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11/24/2014

ABUSEDETERRENTMARKETWhatsinthePipeline?AbuseDeterrentProducts|Articles|drugdevelopmentanddeliverybackissues|DrugDe

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Issue:November/December2014,PostedDate:11/18/2014

ABUSEDETERRENTMARKETWhatsinthePipeline?
AbuseDeterrentProducts

INTRODUCTION

Reducingmisuseandabuseisoneofthemoreinterestingapplicationsofformulationanddrug
deliverytechnologytorealworldchallenges.Problemsrelatedtotheabuseofcentralnervous
systemactingproductsarewellknownandyetremainasignificantchallengeforthemedical
community,families,aswellaslawenforcementandthecourts.

Seriousattemptstoreducetheabuseofprescriptiondrugs,mostnotablyopioids,havebeen
ongoingformorethanadecadewithsomesignificantadvancesrealized.Yetthereremainsmuch
tobedone.Fromtheperspectiveofthepharmaceuticalindustry,thereareatleasttwoapproaches
thatpromiseatleastsomereliefforthisproblem.Theidealsolutionfromtheperspectiveofmany
isthedevelopmentofincreasinglywelltoleratednovelagentscapableoftreatingindicationssuch
aspain,anxiety,depression,andhyperactivity,withoutanyabuseliability.Thisholygrailsolution
isyettoberealized.Thefallbackapproachhasbeentolooktothepharmaceuticalsciencesfor
waystoreducetheabuseandmisuseofagentsthathavealonghistoryofefficacyandsafety
whenusedasprescribed.Wewillusethetermabusedeterrenttodescribethesedesired
featuresandbenefits.Thisexpressionencompassesawidevarietyofactionsallrelatedto
reducingthenonprescribeduseofaproduct,intermsofintentorprocedure.

WedecideditwouldbeinterestingtointerrogatethePharmaCircledatabaseandseewhat
successeshavebeenachievedwithrespecttoabusedeterrentformulationsintermsofapproved
andpipelineproducts.Wealsotookamoregenerallookattheformulationapproachesbeing
appliedtoabusedeterrence.

Somebackgroundthisshortreviewincludesonlyproductsandtechnologiesthathavereached
thestageofclinicaldevelopment.Researchandpreclinicalproducts,andtheirassociated
technologies,havenotbeenincluded.Forthepurposeofthisarticle,someproductsthathavenot
reportedresultsoractivityfor4ormoreyearshavebeenlabeledasinactive,eventhoughthe
sponsoringcompaniesmaystilllistthemintheirproductpipelines.

THEABUSEDETERRENTPRODUCTPIPELINEAPPROVED&CLINICALSTAGE
PRODUCTS
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QueryingthePharmaCircleProducts&Pipelinedatabasewiththetermsabusedeterrentand
abuseresistantreturnedatotalof129productsasbeingatsomestageofannounced
development,marketedthroughclinicaltopreclinicalandresearch.Limitingthislisttoproducts
thatareactiveandeitherapproved,filedwithregulatorybodies,orinclinicaldevelopmentreduces
thenumbertoamuchmoremanageablelistof53products.Thisexcludesanadditional10clinical
productsthathavebeenformallydiscontinuedorhaveprovidedsuchlimitedupdatestosuggest
theyareineffectdiscontinued.ThislistiscurrentasofmidSeptember2014.

ThedistributionoftheseproductsbytypeandstagearesummarizedinTable1.Whatisalittlebit
surprisingisthenumberofgenericabusedeterrentproducts(19)thathavereceivedtentative
approvalorhavetheirapplicationsunderreview.Thefourapprovedproductsbeingtargetedby
thesegenericsareShiresVyvanse,EndosOpanaERCrushResistant,AcurasOxecta,and
PurduePharmasreformulatedOxyContin.

Ifwetakeoutthegenerics,thereremainatotalofnineproductsthatareMarketed,Approved,orin
Registration.Atotalofsevenproductshavebeenapprovedwithadirectorimpliedabuse
deterrentorabuseresistantclaim.TheseproductsarelistedinTable2.

FORMULATIONSTRATEGIES

Fourgeneralformulationstrategiesarecurrentlyemployedtoreduceoreliminatethepotentialfor
theabuseandmisuseofpsychoactivepharmaceuticals.Theseare:

Type1Formulationsthatphysicallylimittheabilityofproductstobemechanicallyorchemically
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modifiedforthepurposeofinjection,insufflation,orrapidoralabsorption.

