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