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PHILIPPINE DRUG DISCOVERY AND DEVELOPMENT PROGRAM DEPARTMENT OF SCIENCE AND TECHNOLOGY PHILIPPINE COUNCIL FOR HEALTH RESEARCH AND DEVELOPMENT WHY DRUG DISCOVERY? •  One of the health R&D prioriCes under the agenda thrust of DOST for 2011-­‐2016 is developing health products and technologies to address pressing health problems •  The NaConal Unified Health Research Agenda (NUHRA) stresses focus in the area of drug discovery and development especially those coming from natural sources. PHILIPPINES AS A BIODIVERSITY HOTSPOT •  The Philippines being one of the megadiverse countries in the world in terms of species thriving makes it favorable for the discovery of novel compounds from indigenous/endemic terrestrial and marine species. •  ConservaCon InternaConal assessed that of more than 9000 plant species in the country, 65.8% of these are considered endemic. NATURAL PRODUCTS AS A DRUG SOURCE
•  Of the total New Chemical EnCCes (NCEs) approved by the US FDA from 1981 to 2002, 52% are natural products, natural products derived, or natural products mimics. (Newman, 2003) •  Even some of the important drugs that are currently on-­‐market are derived from a natural source. ACTUAL FUNDING PER PRIORITY AREA
(PCHRD DATA)
Dengue 16% Func1onal Foods 1% Others 5% Drug Discovery 58% Genomics 18% Diagnos1cs 2% Dengue 19% Func1onal Food 1% Others 4% Drug Discovery 55% Genomics 18% 2012 Diagnos1cs 3% 2013 PHILIPPINE INITIATIVES ON MEDICINAL PLANT RESEARCH NATIONAL INTEGRATED RESEARCH PROGRAM ON MEDICINAL PLANTS (NIRPROMP) ü  The NIRPROMP was established in 1977 to develop safe and effecCve medicinal preparaCons from indigenous plants to cushion the effect of escalaCng prices of drugs and to increase the availability of drugs especially in the rural areas. ü  ParCcipants under this program are researchers from the UP System (College of Medicine, Pharmacy, Agriculture and Science). ü  Other insCtuCons involved in past acCviCes of the program include UST, PIPAC-­‐Ateneo, JRMMC, and CLSU SAMPUNG HALAMANG GAMOT ü  The Department of Health in consultaCon with NIRPROMP researchers idenCfied 10 medicinal plants which can be used for Primary Health Care: Lagundi (Vitex negundo) Yerba buena (Mentha cordifolia) Sambong (Blumea balsamifera) Tsaang gubat (Carmona retusa) Ampalaya (Momordica charan8a) Niyug-­‐niyogan (Quisqualis indica) Bayabas (Psidium guajava) Akapulko (Cassia alata) Ulasimang bato (Peperomia pellucida) Bawang (Allium sa8vum) Out of the 10 plants, 5 are already listed in the Philippine NaConal Drug Formulary (PNDF). MEDICINAL PLANT TECHNOLOGIES GENERATED BY NIRPROMP Plant Name Lagundi (V. negundo) Dosage Form Indica1on Tablets and Pediatric Syrup Cough and Asthma Sambong (B. balsamifera) Tablets Urolithiasis; diuresis Akapulko (C. alata) loCon Fungal infecCons Yerba buena (M. cordifolia) Tablets Pain of moderate severity Ampalaya (M. charan8a) Tablets Diabetes mellitus Type II Tsaang gubat (C. retusa) Tablets Biliary/ gastrointesCnal colic OUTPUTS OF THE NIRPROMP ü  A guidebook was also published that idenCfied 83 plants which passed rapid screening tests for its proper therapeuCc use. GOVERNMENT INVESTMENT ON NIRPROMP ü  Total Grant Investment in NIRPROMP from 1977 to 2009: PHP 97.8 M ü  It is esCmated that about PHP 20-­‐25 M is spent for the conduct of research and development of a single plant drug. ü  PITAHC and PCHRD shared in funding the program from 2005-­‐2007. ADOPTORS OF TECHNOLOGY GENERATED BY NIRPROMP Licensing Agreements for the commercial producCon of the medicinal technologies generated by NIRPROMP were made with the following companies: ü NatraPharm Inc. (1997) Pascual Laboratories (1995 to present) ü New Marketlink Inc. (2009) GruppoMedica (1997) ü Lloyd Laboratories (1998) Herbcare CorporaCon (2009-­‐2012) ü United Laboratories (2012) COMMERCIALIZED HERBAL DRUGS Medicinal Plant Product Lagundi Tablet Lagundi Pediatric Syrup Sambong Tablet Akapulko LoCon Yerba buena tablet Brand Name Ascof Tablet, Plemex tablet and Astrol Ascof syrup, Plemex Syrup Re-­‐leaf Tablet Acaderm loCon Dolgesic (launched in Mindanao in 2006) Indica1on Cough, asthma Cough, asthma Urolithiasis/diuresis Fungal InfecCon Pain of moderate severity Millions GROSS SALES OF 4 TECHNOLOGY ADOPTORS FOR