新藥項目引進評估方法(Pharma-Business-Development-A-scientist-view)課件

1、Our PatientsOur PeopleOur BusinessOur CommunityPharmaceutical Business DevelopmentA Scientists ViewRobert J. Cobuzzi Jr., Ph.D.Vice President and Acting Head, Corporate DevelopmentEndo Pharmaceuticals Inc.Non-Confidential2Non-ConfidentialCobuzzi - UPenn 2 December 2008DisclaimerThe statements and vi

2、ews presented are my own and not thoseof my employer, Endo Pharmaceuticals Inc.- Bob Cobuzzi3Non-ConfidentialCobuzzi - UPenn 2 December 2008Presentation Agenda Endo Pharmaceuticals Pharmaceutical Business/Corporate Development The Drug Development Process: Integral to BusinessDevelopment Licensing C

3、ase Study GSK-Xenoport Acquisition Case Study AstraZeneca-Medimmune Any Questions?4Non-ConfidentialCobuzzi - UPenn 2 December 20085Non-ConfidentialCobuzzi - UPenn 2 December 2008Our CommunityOur BusinessOur PeopleEndo PharmaceuticalsA proven leader in pain management Specialty pharmaceutical company

4、with expertise in pain management Results-focused organization fueled by employees sharedvalues and a commitment to making a difference forOur Patients6Non-ConfidentialCobuzzi - UPenn 2 December 2008Nearly 90 Years of History1920- Founded as family-run pharmaceutical business in New York City- Later

5、 named Endo Products1969- DuPont acquires Endo1997- DuPont Merck Executives form Endo in management buyout- All of Endo Laboratories LLCs generic products purchased- Deal included 12 key brand products, including Percocet and Percodan! New company named Endo Pharmaceuticals Inc.2000- Endo begins to

6、trade publicly on NASDAQ (ENDP)2007- Net sales $1B+- Compound annual growth rate of 20%+ since 20027Non-ConfidentialCobuzzi - UPenn 2 December 2008A Successful FoundationBuilding for the FutureGrowing US-based pharmaceutical companySuccessful sales and marketing of branded and generic prescriptionph

7、armaceuticalsApproximately, 500 home office employees and 1,000 salesrepresentativesEstablished developmentcapabilitiesStrong cash position withapproximately $1 billionBuild for the Future.Learn from the Past.8Non-ConfidentialCobuzzi - UPenn 2 December 2008Product Portfolio9Non-ConfidentialCobuzzi -

8、 UPenn 2 December 2008Endos Growth Strategy Move from best product to bestsolution Leverage pain adjacencies Invest in new therapeutic areas withfocus on innovation Concentrate on areas of significantunmet medical need, low cost ofentry, and specialized therapeutics Explore all platforms including s

9、mallmolecule, large molecule and drug-device interplay10Non-ConfidentialCobuzzi - UPenn 2 December 2008Pharmaceutical Business/Corporate Development11Non-ConfidentialCobuzzi - UPenn 2 December 2008The deal is a beginning, not an end!The purpose of a deal is to solve a problem People make deals to ac

10、cess goods or services Organizations make deals for the same reasonEndos problem No internal drug discovery Development candidates and approved drugssourced externally by Business/CorporateDevelopmentDeal solutions can take multiple forms Licenses, Acquisitions, Partnerships Each requires additional

11、 work by licensee e.g., development, marketing and/or sales12Non-ConfidentialCobuzzi - UPenn 2 December 2008License or PartnershipLicense = grant of permission to use from one entity to anotherMolecule, patent, diagnostic test, device or other assetDevelopment, commercializationLimitations for uses,

12、 duration and/or territoryPartnership = association of two or more entities in which the profits and losses are sharedproportionallyDiscovery, development, commercializationTypical Deal TermsUpfront payment - upon deal signingDevelopment and/or commercialization milestonesRoyalty on salesMonetary am

13、ounts vary considerablyBenefitsPayments can be made contingent on successDeals can be terminated with some consideration (money and notification)RisksCan be more expensive than acquisitionCounter party issues e.g., territory control13Non-ConfidentialCobuzzi - UPenn 2 December 2008AcquisitionTypicall

14、y purchase of an asset or stock Asset = organization, product, molecule, patent, diagnostic test, device or other Stock = public or private companyTypical Deal Terms Payment differs Public vs. private entity, development-stage vs. marketed productsStock purchase Asset purchase Contingent rights are

