Slide 1 - The OVCRD by ajizai

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									Closing the Gaps in Philippine
Drug Discovery & Development
Questions:


 1. How can the Philippines respond to global and regional
    opportunities and threats afforded by the rapidly changing
    dynamics in the biopharmaceutical sector?

 2. Do we have the capabilities and infrastructure to develop our own
    innovative biopharmaceutical industry, i.e., beyond generics
    manufacturing?

 3. To what stage can we and should we develop a drug candidate?

 4. Which areas of research should we look into and prioritise?

 5. What are the gaps in the drug discovery and development chain
    that we should fill in for us to be able to address our own health
    and medical needs, while trying to compete in an increasingly
    global industry?
Overview of drug discovery and development



                                            First-in-man?
                                            In-house/outsource?




                                               efficacy



                                                          Monitor side effects
                   250               5




                                                          Compare to other
                                                          Confirm efficacy


                                                          treatments
                                 safety




                                      dose range
  Target ID/Valid                                                                For every 10-20 marketed
                  Safety Pharmacol                                               drugs, only 2 return a profit!
  HTS/Hits
  Lead Optim      Animal Models
  ADME
Active compound “hits” are not drugs



    Disease

                          Drug
                         Target   Biological
                                    Assay



      Compound Libraries                   Active
       Natural Products                  compound
        Existing Dugs                       “Hit”
           Peptides
     Computer-assisted drug
            design
Lead Optimisation: Making them “drug-like”


                                       Hit
         Hit                           to                             LEAD
                                      Lead
  moderate potency                                                    drug-like
                                 Improve potency
   less “drug-like”                                                potent, soluble
                                SAR mainly in vitro
                                                               selective, bioavailable
                                                                         etc


        From original hit in biological screen to drug development candidate


   What gives a molecule drug-like features?
       Physicochemical prop (lipophilicity, acidity/basicity, solubility, permeability)
       Biophysical properties (ADME)
       Pharmacokinetics (Clearance, volume, half-life, BA)
       Toxicology
Fully Integrated Pharmaceutical Company (FIPCo)


                   Pre-      Phase       Phase      Phase        Manufac-   Marketing
   Research
                 clinical      I           II         III         turing    & Distribn




    Value Proposition
      - the experts in bringing drugs from bench to market

    Value Chain
      - have strengths in every level of the development chain
    Revenue Generation Model
      - out-license first few compounds to gain revenues then selectively bring to
        market certain compounds (big pharma need not do this)
          * usually in indication & geographies with manageable distribution
The Philippine Situation: No drug discovery companies


 Generics companies:

                Pre-     Phase   Phase     Phase    Manufac-   Marketing
   Research
              clinical     I       II        III     turing    & Distribn




      smaller research budgets
      R&D limited to satisfying regulatory requirements of BABE
      provides us with OTCs and meds for common indications



      For most other indications, we rely heavily on the multinational
      corporations which have marketing and distribution subsidiaries
      here in the Philippines.
Drugs of the Future



            SMDs               siRNA



             Recomb proteins   miRNA
             and mAbs


             Therapeutic
                               gene therapy
             peptides


            Therapeutic
            vaccines           stem cells
Industry Trends
Blurring distinction between pharma and biotech



          Big pharma ventures into biologics.


          Biotech ventures into small molecule drugs (SMDs).


          Pharma relies on biotech to fill its drying pipeline of drugs.
          (Credit crunch: Big Pharma to the rescue….)


          Biotech is good at making innovative drugs.
          Pharma is good at selling them.



    Once different, now collaborative …………
Dwindling productivity: Biologics to the Rescue




                                     Source: PhRMA 2007; FDA
Outsourcing and the Rise of the CROs


  PRE-CLINICAL:

     ADME-Tox studies (e.g., BioFocus)
     Animal models of disease (e.g., Cerebricon)




  CLINICAL:

      Phase I clinical trials units (e.g., Quintiles)
      Phase I-III (e.g. Quintiles, Parexel)
Patent Cliff / Threat from Generics




                                       Over $63 billion of annual income
                                      washed away due to patent erosion
                                                     by 2014




                                 Source: Royal Society of Chemistry UK (www.rsc.org)
Big Pharma Buying into Generics


    Big Pharma       Generics Company         Location
    Sanofi           Zentiva                  Czech Republic
                     Piramal                  India
                     Medley                   Brazil
    Pfizer           Aurobindo Pharma         India
                     Strides Arcolab          India
                     Claris Life Sciences
    Merck            BioVentures (created)
    Daiichi Sankyo   Ranbaxy                  India
    GSK              Prasco Labs              US
                     Aspen Pharma             South Africa
                     Shenzen Neptunus         China
                     Dr. Reddy’s              India

    Astra Zeneca     Par Pharmaceutical        US
                     Sandoz (generics division
    Novartis         of Novartis)
Drug Discovery Agenda: Translational Gap



  Natural Products Research

         Medicinal Plants
                 antimicrobial, hypoglycaemic, analgesic, anti-cancer
         Marine Natural Products (Pharmaseas Project)
                 pain, antimicrobial, etc?