LAGUNDI SYRUP 70 60 50 TA4 40 TA3 30 TA2 20 TA1 10 0 2010 2011 2012 2013 Millions GROSS SALES OF 3 TECHNOLOGY ADOPTORS FOR LAGUNDI TABLETS 16 14 12 10 TA3 8 TA2 6 TA1 4 2 0 2010 2011 2012 2013 DRUG DISCOVERY OF HEALTH PRODUCTS PROGRAM (DDHP PROGRAM) •  Drug discovery iniCaCve of the University of the Philippines Diliman •  Aims to discover compounds from plant metabolites, venom and toxins from marine organisms and other substances which are acCve against various medical condiCons. THE PHILIPPINES NEEDS A COMPREHENSIVE DRUG DISCOVERY PROGRAM •  With thousands of potenCal plant drugs sCll waiCng to be discovered, a drug discovery and development program has to be implemented to harness the potenCal of our biodiversity to respond to the growing health needs of the Filipinos. •  Drug discovery and development is considered a very resource intensive acCvity. It usually takes a minimum of 15 years to develop one drug and a huge amount of monetary investment is necessary to develop a drug. •  However, with proper strategies, limited resource may be maximized and discovery cost may be minimized without compromising the quality of the products developed from natural source. DRUG DISCOVERY AND DEVELOPMENT PROCESS DRUG DISCOVERY AND DEVELOPMENT PROCESS Drug Target ID Hit/Lead ID Lead OpCmizaCon Candidate SelecCon Clinical Trials RegistraCon Drug Target ID Hit/Lead ID Lead OpCmizaCon Candidate SelecCon DRUG TARGET IDENTIFICATION •  One of the most important steps in developing a new drug •  Genes, Proteins, and RNA are examples of targets to which a drug acts on. •  CharacterisCcs of a good target include efficacious, safe, clinically acceptable, could meet commercial needs and most importantly “druggable” •  Data mining through the use of computers and available biomedical data has led to an increase in target idenCficaCon Clinical Trials RegistraCon Drug Target ID Hit/Lead ID Lead OpCmizaCon Candidate SelecCon HIT/LEAD IDENTIFICATION •  It is during this phase where compound screening assays are developed •  A Hit is a compound which has the desired acCvity in a compound screen and whose acCvity is confirmed upon retesCng •  A Lead is a small drug like molecule which is selected from a series of hits that is able to bind selecCvely to the receptor site on the target, to elicit the desired funcConal response of the target molecule, and to have adequate bioavailability and biodistribuCon to elicit responses in animals and humans and it must also pass toxicity evaluaCon in animals. (Hemi, 2008) Clinical Trials RegistraCon Drug Target ID Hit/Lead ID Lead OpCmizaCon Candidate SelecCon Clinical Trials RegistraCon LEAD OPTIMIZATION AND CANDIDATE SELECTION •  Structure of the lead compound is modified to improve potency, absorpCon, selecCvity, and bioavailability (Medicinal Chemist) •  Further tests like genotoxicity, pharmacokineCc and pharmacodynamics studies, dose linearity, repeat dosing pharmacokineCcs, and metabolic profiling need to be performed during this phase. •  All informaCon gathered about the molecule at this stage are needed for the preparaCon of a target candidate profile which together with toxicological and Chemistry, Manufacture and Control (CMC) consideraCons will form basis of a regulatory submission before human administraCon to begin. Drug Target ID Hit/Lead ID Lead OpCmizaCon Candidate SelecCon CLINICAL PHASE •  4 Phases (Phase I, II, III, IV) •  Clinical Studies should always follow ICH-­‐GCP guidelines and other local and internaConal ethical standards. Clinical Trials RegistraCon KEY ISSUES IN DRUG DISCOVERY AND DEVELOPMENT •  High aoriCon rate •  Factors: Safety, Efficacy, Cost, , PharmacokineCcs, Bioavailability, Toxicology, etc. •  The early determinaCon of the drug defects that produces the factors which lead to failure considerably lowers the cost and Cme of developing therapeuCcally useful drugs. Drug Discovery Process 1/100~1/5000 NCEs Pre-­‐Clinical Studies 1/25 NCEs IND ApplicaCon Market 1/4 NCEs Sufficient income to recover discovery cost The Gradual reducCon of NCEs from discovery to market PHILIPPINE DRUG DISCOVERY AND DEVELOPMENT PROGRAM FRAMEWORK Data Mining and Collection
Public Health Problem Extraction
In vitro Biological Activity Testing
and ADMETox Assay
Bioactive Extracts
Bioactive Compounds