15、possible Monetary amounts vary considerablyBenefits Full ownership and rights to products and candidates Mechanism to acquire enabling technology or know-howRisks Its yours, period14Non-ConfidentialCobuzzi - UPenn 2 December 2008Evaluating the Asset/EntityDoes the asset address a commercial/unmet me

16、dical need? To address a completely unmet need is rare (e.g., cure for congestive heartfailure) Is it sufficiently differentiated from other available therapies?Does the product benefit outweigh the risk profile in the intended indication? Do the available data support effectiveness? Do the availabl

17、e data support acceptable safety and tolerability? Vioxx (rofecoxib) and Avandia (rosiglitazone maleate) cases have raised thebar are there any “early warning signals”?Does the new product have market exclusivity that provides sufficient timeto recoup the investment? Patent life = 20 years from fili

18、ng composition of matter use formulation Hatch-Waxman exclusivity - patent restoration, particularly helpful if no patent 7 years for orphan drug 5 years for new chemical/molecular entity (NCE/NME) 3 years for reformulation15Non-ConfidentialCobuzzi - UPenn 2 December 2008Clear Strategies Achieve Ali

19、gnment, Efficiencyand EffectivenessWhat a strategy tells the BD&Lorganization:! Which assets / technologies are ofinterest! What we are willing to pay! When we need them (portfolio view)! Where we are likely to find certainassets! Who in the organization will championand own the newly acquired asset

20、sHow you know your strategy is clear:! BD commercial leaders articulate samein-licensing priorities! Front line BD personnel have sufficientclarity on needs to screen out 80% ofdeals within a day! Front line BD personnel know how toprioritize and spend their time! BD organization knows what messages

21、to communicate to the prospectivecollaborators regarding business needsnetworkBusiness Development ProcessProcess stepsIdentificationInitial screeningGo/No GoEvaluationGo/No GoDue DiligenceGo/No GoNegotiation/Integration16Activities! Source new assets frommultiple channels! Assess asset against pres

22、etcriteria! Decide which assets pass tonext step! Prioritize assets! Assess asset against presetcriteria! Decide and prioritize whichassets pass to next step (orshould be accelerated).! Develop preliminary businessplan with detailed evaluation! Identify Asset Champion! Decide and prioritize whichass

23、ets pass to next step.! Complete negotiations, dealstructuring and business plan! Integrate asset into portfolioNon-ConfidentialKOLs Pharma VCAcademiaBiotechTech.I.P.NCE505(b)(2)Cobuzzi - UPenn 2 December 200817Non-ConfidentialCobuzzi - UPenn 2 December 2008The Drug Development Process:Integral to B

24、usiness Development18Non-ConfidentialCobuzzi - UPenn 2 December 2008Bobs Scientific “Insights”Data talks All questions have answers, the trick is to ask the “right” questions Good experiments have only one primary endpoint/variableStatistics only identify tendencies in populations No two entities in

25、 a population are even close to identical Tendencies are inform about subgroups/strataMulticellular organisms are governed by interactive systems Nothing happens in isolationDetermination of Benefit vs. Risk is the primary objective Context is everything Non-human experiments provide information, no

26、t answersDrug development is learned through experience, not a classroom It is necessary to understand drug development to evaluate a drug19Non-ConfidentialCobuzzi - UPenn 2 December 2008Pharmaceutical Drug DevelopmentObjective = Demonstrate that benefit(s) risksIdentify a relevant target and a pote

27、ntial modulatorEstablish preliminary safety, pharmacology and chemicalcharacterizationEvaluate human pharmacokinetics and pharmacodynamicsSteps must occur in a regulated sequence intended to ensure safety(animal and human) as well as data reproducibility Development is governed by US Code of Federal

28、 Regulations (CFR)Section 312 and comparable international lawsAll of the above applies to asset evaluation20Non-ConfidentialCobuzzi - UPenn 2 December 2008Drug Discovery (months to years)Identify a specific biological target crucial to a specific disease process E.g., cell surface receptor, ion cha

29、nnel or enzymeSynthesize and screen compounds (tens to millions) based upon targetinteraction generate “l(fā)ead compounds” Requirement = sufficient patent protection to warrant development costChoose compounds for development based upon the following criteria (notcomprehensive):Target specificity (i.e.

