VIEWS: 13 PAGES: 26 POSTED ON: 12/19/2011
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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