“Intelligent Formulation Design to Achieve Maximum Drug ...

Today’s SpeakersAnthony Recupero, Ph.D.Senior Director, Licensing, Pharmaceutical Technologies• Responsibility: North America - creating new product and technology codevelopmentpartnerships with pharma companies to design, develop, andmanufacture novel formulations that enhance product portfolios• Background: Business development, licensing, and marketing in thebiotech, genomics, bioinformatics, and biochemical industries• Previous experience: senior business development and marketing roles atMaxCyte , Gene Logic , and NetGenicsKevin Ostrander, M.S., M.B.A.Director, Licensing, Pharmaceutical Technologies• Responsibility: Expanding technology partnerships outside of NorthAmerica• Background: Drug formulation/process development, businessdevelopment and licensing• Previous experience:• Formulation roles with Sterling Drug, Nycomed, NanoSystems, Elan DrugDelivery• Senior business development positions with Elan, Cardinal Health, NexMedand Watson PharmaceuticalsImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Poll 1When in the cycle of product development does yourcompany decide to utilize an external oral drug deliverytechnology?A. Pre-clinicalB. Phase IC. Phase IID. Phase IIIE. Post-launch (life-cycle management)F. Don’t see value in improved formulationsImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

The Value of Formulation Design• Valuable product development partnerships producedifferentiated products enabled to compete in challengingglobal markets for commercial success• Drug formulation providers offer delivery technologies andproprietary formulation expertise for existing and noveldrug entities, creating unique product attributes resulting indirect clinical advantages for patients• It is becoming critical to incorporate these advantages atearlier points in the product lifecycle which may translateinto premium pricing in the market at launch.Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Today’s Agenda• Introduction to Aptalis Pharmaceutical Technologies• Market Environment• Case Studies1. First and only FDA-approved once-daily muscle relaxant2. Controlled release ODT of an atypical antipsychotic3. Once-daily ADHD treatment with improved SE profile• Q&AImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Introduction to Aptalis Pharmaceutical TechnologiesFormerly Eurand Pharmaceutical TechnologiesImproved Confidential health - © 2011 and Aptalis quality Pharma of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Introduction to Aptalis Pharma• We are a leading international specialty pharmaceutical company thatdevelops, manufactures, markets and distributes cystic fibrosis andgastroenterology products and therapeutic treatments.• We are positioned to expand globally and diversify our portfolio ofproducts and pipeline candidates.• Our capabilities also include:• Global R&D• Drug Formulation• Commercial ManufacturingImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Aptalis Marketed Product PortfolioImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Aptalis Pharmaceutical Technologies• The Aptalis PharmaceuticalTechnologies (formerly EurandPharmaceutical Technologies)are leveraged to develop productswithin the Aptalis product pipelineand portfolioOur Collaboration Partners• Aptalis PharmaceuticalTechnologies will continue toco-develop products with ourpartners using our technologyplatforms and we will continue towork with our existing partners tosupport and supply our licensedand manufactured productsImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Multiple Technology Platforms EnableProduct Feature DifferentiationBreadth of Technology PlatformsCustomizedDrug ReleaseBioavailabilityEnhancementTaste-maskingAdvaTab ®Biorise ®Diffucaps ®Diffutab ®Eurand Minitabs ®Liquitard ®Microcaps ®Orbexa ®DepthPLATFORM BENEFITS:Scaled-up and Validated • Commercialized Worldwide • IP CoverageImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Customized Drug Release TechnologiesCustomizedDrug Release• The release profiles can be tailored tooptimize a drug’s therapeutic performance:• Improve efficacy• Enhance safety• Increase patient acceptability andadherence through less frequentdosing• Diffucaps ® - Flexible multi-particulatesystem for single or drug combinations.Also for drugs that exhibit pH-dependentsolubility characteristics.• Diffutab ® - Sustained release and targeteddelivery in a matrix tablet. Well suited forhigh-dose products.• Eurand Minitabs ® - Tiny cylindrical tabletsto which functional membranes can beapplied to further control release rates.Filled into capsules enabling combinationsof release profiles and actives.