In vivo assays and ADMETox Assays
Formulation Studies
Structure Activity Relationship, Synthesis
and Derivatization
Standardization
Pre-Clinical and Clinical Studies
Lead Drug Candidates
Formulation Studies
Herbal Drugs
Pre-Clinical and Clinical Studies
Drug Candidates
THE CURRENT PHILIPPINE DRUG R&D LANDSCAPE DR. KENNETH HARTIGAN-­‐GO/ASIAN INSTITUTE OF MANAGEMENT DRUG DISCOVERY AND SCREENING LANDSCAPE •  The drug discovery and screening process is well established in both NCR and the provinces. However, there is much room for improvement. It is the general consensus among scienCsts and researchers that there are a good number of capable researchers in the regions. There are several universiCes in the regions that have capabiliCes in drug discovery and screening. CURRENT ISSUES •  Lack of equipment and animal houses throughout the country. •  Difficulty in compleCng structure elucidaCon of isolated biologically acCve component. •  Lack of medicinal chemists, virologists, biochemists, and pharmacologists •  No Cme to conduct research, Cme is consumed mostly to teaching. •  Slow government procurement process. PRE-­‐CLINICAL TESTING LANDSCAPE CURRENT ISSUES •  FDA only recognizes tests following the OECD-­‐
GLP Guidelines •  Researchers admit not following the OECD GLP Guidelines •  Very few organizaCons are experienced in carrying out animal tesCng •  Laboratories dedicated for Pre-­‐Clinical TesCng are not widely available in the country. •  Animal sources are scarce. CLINICAL TESTING Landscape •  Clinical research industry in the Philippines is worth at least PHP 500 million. •  As of 2011, there are 184 ongoing trials. 119 are open for enrollment. The majority is in Phase 3, followed by Phase 4 Current issues •  Lacks many support infrastructures and policies, such as, a unified naConal guideline on clinical trials, technical capability for evaluaCon of clinical trial documents, monitoring system that has capability to conduct audits at the sites •  Lack of local Clinical Research OrganizaCon (CRO) INTERVENTIONS TUKLAS LUNAS DEVELOPMENT CENTERS •  In order to iniCate the program and encourage medicinal plant research in the rural areas where the richness of Philippine biodiversity is evident, there is a need for the establishment of screening and extracCon centers in various universiCes in the regions to study the rich flora and fauna which are endemic and/or indigenous to the area. •  Support: Research and Equipment Grant BIOACTIVITY FACILITY •  Once the TLDC’s and other research insCtuCons have idenCfied the various plant extracts with significant bioacCvity through their preliminary assays, these extracts need to be analysed further through a baoery of advanced disease specific assays. •  Assays may be in-­‐vitro, in-­‐vivo, or in-­‐silico •  Support: Research and Equipment Grant DRUG PRE-­‐FORMULATION/FORMULATION CENTERS •  Comprehensive pre-­‐formulaCon studies provide a foundaCon or scienCfic basis in the formulaCon of a drug by understanding its physicochemical properCes. •  Excipients and delivery systems of drugs should be carefully studied to ensure that safety and efficacy of the product are retained. •  Support: Research and Equipment Grant R&D SUPPORT FOR EXISTING RESEARCHERS ON MEDICINAL PLANTS •  Acknowledging that there are exisCng insCtuCons in the Philippines that are acCvely conducCng researches on medicinal plants, the strengthening of their research capabiliCes to conduct drug discovery and development acCviCes will be prioriCzed. •  Support: Research and Equipment Grant DNA BARCODING OF PHILIPPINE MEDICINAL PLANTS The geneCc barcode of Philippine medicinal plants will be documented in order to determine the medicinal plant’s molecular idenCty which is important in protecCng consumers against the use of adulterants in herbal medicine (plants with similar morphology but different from the bioacCve plant source) that may cause accidental poisoning. The geneCc sequences of all idenCfied medicinal plants will be stored in a database following internaConal standards for easy retrieval. DOST-­‐ITDI LABORATORY ANIMAL RESOURCE CENTER •  ExisCng lab animal source: RITM and FDA •  Establishment of a laboratory animal breeding center which will be the source of animals with homogenous and good geneCc lineage for