Threeultrasoundcontrastagents(Definity,OptisonandLumason)areFDAapprovedfor echocardiographyintheU.S.Definitycurrentlyhasover75%marketshare.Definity?sdominanceinthemarket isduetoitseaseofadministrationviaIVinfusionandrobustultrasoundcontrast.Definityhasshelf-lifeof2 yearsandmustbestoredunderrefrigeratedconditions.Definityhasanunpleasantsideeffectofbackpainin about2%ofpatients.Insomegroups,e.g.patientswithsicklecelldisease,therateofsideeffectsismuch higher,e.g.about20%.Themostlikelyetiologyofthebackpainiscomplementactivation.Definityisstabilized bythreephospholipidsoneofwhichisdipalmitoylphosphatidicacid(DPPA).Theinvestigatorsinthisproposal haveshownthatDPPAshortensthestoragelifeofDefinityandlikelycausesthesideeffectofthebackpain. MicrovascularTherapeutics(MVT)hasdiscoveredthatnotonlyisDPPAthemostrapidlyhydrolyzedlipidin theDefinityformulationbutthatDPPAalsoacceleratesthehydrolysisoftheotherlipids.WhenDPPA hydrolyzesitformslyso-PA-apotentstimulatingmoleculecausinginflammationlikelyresponsibleforthe adversesideeffects.MVThasinventedastable,neutralMB(MVT-100).ComparedtoDefinity,MVT-100is fourtimesmoreresistanttohydrolysis.Inamodelofcomplement-mediatedrenalretentionMVT-100hadfewer bioeffectsthanDefinity?whichshouldtranslateintosignificantlylessadverseevents.Echocardiographyin pigsshowsthatMVT-100iscomparable,ifnotsuperiortoDefinity,inprovidingLVopacificationand myocardialperfusioncontrast.MVThasreceivedguidancefromtheFDAthatMVT-100canbedeveloped viathe505(b)(2)pathway,noadditionalanimalstudiesarerequired;?anacceleratedclinicalprogram canbeusedtoleadtoapproval.MVT-100willserveasaplatformfordevelopmentoftheranostics.
SpecificAims :1.GMPmanufactureMVT-100,fileIND.2.Doserangingstudyin32volunteers(bolusand infusion,DefinityvsMVT-100)3.Pivotalstudyin61patientswithsuboptimalechocardiograms;?significant improvementinLVborderdelineationin>85%ofsubjects.4.FileNDA Rationale:MVT-100isanimprovedproduct.PerfluoropropaneistheAPIandthelipidsareexcipientsinthe product.The505(b)(2)pathwayallowsforanacceleratedapprovalpathwayforsuchproducts.UponNDA submission,typical11-monthreviewperiodbytheFDAbeforeapproval.Thedevelopmentpathwaywillyield identicallabelclaimsasthoseforDefinity.Additionallabelclaimscanbepursuedlaterorinparallel. Expectedoutcomesofresearch:DevelopmentofanFDAapprovedimprovedperflutrenproduct,MVT-100 withlongershelf-life(potentialforroomtemperaturestorageandterminalsterilization?increasingsafetyofthe product)anddecreasedadversesideeffects.Sincetheproductiselectrostaticallyneutral,MVT-100willalso serveasarobustplatformfordevelopmentofmolecularimagingtargetedultrasoundcontrastagents andtheranosticagents.
Ultrasound is one of the most common imaging examinations and has advantages of absence of ionizing radiation, portability and relatively low cost. Ultrasound contrast agents are used to improve the accuracy of ultrasound and Definity (perflutren) is the world's leading ultrasound contrast agent but perflutren has to be refrigerated and has a side effect of back pain. The investigators have developed a new, improved perflutren for room temperature storage with decreased side effects.