• Microcaps ® - Encapsulated drug particlesfor controlled release profiles and/ortastemasking.• Orbexa ® - Highly concentratedmultiparticulate system enabling high drugloading and release profiles; suited fordrugs requiring granulation or sensitivemoleculesImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Pharmaceutical Market TrendsGiven the macro trends of the pharmaceutical marketingenvironment, it is clear companies need to maximizeasset value for a shorter and more competitive life cyclethan previously experienced.Improved Confidential health - © 2011 and Aptalis quality Pharma of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market ConditionsR&D Challenges and Increased Spending40R&D Costs – US, Europe, and Japan3530Billions US$25201510USJapanEurope501985 1990 1995 2000 2005 2006 2007Sources: EFPIA, JPMA Data Book 2008, PhRMA Annual Survey 2008Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market ConditionsR&D Challenges and Increased Regulatory Scrutiny60New Chemical Entities Approved – US and Japan50403020USJapan100199019911992199319941995199619971998199920002001200220032004200520062007Sources: JPMA Data Book 2008, FDAImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market ConditionsBrand Erosion and Generic CompetitionExample of Brand Erosion of $1B+ Flomax® (tamsulosin) in the U.S.Sources: IMS Data ; TRx DispensedImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market Conditions1,800Changes in Market Share Relative to DifferentiationTRx for Six Oral Branded UT Antispasmodic TherapyDispensed TRx in 1000's1,6001,4001,2001,0008006004002000DITROPAN XL DITROPAN DETROL LADETROL VESICARE ENABLEXTOVIAZ SANCTURA XR SANCTURAImportance of Differentiation in Crowded MarketsSources: IMS Data ; TRx DispensedImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market Conditions300Varying Degrees of Market SuccessExpanded View of UT Antispasmodic Market250Dispensed TRx in 1000's200150100500DITROPAN XL DITROPAN DETROL LADETROL VESICARE ENABLEXTOVIAZ SANCTURA XR SANCTURAFocus on Late Entrants to the MarketSources: IMS Data ; TRx DispensedImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Case Study 1Product: Amrix ® (Cyclobenzaprine HCl) Extended-Release CapsulesPartner: CephalonImproved Confidential health - © 2011 and Aptalis quality Pharma of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Amrix ® (Cyclobenzaprine HCl ER Capsules)Drug Overview and Patient NeedDRUGCyclobenzaprine hydrochloride - a generic skeletalmuscle relaxant that relieves muscle spasm of localorigin without interfering with muscle functionNEED • Develop a once-daily formulation that helpsincrease patient adherenceCHALLENGE(S) • Successfully extend efficacy of a singleadministration up to 24 hours while…• Improving patient adherence, resulting in betterpatient outcomesImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Amrix ® (Cyclobenzaprine HCl ER Capsules)Result:• Formulated using Diffucaps ® technology• 15 and 30 mg QD (v. 10 mg IRmarketed)• Demonstrated much lower incidence ofsomnolence than immediate-releasecyclobenzaprine in clinical studies• FDA Approved in 2007• Licensed to Cephalon (N. America)• 2010 U.S. sales of $124 million• Patent granted provides additional protection• Three patents now issued and twoothers pending• Licensed out to an additional 20+ ex-U.S.countriesAmrix®:The first and only FDA-approved oncedailyskeletal muscle relaxantImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Amrix ® - Capsule Containing SR Beads• Highly reproducible release profile• Physically/chemically stableImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Plasma ProfilesAmrix ® with reduced sedation is better tolerated compared to Innovator product10 mg cyclobenzaprine IR dosed 3 times daily and Amrix ® (ER capsule) dosed once daily*Darwish et al, ‘Single-Dose Pharmacokinetics of Once-Daily Cyclobenzaprine Extended Release 30 mg versus CyclobenzaprineImmediate Release 10 mg Three Times Daily in Healthy Young Adults’, Clin Drug Invest 2008: 28 (12): 793-801Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Amrix (Cyclobenzaprine) Clinical DataMost Common AdverseReactions from PostmarketingSurveillance ProgramClinical Studiescyclobenzaprine 10mg TIDDrowsiness 39%Dry Mouth 27%Dizziness 11%Incidence of the Most Common AdverseReactions Occurring in 3% of Subjects in AnyTreatment Group in the Two Phase 3, Double-Blind AMRIX TrialsSomnolence(Drowsiness)AMRIX 15mgN=127AMRIX 30mgN=126PlaceboN=1281% 2% 0%Dry Mouth 6% 14% 2%Dizziness 3% 6% 