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  • 1. Preclinical Development, an overview: do we need a change? Carolina Salcedo, PhD Director Pharmacology, SANIFIT JORNADA TOX® Barcelona, 1 de febrer de 2013 CERETOX Photo: Can open innovation close the pharma productivity gap? By John McCulloch @ MaRS June 7, 2011- Confidential - 1
  • 2. Drug Discovery and Development Target Lead Candidate Preclinical Clinical Discovery selection and Registration selection Development Trials optimization From 1000nds to 1-3 1-3 1 3-5 years 400 M $ 1 year 5-7 year 1B$ 5-7 years JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 2
  • 3. Preclinical Development Preclinical Package 1. Chemistry, manufacturing and controls (CMC) 2. Efficacy 3. Safety 4. Toxicology 5. ADME & PK 6. Documentation : IB + IMPD JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 3
  • 4. Preclinical Development Candidate Preclinical Clinical selection Development Development Exploratory toxicology Regulatory toxicology Exploratory safety Regulatory safety Predict toxic/safety concerns  Provide a safety margin Select a candidate  Define the dose/concentration to start human trials (NOAEL) Help in next step study designs  Define max dose/concentration to be dosed in humans  Target organs/ Rescue treatments  JORNADA TOX® Obtain regulatory approval of clinical - Confidential - (Barcelona, 1 de febrer de(IB, IMPD) 4 studies 2013 - CERETOX)
  • 5. Critical tasks Candidate Preclinical Clinical selection Development DevelopmentExploratory toxicology Regulatory toxicologyGeneral toxicity in Repeated dose toxicitysilico/ in vitro GenotoxicityPreliminar genotoxicity Preliminary toxicity Local tolerance in vivo Immunotoxicity Reproductive/juvenile tox. Additional/follow-up studies CarcinogenicityExploratory safety Regulatory safetyOff-target binding profile CNSPreliminary CV safety Cardiovascular Follow-up studiesPreliminary CNS safety Respiratory Additional studies JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 5
  • 6. Exploratory toxicology&safety Toxicology Assay Safety Assay General Tox Citotox General Off -targets Glutathion Depletion QT hERG Phospholipidosis Purkinge Phototox Guinea Pig ECG Genotox Ames CNS Irwin Micronucleus Others? Renal, GI Special Tox LLNA Topical irritation In vivo Acute Tox Repeated Dose Tox Others Zebrafish In silico DEREK, TOPAK, OncoLogic, CASE JORNADA TOX®- Confidential - 6 (Barcelona, 1 de febrer de 2013 - CERETOX)
  • 7. Regulatory safety&toxicology EMA/FDA ICH guidelines: • Guidelines are not recipes! • Tailored to your compound M3 S1- Carcinogenicity S2 - Genotoxicity S3- Toxicokinetics /PK S4- Duration of chronc testing in animals S5 -Reprotoxicity S6 -Biotechnology S7- Safety Pharmacology /QT S8- Immunotoxicology Toni Guzman !!! JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 7
  • 8. Regulatory safety&toxicology The toxicological development plan depends on: • Design of the clinical trial that will be supported: duration, population • Administration route • Therapeutic indication • Pharmacological target • Exposure / Metabolism The toxicological development plan need to answer: • What is the maximal dose without adverse effects? • What are the main targets of toxicity ? • Are the effects reversible ? Monitorable ? JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 8
  • 9. Regulatory safety&toxicologyAre differences really due to the treatment? • Dose response (and exposure response!) • Consistency between sexes (not necessarily!) • Consistency with other parameters and other available studies • Artifacts possible? • Anomalous values in vehicle group?If they are related to the treatment, are they adverse? • Exaggerated pharmacology or off-target effect? • Magnitude of the difference compared to physiological range. • Direct versus indirect effects. Feedback response effects. Stress-related effects.If they are adverse, are they relevant to humans??? JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 9
  • 10. Safety margin 28d 28d Rat Dog Rat Human In vitro Cell Animal Animal Rat No rodent Resp Cardio CNS Off- hERG Active Ph I activity Model Model Tox Tox safety Safety safety targets (Pred) 105 MLD 104 LOAEL NOAELConcentration (nM)* 103 EC50 ID50 IC50 102 HEC Good Tol & IC50 pA2 Biomark Kd 101 JORNADA TOX® - Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX)