  Oncology mAbs

  No SMD research ?

  Dengue Vaccines
Natural Products: Record of Productivity


   Small-molecule NCEs 1981-2002
                                                    ANTIBACTERIALS: 78%
                             6%
                                                    ANTICANCER: 74%
     39%                                      27%         n=877

                                              5%

                          23%




    natural products
    natural product derivatives
    synthetic compounds with NP pharmacophores
    natural product mimic
    other
   Source: Newman, Cragg & Snader (NIH/NCI)
Modernisation of Natural Products Research



                      NOT ALL GINSENG IS THE SAME:


                Rg1   (sterol ginsenoside)                  Rb1 (sterol ginsenoside)

                  Glucocorticoid receptor                     Estrogen receptor




         upregulates a
        growth receptor                                     different pathway




      stimulates blood vessel growth         inhibits blood vessel growth
Gaps in understanding of the biopharma business


  NIRPROMP ?

  Criteria for drug discovery programs:


   1. Should address unmet medical need
   2. Market potential should be considered to allow a
      return on investment
   3. Product differentiation; preferably first-in-class and
      demonstrate superior efficacy for it to capture and
      sustain a good market share.


  Need to re-focus efforts !
Cuba: Lessons on Priorities and Strategy


    More than 60 commercial products
    and 1200 patents since 1981.

       1981      1990       2000      2007

            3                      38
                       19
       Cancer therapies, vaccines for tropical
       Diseases, AIDS medications, etc
1st World Results on Third World Budget
Clock for commercialisation begins ticking



                                                           CLINIC

                                              Lead
                                          optimisation

                            Hit-to-Lead
               Develop
               biological
    Identify    screen
    disease
     target
                                   Composition of matter
                                         patents


                     INCREASING VALUE
Gaps in the Drug Discovery & Development Continuum



                 Pre-      Phase     Phase      Phase     Manufac-       Marketing
   Research
               clinical      I         II         III      turing        & Distribn



     HTS       MedChem      ADME-Tox         Animal Models

   Safety pharmacology (pre-clinical)
   Detect undesirable secondary pharmacologic effects on critical organ systems:

   Cardiovascular: bp, heart rate, ECG, QT issues
   CNS: motor activity, behavioural changes, coordination, sensory/motor reflexes
   Respiratory: resp rate, tidal volume, blood oxygentaion
   GI: gastric secretion, GI injury potential, bile secretion, transit time in vivo
   Renal: urinary vol, spec grav, osmolal, pH, fluid/electrol bal, blood chem, GFR

   + genotoxicity, carcinogenicity and reproductive toxicology studies
Disconnect: industry needs/scientific expertise



            Skills gap:               Skills gap:
            MEDICINAL CHEM            PROTEOMICS/
                                      METABOLOMICS




            Skills gap:               Skills gap:
            ADME-Tox                  BIOPROCESSING
Gap: Hardly any research into biologics



  By 2014:
                            7 out of 10 drugs will be biologics.
                            Top 5 will be mAbs.

                            Avastin will be number 1
                            Humira will be close 2nd

                            Both to bring around $9 billion a year
  Source: Evaluate Pharma




   UP NIMBB:                Magnifies lack of critical mass (and facilities)
    AMOR 1 & 2              In molecular biology research?
Nor biosimilars ….

Biologics are difficult to replicate …..
 The process is the product !


                   Manufacturing processes are complex
                   (and never fully disclosed)



                   Supplemental approvals for minor changes



                   Different product iterations and versions may require
                   Further lengthy clinical trials
The Way Forward



    Diversify funded research
    Incorporate commercial criteria in proposal assessments
             unmet medical need
             market potential/ROI
             product differentiation
             etc
    Bring drug candidates through to phase I if possible
    Develop capabilities in med chem & prescribed assays
    Mind the skills gap (from pre-clinical R&D to clinical trial mgt)
    Pour in money …..

								
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