30、, doesnt interact with other critical targets within the body)Sufficient potencyNo overt or limiting toxicity(-ies)ADME properties support desired effect (route-dependent)Minimal drug interaction predictedConduct initial animal pharmacology studies to evaluate activity in modelsintended to mimic the

31、 human condition of interest Choose models and interpret data carefully!Non-ConfidentialPreclinical Testing (9 months to 3 years)Animal toxicology studies and further pharmacologiccharacterization Exposure duration in excess of initial clinical exposurePharmacokinetic testing Focused on ADME (absorp

32、tion, distribution, metabolism and excretion)Physicochemical characterization chemical structure, purity, stability and shelf-lifeChemistry, Manufacturing and Controls (aka, CMC) Pharmaceutical development studies to convert the activepharmaceutical ingredient (API) into the intended clinical “dose

33、form”(e.g., tablet) Optimize manufacturing (API and final dosage form) on an industrialscale for the lowest feasible cost Establish stability of intended clinical dosage form21Cobuzzi - UPenn 2 December 200822Non-ConfidentialCobuzzi - UPenn 2 December 2008Investigational New Drug (IND) ApplicationIN

34、D Application Submitted to the U.S. Food and Drug Administration (FDA) to request permissionto begin human/clinical testing Summarizes results of pre-clinical experiments FDA has 30 days to comment from time of submissionApplication includes a clinical trial plan Describes the disease state(s) and t

35、ypes of human studiesInitial clinical study protocol is included in the IND Typically describes methodology and analytics to identify a safe and tolerabledose Individual study protocols are approved by the Institutional Review Board (IRB)Progress reports are submitted at least annually to FDA23Non-C

36、onfidentialCobuzzi - UPenn 2 December 2008Clinical Trials ($ + ttt)Phase 1 (6 months to 1 year) Small pharmacokinetic studies typically in “normal healthy volunteers” Purpose = identify safe dosage range and initial human ADME characterization Study costs = $0.5 M to $2 MPhase 2 (6 months to 2 years

37、) Initial exploratory trials in small groups of volunteer patients (n = 20 to 50) toestablish proof-of-concept in target disease state (aka, Phase 2a) Larger, placebo-controlled trials (n = 50-500) with volunteer patients to determineoptimal efficacious dose, safety and tolerability Each study costs

38、 = $1 M to $50 MPhase 3 (1 year 5 years) Placebo-controlled trials that can include thousands of volunteer patients with thedisease of interest Studies confirm (clinically and statistically) drug safety, tolerability andeffectiveness Requires replicate studies at intended dose Each study costs = $1

39、M to $250 M)24Non-ConfidentialCobuzzi - UPenn 2 December 2008New Drug Application (NDA) ProcessNDA = request to the FDA for permission to market the drugAll data to demonstrate safe and efficacious in treating the intended patients and can bemade consistentlyDocument format and content governed by U

40、S CFR 314 and comparable international lawsTypically ! 100,000 pages of information filed electronicallyFDA Review/Approval (10 to 18 months )Review timelines and submission cost governed by Prescription Drug User Fee Act (PDUFA)FDA can convene outside Advisory Committee to address specific issues (

41、e.g., commentingon a specific safety issue such as PML/Tysabri)Not all NDAs are approved on initial submission*Only 64% of NDA reviews completed in 2007 resulted in an “Approval”28% of reviews were deemed “Approvable”, 8% were “Non-approvable”Unapproved NDAs now issued “Complete Response Letters” by

42、 FDAComplete response indicates indicates that changes must be made before the applicationcan be approved, but does not give insight into ultimate approvability* Source = Reuters 2008 - /article/pressRelease/idUS130687+09-Jan-2008+PNW2008010925Non-ConfidentialCobuzzi - UPenn 2 December 2008Post-mark

43、eting StudiesFDA requires continued monitoring of approved products Spontaneous adverse events must be reported periodically or on anexpedited time-scale depending on multiple factorsFDA may require, or sponsor may choose, to conduct post-approvalstudies (Phase 4) Learn more about the drug effect on

44、 a particular group of patients Support a risk minimization programStudies conducted to support new uses of an approved drug (newindications) are submitted to the FDA for review in the form of aSupplemental NDA An sNDA typically requires less time than the original NDA to review (6-12 months)26Non-C

45、onfidentialCobuzzi - UPenn 2 December 2008Licensing Case StudyBeauty is in the eye GSK Licenses Gabapentin Prodrug from Xenoportto treat Restless Leg Syndrome (RLS)27Non-ConfidentialCobuzzi - UPenn 2 December 2008GSK-Xenoport Joint Press ReleaseLONDON & SANTA CLARA, Calif., Feb 08, 2007(BUSINESS WIR

46、E)GlaxoSmithKline (GSK) and XenoPort, Inc.(Nasdaq:XNPT) today announced an exclusiveagreement to co-develop and commercializeXP13512, a unique prodrug of gabapentin thatimproves its bioavailability, in the US and othercountries worldwide, excluding certain Asiancountries. XP13512 is currently in Pha

