-06-05
Project End
2023-05-31
Budget Start
2019-06-05
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239