2%*AMRIX® Prescribing InformationImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Customized Drug ReleaseDiffucaps technology facilitates the development andcommercialization of novel, controlled-release deliverysystems in a variety of dosage forms.Inert CoreDrug LayerAdvaTab ® -CR ODTSeal Coat(optional)Sustained ReleasePolymer LayerDiffucaps ® Coating Technology ApplicationsImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Diffucaps ® TechnologyAdvantages…• Customize PK to the desired profile bycombining any ratio of (up to 4 different)CDR beads• Multiparticulate bead system providesadvantages for single and drugcombinations:• Dosage strength flexibility• Required PK profile• Optimal release profiles• Ability to target clinical benefits in efficacyand tolerability• Reposition current drug for additionalmarkets• 4 FDA approved Diffucaps ® products onthe market since 2001• More than 10 brands commercialized in35+ countriesImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Case Study 2Product: Melperone - Controlled Release Orally Disintegrating TabletPartner: ConfidentialImproved Confidential health - © 2011 and Aptalis quality Pharma of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

U.S. Market ExampleFast-Dissolve/Oral Disintegrating Tablet (ODT) Market• More than ninety ODT products in the U.S. market (includes OTC)• Forty-three marketed Rx ODT products (Brand and Generic)Total Market Size(Extended Units)559 Million$1.3B Total ODTSales – 3 LargestProductsApproved Uses toTreat the FollowingDisorders• Nausea/Vomiting• Migraine• Alzheimer’s Disease• GERD/GI ulcers• Depression• Seizures• Parkinson’s Disease• Schizophrenia• Bipolar Disorder• AnxietyIMS Data – MAT 5/10Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market Conditions$35.00$30.00ODT Formulations Support a Variety of Pricing StrategiesSelect Product Pricing – Unit Dose WACPremium, Equivalent and Discount Strategies$29.06 $28.08$7.29 $7.29$25.00$20.00$20.89 $22.15 $0.42$15.00$10.00$5.00$5.45 $5.45$10.30$9.32$8.25$0.00Prevacid DR CapPrevacid SolTabSource: Gold Standard 7/10Zyprexa 5mg ODTZyprexa 5mg TabZyprexa 20 mg ODTZyprexa 20 mg TabAricept ODTAricept TabZofran 4mg ODTZofran 4mg TabGeneric Zofran 4mgODTSaphrisImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Market ConditionsODT Products Can Be Launched Under Multiple StrategiesRange of ($) Share for ODT products within a FranchiseAricept ODT0.4Zyprexa Zydis10Prevacid SolTab23Maxalt MLT45Saphris®1000 20 40 60 80 100IMS DATA – MAT 5/10Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Melperone – Controlled Release ODTDrug Overview and Patient NeedDRUGMelperone – a generic atypical antipsychotic marketed inEurope for over 30 years for treatment of organic dementia,senile dementia, schizophrenia, non-specific psychosis andpsychosis with Parkinson’sNEED • Maintain therapeutic drug levels whilst reducing C max• Adverse events of current IR drug formulation taken BID appearto be C max related• Develop a novel once-a-day (QD) dosage form• Improved patient compliance – less frequent dosing in ODTpresentation to enhance administration in patients exhibitingdysphagia or known to ‘cheek’ treatmentsCHALLENGE(S) • Maintaining Diffucaps ® CR bead integrity through AdvaTab ®ODT tablet compression operation• Ensuring Diffucaps ® beads are of sufficiently small size toguarantee good organoleptic properties of the finishedAdvaTab ® dosage formImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Melperone – Controlled Release ODTDrug Overview and Patient NeedCurrent DosageFormsOral Syrup at 5mg/mL strengthIR Tablets at 25 mg, 50 mg and 100 mg strengthsADME/PK Highlights • 50-70% Oral Bioavailability• Half-life is approximately 8 hrs (steady state)• Primarily hepatic eliminationSide Effects • Include: Constipation, diarrhea, dizziness, dry mouth,headache, nausea, restlessness, insomnia andothers.Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Melperone – Controlled Release ODTVarying Sizes of Multi-particulates to Achieve Specific FormulationRequirements – ODT vs. Standard CapsuleControlled release beads for ODTControlled release beads for CapsuleImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Melperone – Controlled Release ODTCR ODT Achieved Parity with CR Capsule Formulation In Human PK StudyHuman PK Study – Comparison of IR/CR PresentationsImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Melperone – Controlled Release ODTComparative Data from Human PK StudyParameter25 mg IRSyrup50 mg IRSyrup50 mg CRODT 150 mg CRODT 250 mg CRCapsuleAUC 0-last(hr*ng/mL)C max(ng/mL)132.7 331.3 258.9 264.6 252.119.3 58.8 20 16.2 17.0T max(hr)1.8 1.0 4.9 5.9 5.8Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

