Closing the Gaps in Philippine Drug Discovery & Development.
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Transcript of 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
For every 10-20 marketeddrugs, only 2 return a profit!
dose range
First-in-man?In-house/outsource?
safe
ty
effica
cy
Confi
rm e
ffica
cyM
onito
r sid
e eff
ects
Com
pare
to o
ther
tr
eatm
ents
250 5
Target ID/ValidHTS/HitsLead OptimADME
Safety PharmacolAnimal Models
Active compound “hits” are not drugs
Disease
Drug Target Biological
Assay
Active compound
“Hit”
Compound LibrariesNatural Products
Existing DugsPeptides
Computer-assisted drug design
Lead Optimisation: Making them “drug-like”
Hit
Hit to
LeadLEAD
moderate potencyless “drug-like”
Improve potencySAR mainly in vitro
drug-likepotent, soluble
selective, bioavailableetc
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)
ResearchPre-
clinicalManufac-
turingMarketing& Distribn
Phase I
Phase II
Phase III
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
ResearchPre-
clinicalManufac-
turingMarketing& Distribn
Phase I
Phase II
Phase III
smaller research budgets R&D limited to satisfying regulatory requirements of BABE provides us with OTCs and meds for common indications
Generics companies:
For most other indications, we rely heavily on the multinational corporations which have marketing and distribution subsidiarieshere in the Philippines.
Drugs of the Future
SMDs
Recomb proteins and mAbs
Therapeutic peptides
Therapeutic vaccines
siRNA
miRNA
gene therapy
stem cells
Pharma relies on biotech to fill its drying pipeline of drugs.(Credit crunch: Big Pharma to the rescue….)
Once different, now collaborative …………
Big pharma ventures into biologics.
Biotech ventures into small molecule drugs (SMDs).
Biotech is good at making innovative drugs. Pharma is good at selling them.
Blurring distinction between pharma and biotech
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
Source: Royal Society of Chemistry UK (www.rsc.org)
Over $63 billion of annual incomewashed away due to patent erosion
by 2014
Big Pharma Buying into Generics
Big Pharma Generics Company LocationSanofi Zentiva Czech Republic
Piramal IndiaMedley Brazil
Pfizer Aurobindo Pharma India
Strides Arcolab IndiaClaris Life Sciences
Merck BioVentures (created)Daiichi Sankyo Ranbaxy India
GSK Prasco Labs USAspen Pharma South AfricaShenzen Neptunus ChinaDr. Reddy’s India
Astra Zeneca Par Pharmaceutical US
NovartisSandoz (generics division 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
ANTIBACTERIALS: 78%ANTICANCER: 74%
Source: Newman, Cragg & Snader (NIH/NCI)
n=877
Natural Products: Record of Productivity
Modernisation of Natural Products Research
Glucocorticoid receptor
Rg1 Rb1
Estrogen receptor
upregulates agrowth receptor
stimulates blood vessel growth inhibits blood vessel growth
different pathway
NOT ALL GINSENG IS THE SAME:
(sterol ginsenoside) (sterol ginsenoside)
Gaps in understanding of the biopharma business
Criteria for drug discovery programs:
1. Should address unmet medical need2. Market potential should be considered to allow a
return on investment3. Product differentiation; preferably first-in-class and
demonstrate superior efficacy for it to capture and sustain a good market share.
NIRPROMP ?
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
19
38
Cancer therapies, vaccines for tropicalDiseases, AIDS medications, etc
1st World Results on Third World Budget
Clock for commercialisation begins ticking
Identify disease target
Develop biological
screen
Hit-to-Lead
Lead optimisation
CLINIC
INCREASING VALUE
Composition of matter patents
Gaps in the Drug Discovery & Development Continuum
ResearchPre-
clinicalManufac-
turingMarketing& Distribn
Phase I
Phase II
Phase III
HTS MedChemADME-
ToxAnimal Models
Safety pharmacology (pre-clinical)
Detect undesirable secondary pharmacologic effects on critical organ systems:
Cardiovascular: bp, heart rate, ECG, QT issuesCNS: motor activity, behavioural changes, coordination, sensory/motor reflexesRespiratory: resp rate, tidal volume, blood oxygentaionGI: gastric secretion, GI injury potential, bile secretion, transit time in vivoRenal: 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:MEDICINAL CHEM
Skills gap:ADME-Tox
Skills gap:PROTEOMICS/METABOLOMICS
Skills gap:BIOPROCESSING
Gap: Hardly any research into biologics
Source: Evaluate Pharma
7 out of 10 drugs will be biologics.Top 5 will be mAbs.
Avastin will be number 1Humira will be close 2nd
Both to bring around $9 billion a year
By 2014:
UP NIMBB: AMOR 1 & 2
Magnifies lack of critical mass (and facilities)In molecular biology research?
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 requireFurther lengthy clinical trials
Nor biosimilars ….
The Way Forward
Diversify funded researchIncorporate commercial criteria in proposal assessments
unmet medical needmarket potential/ROIproduct differentiationetc
Bring drug candidates through to phase I if possibleDevelop capabilities in med chem & prescribed assaysMind the skills gap (from pre-clinical R&D to clinical trial mgt)Pour in money …..