Type2Formulationsthatincludeanantagonistoraversiveagentthatblocksthedesired
propertiesoftheproductwhenabused,ormakesitunpalatableortoxicwhenrepurposedfor
administrationbyinjectionorinsufflation.

Type3Modifiedformulationreleaseproductsthatlimitthepossibilityofrapidabsorptionofthe
active.Thiscanbeachievedthroughsomesortofmolecularmodification(prodrug)orsustained
releaseengineeringnoteasilyovercomeusingmechanical,physical,orkitchenchemistry
procedures.

Type4Thefourthapproachcombinestwoormoreoftheaforementionedapproaches,most
commonlysomesortofmodifiedreleasecombinedwithphysical/chemicalresistancefeatures.
Thesubcategoriesare:

Type4a:Type1&Type2
Type4b:Type1&Type3
Type4c:Type2&Type3
Type4d:Type1&Type2&Type3

Ananalysisoftheapprovedandclinicaldevelopmentpipelineasafunctionoftechnology
approachispresentedinTable3.(Note:genericproductsarenotincludedinthisanalysis.)Some
assumptionsweremaderegardingtheexactabusestrategiesofcertainpipelineproductsofwhich
therewaslimitedpublicinformation.Alittlebitofexplanationisinordertoaddresswhatappearto
beinconsistencieswiththefiguresinTable3.

TherearenopureType2productsindevelopmentasbestascanbedetermined.TheType2
strategy,incorporatinganantagonistoraversiveagent,isonlyseenincombinationwithsomesort
ofmodified/extendedreleasetechnology.Ofcourse,extendedrelease,Type3wastheoriginal
abusedeterrentstrategyuntilitwasrealizedthattheseproductscouldbecrushed,overcomingthe
modifiedreleasecharacteristicsoftheproductsandnegatinganyabusepreventionbenefits.One
immediatereleasedevelopmentprogramusinganaversiveagent,niacin,asopposedtoan
antagonist,wasterminatedafteranFDAAdvisoryPanelsuggestedthisapproachintroduced
safetyissues.

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Atthispoint,therearenoapprovedorclinicalstageproductsidentifiedasbeingType4d,
incorporatingallthreeabusedeterrentstrategies,althoughthereappeartobeacoupleinthe
preclinicalstage.

ThesharpeyedreaderwillnotethatthereisaoneproductdiscrepancybetweenTables1and3.
Thisisanoutlierproduct,atransdermalformulationoffentanylthatmakesclaimtoreducingthe
potentialforabusebyexhaustingthefentanylthroughefficientdeliveryandleavinganegligible
amountofactiveinthepatchaftertheprescribed3daydosing.Thismakestheusedpatches
lessattractiveforsmokingorextractionusingkitchenchemistrytechniques.

REGULATORYCONSIDERATIONS&GENERICFORMULATIONS

Itsremarkabletoseehowmany505(j)productsarelinedupattheUSFDAwaitingtocapturethe
genericopportunityrepresentedbycurrentlyapprovedabusedeterrentproducts.Theleading
productfromaunitsandrevenueperspective,PurduePharmasOxyContin,islikelytobesubject
togenericsassoonasOctober2014onthebasisofasettlementwithActavis.Thisagreement
limitsthenumberofunitsthatActaviswillbepermittedtodistributeaftertheFDAapprovestheir
generic.

Thewholequestionoftheregulatoryrequirementsnecessarytosecurealabelclaimofabuse
resistantordeterrentisstillnotclear.PurduemanagedtosecurelanguageinitsUSproduct
labelingforOxyContinthatreviewedtheabusedeterrencestudiesconductedfortheproduct.This
contrastswiththenewformulationofOpanaERfromEndothatisidentifiedascrushresistant,but
carriesnoabuseresistantordeterrentinformationinitspackageinsert.Clearly,thereisaminimal
amountofdatathatneedstobeprovidedtosecureabuseresistantand/ordeterrentlanguagein
theproductlabeling.Exactlywhatthismightbeisnotobvioustothecasualobserver.

Thisissueofexactlywhatperformancetargetsandstudiesarerequiredtocaptureanabuse
deterrentclaimwillhaveanimpactontheapprovalandclaimsoffutureproducts,including
generics.Regardless,productsthatincludeanysortofabuseresistantordeterrentfeaturesarea
netbenefittothepublicwhetherornottheyreceivethecorrespondingclaimsfromtheregulatory
bodies.