  • 11. Estimation of dose for FIH If they are adverse, are they relevant to humans??? Monitorable, Reversible (Rescue treatment) Jumping into human doses: FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers • Establish HED/MRSD based on NOAEL/MABEL • Apply safety margin • Define a escalation range JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 11
  • 12. However….are we doing well?Jonathan Hitchcock, 2003 Pfizer JORNADA TOX® - Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 12
  • 13. The Attrition Problem Pedro Cuatrecases, Drug discovery in jeopardy, 2006 • Productivity 1-2 drugs/10 reach market • Budgets increase x30 since 1970 ($5billion /year) • Revolutionary scientific advances in last 20 years, offering new and innovative opportunities JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 13
  • 14. The Attrition Problem Angela Dunne, GSK, 2011 The attrition rate for drug discovery programs from target to clinic is unacceptably high –Causes a lack of new medicines to treat diseases of high unmet need –Results in inefficiency of drug discovery organizations, requiring large target portfolios to ensure sufficient medicine output Significant contributors to attrition post-candidate are lack of efficacy and/or toxicity –Deployment of more physiological screens earlier in the drug discovery process should make a significant impact in the overall attrition rate JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 14
  • 15. The Attrition ProblemJim Kling, MSN Health & FitnessFDA agency failed to catch serious side effects in a number of drugs beforethey were approved, thus forcing embarrassing withdrawals Drug Company Indication Why Expiration date Vioxx Painkiller CV events 2004 Merck Bextra Painkiller CV events 2005 Pfizer Zelnorm IBS Heart problems 2007 Novartis Tysabri MS Progressive multifocal 2005 Biogen Idec leukoencephalopathy Neurospec Appendicities Life-threating side effects 2005 Palatin Thec. diagnosis Cylert ADHA Liver failure 2005 Abbot Permax Parkinson Blood backlow to aortic valves 2007 Valentant Baycol Cholesterol Fatal rhabdomyolysis 2001 Bayer Palladone Narcotic painkiller Sever effecst when taken with 2005 Purde Pharma alcohol JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 15
  • 16. The Attrition Problem: reasons (I) • Patient population is heterogeneous. Differ at genetic level with regard to drug transport, metabolism, expression of disease, etc • Early testing using tissues, cells, are just partially predictive. • Preclinical testing in animals models is modestly predictive of effects in humans • To many repeats, mainly in Discovery • Marketing • Management JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 16
  • 17. On track? Candidate Preclinical Clinical selection Development DevelopmentChallenges OpportunitiesIncreasing predictability and regulatory acceptance Creating entirely new therapeutic approaches (gene therapy,of in silico / in vitro methods antibody therapy, stem cells).Adding more knowledge to the drug discoveryprocess, so as to make success more certain : Pharmacogenomics–Drugs and dosage chosen based on genetic Genomics, proteomics, metabonomics composition –‘personalised medicine Molecular toxicology Transgenic animal models Biomarkers Help pharmaceutical companies Bioinformatics to get their programmes to failThe only way to reduce costs and reduce time efficientlyto launch is by reducing repeats, at any stage. - Confidential - JORNADA TOX® 17 (Barcelona, 1 de febrer de 2013 - CERETOX)
  • 18. On track ! 1. Olson H, 2000 : survey from 12 pharmaceutical companies with data compiled from 150 compounds with 221 Human Toxicity (HT) events reported. Positive HT concordance rate of 71% for rodent and nonrodent species 2. 1991- 40% of attrition was due to poor PK/BA Implementation of sophisticated panels of early in vitro ADME 2000 – a reduction to 10% 3. Fresh from the biotech pipeline 2011 (Jim Klings): Drugs approvals were up in 2011, reversing the trend, thanks to biologics JORNADA TOX®- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 18