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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
safety
5
Confirm efficacy
Monitor side effects
Compare to other
treatments
250
efficacy
First-in-man?
In-house/outsource?
dose range
Target ID/Valid
Safety Pharmacol
HTS/Hits
Animal Models
Lead Optim
ADME
For every 10-20 marketed
drugs, only 2 return a profit!
Active compound “hits” are not drugs
Disease
Drug
Target
Compound Libraries
Natural Products
Existing Dugs
Peptides
Computer-assisted drug
design
Biological
Assay
Active
compound
“Hit”
Lead Optimisation: Making them “drug-like”
Hit
moderate potency
less “drug-like”
Hit
to
Lead
Improve potency
SAR mainly in vitro
LEAD
drug-like
potent, soluble
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)
Research
Preclinical
Phase
I
Phase
II
Phase
III
Manufacturing
Marketing
& 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:
Research
Preclinical
Phase
I
Phase
II
Phase
III
Manufacturing
Marketing
& 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
Recomb proteins
and mAbs
siRNA
miRNA
Therapeutic
peptides
gene therapy
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
Sanofi
Generics Company
Zentiva
Piramal
Medley
Location
Czech Republic
India
Brazil
Pfizer
Aurobindo Pharma
India
Strides Arcolab
Claris Life Sciences
India
Merck
Daiichi Sankyo
BioVentures (created)
Ranbaxy
India
GSK
Prasco Labs
Aspen Pharma
Shenzen Neptunus
Dr. Reddy’s
US
South Africa
China
India
Astra Zeneca
Par Pharmaceutical
US
Sandoz (generics division
of Novartis)
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
6%
39%
27%
5%
23%
natural products
natural product derivatives
synthetic compounds with NP pharmacophores
natural product mimic
other
Source: Newman, Cragg & Snader (NIH/NCI)
ANTIBACTERIALS: 78%
ANTICANCER: 74%
n=877
Modernisation of Natural Products Research
NOT ALL GINSENG IS THE SAME:
Rg1
(sterol ginsenoside)
Glucocorticoid receptor
upregulates a
growth receptor
stimulates blood vessel growth
Rb1 (sterol ginsenoside)
Estrogen receptor
different pathway
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
3
2000
2007
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
Identify
disease
target
Develop
biological
screen
Composition of matter
patents
INCREASING VALUE
Gaps in the Drug Discovery & Development Continuum
Research
HTS
Preclinical
MedChem
Phase
I
Phase
II
ADME-Tox
Phase
III
Manufacturing
Marketing
& Distribn
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
Source: Evaluate Pharma
UP NIMBB:
AMOR 1 & 2
Both to bring around $9 billion a year
Magnifies lack of critical mass (and facilities)
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 …..