47、se IIIdevelopment for Restless Legs Syndrome (RLS)and in Phase II development for neuropathic pain.Prior clinical trial results have been encouraging.28Non-ConfidentialCobuzzi - UPenn 2 December 2008GSK-Xenoport Deal Terms Up-front = $75 million Aggregate milestone payments of $65 million for develo

48、pment activities leadingup to the NDA filing for RLS $210 million in other potential development andregulatory milestone payments $290 million in potential sales milestonepayments for RLS and neuropathic pain Double-digit royalty payments on US salesunless XenoPort elects to co-promote, then netprof

49、it share, and entitled to detail REQUIPproducts currently in development by GSK Asian rights previously licensed by XenoPort toAstellas Pharma Inc.29Non-ConfidentialCobuzzi - UPenn 2 December 2008What would you have done? What was the commercial/unmet medical need? Does the product benefit outweigh

50、the risk profile in theintended indication? Does the new product have IP or just Hatch-Waxmanexclusivity i.e., is there sufficient time to recoup theinvestment?30Non-ConfidentialCobuzzi - UPenn 2 December 2008Restless Leg Syndrome Cause of painful legs that is more noticeable at rest Symptoms worsen

51、 in early evening and night Pathobiology poorly understood Comorbid to multiple conditions including anemia, kidneydisease, diabetes, Parkinsons disease, peripheral neuropathy,migraine, etc. Drug side effect seen with antiemetics, anticonvulsants,antipsychotics, etc. May relate to imbalance of centr

52、al dopaminergic pathways,e.g., hypoactivation of D2 receptors31Non-ConfidentialCobuzzi - UPenn 2 December 2008XP13512 (aka, Solzira)Transported pro-drug of gabapentin Intended to address low bioavailability of gabapentin by targeting high-capacity nutrient transporter Gabapentin absorption is low, s

53、aturable and limited to duodenum andupper jejunum Rapidly converted and 70% bioavailableQualifies as a New Molecular Entity Potentially long patent life in addition to Hatch-Waxman exclusivityClinical studies complete, NDA filed Phase 3 RCT in n=220 pts with moderate to severe RLS Statistically sign

54、ificant mean change from BL at week-12 in IRLS scale Significant change in responder rate of Clinical Global Impression at 12-weeks 10 Nov 2008 press release indicates NDA withdrawn by GSK Cited that data for a single study must be reformatted Delays payment of $23 M milestone to Xenoport32Non-Confi

55、dentialCobuzzi - UPenn 2 December 2008Problem Solved?GSKs Existing RLS Drug was Requip (ropiniroleHCl) Non-ergoline dopamine D2 and D3 dopamine receptoragonist Approved for treatment of RLS in 2005 GSK developed the RLS indication and marketPotential issues with Requip for RLS Risk of cardiac valulo

56、pathy and other adverse effects Impending patent expiry of immediate release form Off-label use of gabapentin indicated effectiveness inRLSPotential benefits of Solzira Neurontin was a huge commercial success with a lot ofpotential uses, including RLS Long patent life Relatively benign safety profil

57、e of gabapentin (sedation) Helps enhance RLS franchise in which GSK investedheavilyRequip (ropinirole HCl) GlaxoSmithKline Initially Approved 1997 Generic Entry 2008(Multiple Companies)33Non-ConfidentialCobuzzi - UPenn 2 December 2008Solzira UpdateGSK and XenoPort Announce Plans to Withdraw and Resu

58、bmitNew Drug Application Requesting Approval of Solzira(TM) forRestless Legs Syndrome RESEARCH TRIANGLE PARK, N.C. &SANTA CLARA, Calif., Nov 10, 2008 (BUSINESS WIRE)GlaxoSmithKline (NYSE:GSK) and XenoPort, Inc. (Nasdaq:XNPT)announced today that the New Drug Application (NDA) for Solzira(TM)(gabapent

59、in enacarbil) Extended Release Tablets for the treatment ofmoderate-to-severe primary Restless Legs Syndrome (RLS) has beenwithdrawn. The United States Food and Drug Administration (FDA) hasrequested that the data in a single study be reformatted. In addition,GSK will conduct a review of other trial

60、 data sets taking this input intoaccount. The withdrawal does not relate to the content of the filing. GSKplans to resubmit the NDA quickly once this work is complete.The resubmission will lead to a delay in the receipt by XenoPort ofmilestone payments of $23 million in the aggregate from GSK andAst