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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 DrugsCreated and manufactured with living organismsProteins as replacement for deficiencyProteins to mimic an in vivo functionProteins or peptides as antibioticsAntibodies to block a disease-promoting activityPeptides to mimic the effect of proteinsPeptides to reproduce the actions of antibodies
but betterRequire quite different manufacturing
operations from small molecules
The Biotech Revolution 19401940 few useful drugsNZ pioneer Sir Horace Smirk Malignant hypertension killed in few monthsDropping BP saved livesUniversity made huge contributionWellcome Trust set up full Institute in
DunedinEarly Biologics were animal derived: insulin
Biotech Revolution: The FortiesPenicillin. Fleming, St Mary’s. Rupert HareMultiple coincidences, could never repeat itFlorey, Oxford and Rockefeller made it
happenMerck up scaled the biological process,
Abbot, Pfizer, Squibb joined inFirst 5 months 1943 drug for 180 patients
world wideMid 1944 drug for 40,000 each monthDiscovery then development and
manufacture
NCEs to Biologics: The FiftiesTB Huge problem Biggest killerStreptomycin bacterial derived antibioticNew antihypertensives lots of side effectsPain relief still very old drugs, morphine,
aspirin, paracetamolSome new drugs effective but dangerous:
Chloramphenicol, Phenylbutazone: bone marrow
After antibiotics new drugs all small molecules
Chemists rule!!!
Sixties: Pharmaceutical ExplosionAcute Lymphoblastic Leukaemia: Survival 3 monthsCytotoxic drugs from germ warfare. Lethal and develop
resistance fastMultiple drugs now move to many patients cured 1966-9NZ too small to participate: Dr Fred Gunz NZ pioneerNew antihypertensives, diuretics, gout: Earliest testing
in NZHuge shift in medical practice: AMI in hospital 6 weeks
down to 3 daysThalidomide boosted FDA’s role and reputationGLH the centre of heart surgery, cutting up, cutting edge
Seventies: Avalanche of NCEsTreating Chronic Disease: Good for patients. Good
for business. Bad moods=good drugs to helpFirst statins: Merck: lovastatin. Save the dietNSAIDs: lots of themHeart drugs: hypertension, CHF, arrhythmiasDepression but not for drug companies: LibriumH-2 blockers for gastric ulcers: Tagamet first billionTough for universities to compete. Expensive, ultra
high throughput screening millions NCEs in librariesLittle NZ involvement. Too small
Eighties: Golden years: First new generation biologicsPharmaceutical industry fine old time. 99% NCEsSwallow, puff it, inject it, spray it, inhale it, patch
itNew Asthma drugs: NZ bigger clinical role again,
Glaxo the NZ companyMore depression to treat: whoopee !! Prozac. Genentech founded, capital $10,000. Now RocheHuman insulin: recombinant production 1982Tissue Plasminogen Activator: Belgium University
1984 Genentech Boehringer IngelheimNZ very active Harvey White: SK vs TPA
Nineties: Winds of ChangeFewer NCEs submitted and approved, more me tooLipitor No.5 statin but biggest seller. Power of
marketingHIV drugs, slow with old drugs, peptides needed as
protease inhibitors.Some NCEs << Mab IIb/IIIa antagonists: abciximabFactor VIII for haemophiliaTNK TPA Bolus, 19,000 patients. NZ right outAnti TNF drugs: Remicade, Enbrel for RA. Big signalAmgen: EPO: Anaemia, good for Tour de France
Alarm and Hope: 2000. Is it all over?Fewer innovative NCEsEpidemiology supplying fresh health scares on
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 sciencesIf nothing much goes, NZ is doing the same
The Norties: Biologics AwakenDeath of some NCEs: VioxxEven fewer approvedMAb lots of them: FDA now over 300 INDsAvastin: humanised MAb vs VEGF for NSLC,
Colon Ca, diabetic retinitisHerceptin: Her 2 positive breast CaMany small biotechs purchased by Big
PharmaCreative molecular biology in Academia
Why Opportunity For Universities?NCEs waterfall now a trickleMost disease targets not amenable to small
moleculesMost of new innovative drugs are now
biologicsBy 2020 >50% all new drugs biologicsMAb show new deliveries more patient
friendlyMost big pharma novices at biologicsUniversities with close mix of biology,
molecular biology and chemistry do well eg HERE
How to Compete?Right mix of skills: chemistry, biology,
molecular 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 IPTalk and argue and think and do
Can NZ Do It? NeurenLiggins Institute and Neuren collaborated with AC
Chemistry and Margaret BrimbleBiological observation: IGF1 upregulated with brain
injury. ? Response ? Natural protective moleculeSmall tripeptide of IGF1 protects brain injury up to
hours after.Imaginative chemistry produced analogue NNZ2566After 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?: AFTSmall NZ company from garage: Hartley
AtkinsonSuccessful generic business but now new
drug combosIn your face for the big guys. Hit the codeine
kingsParacetamol plus ibuprofen Why not thought
of first?MHRA says one study to doFDA IND says one study to do for acute and
for OAPlanning for NDA and global launchMarket 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 block with small molecules, but can by MAb, or even better with small peptides.
Also can act inside cellsUse as their source of peptides the genomes
of ancient bacteria, mostly extremeophileHundreds of billions of structures, enriched
by evolution for biological relevanceSophisticated search engines
Some Wise Reminders: Father Doug Biologic association does not always= causationBut it can!!Blue sky research may be green cash returnBe Alert: Serendipity is just around the cornerMany new drugs have been found by accidentFavoured biological process to block may improve
disease but may be negated by compensatory processes
Marc Feldmann and TNFYou might have thought of it first. AFTPlans to satisfy the grant might be the ones that miss
the new and unique observations