ABUSEDETERRENTFORMULATIONSTHEFUTURE

Althoughstillinrelativeinfancy,thewholeareaofabusedeterringformulationsislikelytogrowup
veryquickly,andlikelywithoutanyprivilege.Itsnotunlikethemid1990s,wheresustainedrelease
formulationsquicklybecameastandardpartofeverycompanysformulationtoolbox.Itwasatthis
pointnolongernecessarytosecureexternalexpertisetocreatealongactingformulationofa
proprietarymolecule.Thispointwasemphasizedbytheparallelemergenceofsustainedrelease
genericproductsinthemidtolate1990s.

Itmaybethatthegoldenageofabusedeterrentformulationtechnologieshasalreadypassed
beforeithashadachancetoflourish.Thatsnottosuggestabuseresistantanddeterrent
formulationsinthepipelinewontbeapprovedandprovideimportanttherapeuticbenefits.Rather,
theopportunitytoprofitthroughmarketshareandpricingflexibilityasaresultofanysignificant
technologyorregulatoryexclusivitywillbelimited.Theactives,forthemostpartmultisource
opioidsandstimulants,providenorealpatentexclusivity.Andwiththedevelopmentofmultiple
abusedeterrentformulationstrategies,thereappearstobelittlepotentialforanytrueexclusivity
fromatechnologyperspective.Itisdifficulttoimaginethatanycompanywillbeabletocapturethe
typeofprofitwithabusedeterrentproductsortechnologiesashasbeenenjoyedbyPurdue
PharmaandtheirreformulatedOxyContin.
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Itsnothardtopredictthatwewillseemoreandmoreabuseresistantanddeterrentformulations
ofopioidsandstimulantshitthemarketinthenearfuture,followedbytheirgenericequivalents.
Therealmoneytobemadewillbefoundinthoseproductsthatchangethewholeparadigm
novelmoleculesthatretaindesiredanalgesicorpsychoactivepropertiesbutwithoutanyinherent
addictiveorabusereinforcingproperties.Itspossiblethesemoleculeswillbediscovered,butit
doesnotseemitwillbeanytimesoon.Inthemeantime,patients,physicians,andsocietyasa
wholewillneedtolooktotheingenuityofpharmaceuticalscienceprofessionalstoprovide
meaningfulneartermsolutions.

Toviewthisissueandallbackissuesonline,pleasevisitwww.drugdev.com.

Dr.JosefBossartisManagingDirectorofThePharmanumbersGroup,a
boutiqueresearchandconsultinggroupprovidingthebiopharmaceutical
industrywithanalysisandinsightsthatimprovebusinessoutcomes.Hehas
morethan3decadesofexperienceinthebiopharmaceuticalsector,
includingseniorsales,marketing,businessdevelopment,andmanagement
positionswithinBigPharma,SpecialtyPharma,andEmergingPharma
companies.HeearnedhisPhDinMedicinalChemistryfromTheOhio
StateUniversity,CollegeofPharmacy.

Dr.TugrulT.KararliearnedhisPhDinPharmacologyfromtheUniversity
ofFloridaandhisMBAfromDePaulUniversity.Dr.Kararliworkedat
Searle/Pharmaciafor18yearsandheldvariouspositionsand
responsibilitieswithinthePharmaceuticalSciencesdepartment,
participatinginpharmaceutics,productdevelopment,anddrugdelivery
activities.AstheChairmanoftheGlobalDrugDeliveryTechnologyTeam
atPharmacia,hewasresponsibleforidentifying,planning,andexecuting
thedrugdeliverytechnologystrategiesformarketedanddevelopment
products.Dr.Kararlihasauthorednumerousarticlesonvariousaspectsof
pharmaceuticsanddrugdeliveryandholdsmorethanadozenUSand
internationalpatents.Currently,heistheFounderandPresidentof
PharmaCircleLLC,aknowledgemanagementservicecompanyinthedrug
deliveryandpharmaceutical/biotechnologyfields.

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Mr.KurtSedoisVicePresidentofOperationsatPharmaCircleLLC.He
earnedhisBSinChemistryandMathematicsfromtheUniversityof
WisconsinStevensPoint.PriortojoiningPharmaCirclein2003,heheld
variousR&DScientistpositionswithinSearle/PharmaciasPharmaceutical
SciencesDepartmentinAnalyticalDevelopmentandDrugDelivery.

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