tesCng of potenCal drugs. •  The facility will be complying with guidelines set by the Bureau of Animal Industry and cerCfied by accreditaCon socieCes like the Philippine AssociaCon for Laboratory Animal Science (PALAS) GUIDEBOOK ON MEDICINAL PLANT RESEARCH •  A book which discusses the proper methodologies in conducCng natural products research towards drug discovery and development will be developed to engage and support the Filipino researcher in conducCng this kind of studies. •  The methodologies discussed in this book shall be in compliance with the standards set by the OrganisaCon for Economic CooperaCon and Development (OECD), World Health OrganisaCon (WHO), InternaConal Conference on HarmonisaCon (ICH), and Food and Drugs AdministraCon (FDA) DRUG RESEARCH DATABASE •  Open-­‐source drug research content management system •  Serves as a channel for local researchers and interested adopters to access updated informaCon on possible drug candidates for novel therapeuCcs in the country. CONFERENCES AND SYMPOSIA Sponsorship of conducCng regular symposia to ensure that the Filipino researchers are updated with the latest technologies, trends and discoveries in the field of drug discovery and development. Foreign and local speakers shall be invited to conduct lectures regarding the recent trends in pharmaceuCcal product development and natural products as sources of medicine. SCHOLARSHIPS AND TRAININGS The shortage of manpower in the area of pharmaceuCcal research and development gives importance in invesCng in human resource development through provision of training and graduate scholarships to interested students and science workers to both local and foreign universiCes and/or training insCtutes in the following areas: 1.  Medicinal Chemistry 2.  Combinatorial Chemistry 3.  PharmaceuCcal Chemistry 4.  Virology 5.  Biochemistry/Biotechnology 6.  Pharmacology 7.  Molecular Biology 8.  Other allied sciences related to drug discovery and development NOVARTIS NEXT GENERATION SCIENTIST
PROGRAM
•  A three (3) month intensive internship program for talented and moCvated research scienCsts from emerging countries which will be hosted at NovarCs’ research site at Basel, Switzerland. •  The internship aims to build scienCfic and leadership capability in emerging countries by enhancing the skills of local scienCsts and by facilitaCng the knowledge transfer to a wider scienCfic community upon returning home. •  Successful candidates will typically work in drug discovery and clinical research disciplines. •  Internship includes: ScienCfic/Clinical Research Infrastructure/Training, Travel, AccommodaCon & Visa fees, SCpend and Health Insurance. INTER-­‐AGENCY EFFORT •  Several agencies play an important role in achieving the success of the drug discovery and development program: 1. Department of Health and key agencies 2.  Department of Agriculture and key agencies 3.  Department of Environment and Natural Resources 4.  NaConal Commission for indigenous People 5.  NaConal Biosafety Commioee of the Philippines 6.  Commission on Higher EducaCon 7.  Philippine Health Research Ethics Board/NaConal Ethics Commioee These agencies will be acCvely involved to hasten research efforts and minimize bureaucraCc delays Partnerships with the private sector (i.e. pharmaceuCcal companies, biotechnology firms, CROs) will be fostered to conduct further studies on compounds that show potenCal success to be developed as a drug. Data Mining and Collection
Tuklas Lunas
Public Health Problem Extraction
In vitro Biological Activity Testing
Bioactive Compounds
In vivo assays and ADMETox Assays
Formulation Studies
Structure Activity Relationship, Synthesis
and Derivatization
Bioactivity Facility
Bioactive Extracts
Standardization
Pre-Clinical and Clinical Studies
Lead Drug Candidates
Formulation Studies
Herbal Drugs
Pre-Clinical and Clinical Studies
Drug Candidates
PF/FC
DNA Barcoding
and ADMETox Assay
PROGRAM WORKFLOW
Bioassay Facility Lab Animal Resource Center Private DNA Barcoding of Medicinal Plants Pre/FormulaCon Center Pre-­‐/Clinical Studies Other Medicinal Plant Researchers Government RDI Drug or Herbal Drug Technology Takers Academic Research Researchers/ Technology Takers Public IP ProtecCon TLDCs Drug Research Database THANK YOU www.pchrd.dost.gov.ph