AdvaTab ®Orally Disintegrating Tablet (ODT) TechnologyMarketing Considerations• Successfully commercialized• Perception of a faster acting drug(undocumented patient perception)• Target Patient Populations:• Patients that exhibit dysphasia,tendency to 'cheek' medications• Pediatric/Geriatric Patients• Stroke, MS, GERD, Parkinson’spatientsEnabling Product Differentiation:Combining Technologies• Can be combined with Microcaps ®taste-masking and/or Diffucaps ®customized drug releasetechnologies to create tablets with:• High dose capacity• Customized release profiles• Pleasant taste and mouthfeelMicrocaps IRTaste-masking TechnologyDiffucapsCR TechnologyImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Case Study 3Product: Metadate CDPartner: Celltech (UCB)Improved Confidential health - © 2011 and Aptalis quality Pharma of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Metadate CD ® (Methylphenidate HCl ER)Drug Overview and Patient NeedDRUGMethylphenidate – a central nervous system(CNS) stimulant for use in treatment of ADHD(Schedule II Controlled Substance)NEED • Develop a once-daily (qd) controlled release formthat addresses issues for school-aged children:• Inability to take doses of while at school• Side effects such as loss of appetite, insomniaCHALLENGE(S) • Successfully extend plasma levels over ~8 hoursto achieve plasma levels with similar AUC to BIDdosing• Minimize frequency of side effects (appetite lossand insomnia) compared to BID dosing whilemaintaining efficacyImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Metadate CD ® (Methylphenidate HCl ER Capsules)• Highly reproducible release profile• Physically /chemically stableImproved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Metadate CD ® (Methylphenidate HCl ER Capsules)Results: Metadate CD: 20 mg ER Capsules• Formulation achieved similar C max andAUC versus twice-daily methylphenidateIR (2X10 mg), dosed morning and schooltime• Dosage form contains both IR for rapidonset of action and ER beads with atapering off plasma profile late in the day• Reduces sides effects of appetiteloss and insomnia commonlyassociated with BID dosing of the IRform• NDA Approved 2001• 2010 U.S. Sales - $124MPlasma concentration profile of Metadate ® CD(closed triangle), 20 mg dosed q.d., in comparisonto methylphenidate HCl immediate release (opensquare) 10mg dosed b.i.d.Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Strategic Patent Protection• Approximately 100 patent families• Consist of over 398 grantedpatents• More than 299 pendingapplications• We endeavor to offer the mosteffective patent protectionpossible to our partners based onour broad and diversified portfolioof pharmaceutical technologies.• Patent portfolio composed ofpatents with claims directed to ourformulation technologies andproduct-related patentsAptalis Pharmaceutical Technologies has Orange Booklisted formulation patents for our U.S. NDA products.Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Conclusions:Commercially Successful Multi-particulate ProductsDrug-Layered BeadsDexedrine(dextroamphetamine)InnoPran XL(propranolol HCl)Amrix(cyclobenzaprine HCl)Entocort EC(budesonide)Coreg CR(carvedilol)Carbitrol CR(carbamazepine)Adderall XR(amphetamines)Prozac Weekly(fluoxetine)Razadyne ER(galantamine HCl)MinitabletsZenpep(pancrelipase)Trilipix(fenofibrate)Metadate CD(methylphenidate HCl)Verelan PM(verapamil HCl)Dexilant(dexlansoprazole)Videx EC(didanosine)Detrol LA(tolterodine)Avinza(morphine SO4)MicoencapsulationMicro K(potassium chloride)Luvox CR(fluvoxamine )EMBEDA(morphine SO4/naltrexone HCl)Indocin SR(indomethacin )Cardizem CD(diltiazem HCl)Nexium(esomeprazole)Cymbalta(duloxetine HCl)Sanctura XR(trospium Cl)Effexor XR(venlafaxine HCl)Melt CongealingZMAX(zithromycin)Improved health and quality of care by providing specialty therapies for patients around the world.Confidential - © 2011 Aptalis Pharma

Schedule A MeetingWith Aptalis AtThese Conferences:BIO Annual MeetingJune 27-30, 2011Washington, D.C.Q & ACRS Annual MeetingJuly 30-Aug 3, 2011National Harbor, M.D.Send us your follow-up questions, schedule a meeting, or requestthat we mail you a free AdvaTab ® technology prototype:Anthony Recupero, Ph.D.Senior Director, Licensing,Pharmaceutical Technologies267-759-9346ARecupero@AptalisPharma.comKevin Ostrander, M.S., M.B.A.Director, Licensing,Pharmaceutical Technologies267-759-9367KOstrander@AptalisPharma.comConfidential - © 2011 Aptalis PharmaVisit www.AptalisPharmaceuticalTechnologies.com