Closing the Gaps in PhilippineDrug 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

Industry Trends

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

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

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 …..