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 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 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 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, 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 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 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 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 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 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 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