Transcript From Small Molecules to Biologics: The Biotech Revolution

New Opportunities for Universities and Small Biotech
Companies:
Is there a role for little New Zealand?
Are we outgunned?
Too small?
Not enough fancy equipment?
Dr Doug Wilson
Biologic Drugs
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Created and manufactured with living organisms
Proteins as replacement for deficiency
Proteins to mimic an in vivo function
Proteins or peptides as antibiotics
Antibodies to block a disease-promoting activity
Peptides to mimic the effect of proteins
Peptides to reproduce the actions of antibodies but
better
 Require quite different manufacturing operations from
small molecules
The Biotech Revolution 1940
 1940 few useful drugs
 NZ pioneer Sir Horace Smirk
 Malignant hypertension killed in few months
 Dropping BP saved lives
 University made huge contribution
 Wellcome Trust set up full Institute in Dunedin
 Early Biologics were animal derived: insulin
Biotech Revolution: The Forties
 Penicillin. Fleming, St Mary’s. Rupert Hare
 Multiple coincidences, could never repeat it
 Florey, Oxford and Rockefeller made it happen
 Merck up scaled the biological process, Abbot, Pfizer,
Squibb joined in
 First 5 months 1943 drug for 180 patients world wide
 Mid 1944 drug for 40,000 each month
 Discovery then development and manufacture
NCEs to Biologics: The Fifties
 TB Huge problem Biggest killer
 Streptomycin bacterial derived antibiotic
 New antihypertensives lots of side effects
 Pain relief still very old drugs, morphine, aspirin,
paracetamol
 Some new drugs effective but dangerous:
Chloramphenicol, Phenylbutazone: bone marrow
 After antibiotics new drugs all small molecules
 Chemists rule!!!
Sixties: Pharmaceutical Explosion
 Acute Lymphoblastic Leukaemia: Survival 3 months
 Cytotoxic drugs from germ warfare. Lethal and develop
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resistance fast
Multiple drugs now move to many patients cured 1966-9
NZ too small to participate: Dr Fred Gunz NZ pioneer
New antihypertensives, diuretics, gout: Earliest testing in
NZ
Huge shift in medical practice: AMI in hospital 6 weeks
down to 3 days
Thalidomide boosted FDA’s role and reputation
GLH the centre of heart surgery, cutting up, cutting edge
Seventies: Avalanche of NCEs
 Treating Chronic Disease: Good for patients. Good for
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business. Bad moods=good drugs to help
First statins: Merck: lovastatin. Save the diet
NSAIDs: lots of them
Heart drugs: hypertension, CHF, arrhythmias
Depression but not for drug companies: Librium
H-2 blockers for gastric ulcers: Tagamet first billion
Tough for universities to compete. Expensive, ultra
high throughput screening millions NCEs in libraries
Little NZ involvement. Too small
Eighties: Golden years: First new
generation biologics
 Pharmaceutical industry fine old time. 99% NCEs
 Swallow, puff it, inject it, spray it, inhale it, patch it
 New Asthma drugs: NZ bigger clinical role again,
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Glaxo the NZ company
More depression to treat: whoopee !! Prozac.
Genentech founded, capital $10,000. Now Roche
Human insulin: recombinant production 1982
Tissue Plasminogen Activator: Belgium University
1984 Genentech Boehringer Ingelheim
NZ very active Harvey White: SK vs TPA
Nineties: Winds of Change
 Fewer NCEs submitted and approved, more me too
 Lipitor No.5 statin but biggest seller. Power of
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marketing
HIV drugs, slow with old drugs, peptides needed as
protease inhibitors.
Some NCEs << Mab IIb/IIIa antagonists: abciximab
Factor VIII for haemophilia
TNK TPA Bolus, 19,000 patients. NZ right out
Anti TNF drugs: Remicade, Enbrel for RA. Big signal
Amgen: EPO: Anaemia, good for Tour de France
Alarm and Hope: 2000. Is it all
over?
 Fewer innovative NCEs
 Epidemiology supplying fresh health scares on
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unsubstantial evidence, commonly reversed by next study.
What is real?
Genetic Revolution: ?? Getting anywhere ?Stamp
Collecting. Personal Medicine the rage, now a whimper
Biologics promising but that is all, ?all hype
?Close down Departments of epidemiology and genetics
and give the cash to more fruitful sciences
If nothing much goes, NZ is doing the same
The Norties: Biologics Awaken
 Death of some NCEs: Vioxx
 Even fewer approved
 MAb lots of them: FDA now over 300 INDs
 Avastin: humanised MAb vs VEGF for NSLC, Colon Ca,
diabetic retinitis
 Herceptin: Her 2 positive breast Ca
 Many small biotechs purchased by Big Pharma
 Creative molecular biology in Academia
Why Opportunity For Universities?
 NCEs waterfall now a trickle
 Most disease targets not amenable to small molecules
 Most of new innovative drugs are now biologics
 By 2020 >50% all new drugs biologics
 MAb show new deliveries more patient friendly
 Most big pharma novices at biologics
 Universities with close mix of biology, molecular
biology and chemistry do well eg HERE
How to Compete?
 Right mix of skills: chemistry, biology, molecular
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biology, understanding of pathology,
Good relations between groups internationally
Forget NZ as a competitor. Don’t worry about Otago or
Massey. Worry about Harvard or Oxford or AFT
Remember the big drug companies are now looking
everywhere, including NZ
Don’t forget IP
Talk and argue and think and do
Can NZ Do It? Neuren
 Liggins Institute and Neuren collaborated with AC
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Chemistry and Margaret Brimble
Biological observation: IGF1 upregulated with brain injury.
? Response ? Natural protective molecule
Small tripeptide of IGF1 protects brain injury up to hours
after.
Imaginative chemistry produced analogue NNZ2566
After extensive testing of multiple drugs 2566 selected by
Walter Reed, US Army research centre, as the single drug to
test to reduce Traumatic Brain Injury. NZ coup!
US Army paying for entire Clinical study under US IND
Can NZ Do it?: AFT
 Small NZ company from garage: Hartley Atkinson
 Successful generic business but now new drug combos
 In your face for the big guys. Hit the codeine kings
 Paracetamol plus ibuprofen Why not thought of first?
 MHRA says one study to do
 FDA IND says one study to do for acute and for OA
 Planning for NDA and global launch
 Market is in billions Just capture small %
 Can NZ? Yes: If smart and very focussed
New Generation Biologics: The
Little Guy. Peptides: Phylogica
 Premise that protein-protein interactions are hard to
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block with small molecules, but can by MAb, or even
better with small peptides.
Also can act inside cells
Use as their source of peptides the genomes of ancient
bacteria, mostly extremeophile
Hundreds of billions of structures, enriched by
evolution for biological relevance
Sophisticated search engines
Some Wise Reminders:
Father Doug
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Biologic association does not always= causation
But it can!!
Blue sky research may be green cash return
Be Alert: Serendipity is just around the corner
Many new drugs have been found by accident
Favoured biological process to block may improve disease
but may be negated by compensatory processes
 Marc Feldmann and TNF
 You might have thought of it first. AFT
 Plans to satisfy the grant might be the ones that miss the
new and unique observations