Berwyn Clarke


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Berwyn Clarke

  1. 1. Stratified Medicine – Implications for pharmaceutical development BioDundee 2012
  2. 2. from Janet Woodcock, Director of CDER, FDA“...the upcoming years may well be known as the age of diagnostics” April 2012
  3. 3. Personalized Medicine Saves Lives 100 5 Year Years Ago Survival 80 Years Ago “Disease of the Blood” ~ 0% 60 Leukemia or Lymphoma Years Ago Chronic Leukemia Indolent Lymphoma Acute Leukemia Aggressive Lymphoma Preleukemia 38 Leukemia types identified: 51 Lymphomas identified: Acute myeloid leukemia (12 types) Mature B-cell lymphomas (14 types) Today Acute lymphoblastic leukemia (2 types) Mature T-cell lymphomas (15 types) Acute promyelocytic leukemia (2 types) Plasma cell neoplasm (3 types) Acute monocytic leukemia (2 types) Immature (precursor) lymphomas (2 types) Acute erythroid leukemia (2 types) Hodgkin’s lymphoma (5 types) Acute megakaryoblastic leukemia Immunodeficiency associated lymphomas (5 types) Acute myelomonocytic leukemia (2 types) Other hematolymphoid neoplasms (7 types) Chronic myeloid leukemia Chronic myeloproliferative disorders (5 types) Myelodysplastic syndromes (6 types) Mixed myeloproliferative/myelodysplastic syndromes (3 types) 70%Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2002, National CancerInstitute. Bethesda,MD,, based on Nov 2004 SEER data submission, posted tothe SEER web site 2005.
  4. 4. Stratified Medicine and Theranostics are a New Concept©Lab21 May 2012
  5. 5. Primary resistance and impact on first HIV therapyPatient 97-513 (blue): Wild-type sensitivityPatient 98-1186 (red): Mutations present for AZT, 3TC and multiple PI resistance Little SJ et al. JAMA 1999; 282: 1142-1148.
  6. 6. Protease Gene Mutations Selected by PIs L K L V M M I A G V V I L IDV 10 20 24 32 36 46 54 71 73 77 82 84 90 IRV MR I I I IL V VT SA I AFTS V M L RTV 10 20 32 33 36 46 54 71 77 82 84 90 FIRV F VL G SQV 10 48 54 71 73 77 82 84 90 IRV V S A D N NFV 10 30 36 46 54 71 77 82 84 88 90 FI N DS I I APV 10 32 46 47 50 54 73 84 90 FIRV V V LVM F L LPV/r 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90 L VL P AFTS Multi-PI 10 46 54 82 84 90Resistance VML Primary Undetermined Significance ©Lab21 May 2012 Secondary
  7. 7. Increasing Prevalence of Resistance Mutations • Researchers reported after studying nearly 12,000 HIV patients in the US during 1999 • More than one fourth of patients have viral resistance to 3 major classes of HIV drugs • 29% of patients have virus that is resistant to 2 classes of drugs • 22% of patients have virus that is resistant to a single class of drugs • Indicates that: • Careful monitoring needs to be implemented during therapy • Preliminary characterisation of all individual HIV patients must be implemented BEFORE therapy is initiated • This has to be factored when designing all new antiretroviral clinical trials Bloor. Antivir Ther 2000;5(suppl 3):132.©Lab21 May 2012
  8. 8. TRUGENE HIV-1 Genotyping Test—the First FDA Cleared HIV Resistance Test• Market clearance for TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System received September 26, 2001• First HIV drug resistance test to receive market clearance from the FDA• First IVD pharmacogenomics test to receive FDA clearance• Integrated system comprised of the chemistry, hardware, software, interpretative patient report, training, certification and service
  9. 9. EGFR Pathways and Drug Targeting
  10. 10. Iressa analysis in NSCLC by EGFR status©Lab21 May 2012
  11. 11. Analysis of CRC response to EGFR inhibitors©Lab21 May 2012
  12. 12. EGFR Pathways and Drug Targeting
  13. 13. Erbitux and Vectibix only effective in 10-20% of resistant metastatic colorectal cancer 38% Kras mut Kras Mutants Kras wt/Braf 52% Mutants ? Kras wt/? 14% Braf mut©Lab21 May 2012
  14. 14. Vemurafenib PFS – 5.3 months vs 1.6 months Chapman et al, NEJM, 2011On August 17, 2011, the Food and Drug Administration (FDA) approvedvemurafenib (Zelboraf, Hoffmann-La Roche Inc.) for the treatment of patientswith unresectable or metastatic melanoma with the BRAFV600E mutation
  15. 15. Rapid Response of Metastatic Melanoma using Vemurafenib©Lab21 May 2012
  16. 16. R&D Productivity is on the decline NMEs per $B R&D spent (inflation adjusted)100 10 10.1 1950 1980 2010 Source: Bernstein Research ―The Long View – R&D Productivity 2010)
  17. 17. Drug Discovery Pipeline Improvement― 79 per cent of candidate drugs that currently fail in clinical development might actually succeed if they were tested only on sub-populations known to be most susceptible to their beneficial effects and least susceptible to side effects‖
  18. 18. Parallel Track Dx and Rx Development Pharmaceutical Preclinical Phase 1 Phase II Phase III Launch Launch Discovery Validation Development Implementation Regulatory Robustness Clinical Validation ReproducibilityDx Marker
  19. 19. FDA Approval for Vemurafenib On August 17, 2011, the Food and Drug Administration (FDA) approved vemurafenib tablets for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA- approved test. The approval was based on an international randomized open-label trial in patients with previously untreated metastatic melanoma with the BRAFV600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test (made by Roche Molecular Systems, Inc.). This companion diagnostic test was approved by the FDA concurrently with vemurafenib’s approval. FDA approves Xalkori with companion diagnostic for a type of late- stage lung cancer Second targeted therapy approved with a test this year On August 26, 2011 the U.S. Food and Drug Administration approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene. Xalkori is being approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year.©Lab21 May 2012
  20. 20. The Emergence of Next-Generation SequencingPharmaceutical industry Diagnostic industryCurrent levels of drug performance are far fromsatisfactory “Today, the response rates vary from 20% to 75%, depending on the drug and the disease” Jürgen Schwiezer CEO, RocheHealth RegulatorsDrug approval agencies are encouraginggreater use of biomarkers and diagnostics indrug development and prescribing decisions,thus promoting the concept of companiondiagnostics for drugsSource: PricewaterhouseCoopers “Moving towards personalized healthcare”
  21. 21. Parallel Track Dx and Rx Development Pharmaceutical Preclinical Phase 1 Phase II Phase III Launch Launch Discovery Validation Development Implementation Regulatory Robustness Clinical Validation ReproducibilityDx Marker
  22. 22. Trofile Model • Pfizer developed a new HIV-1 inhibitor – Maraviroc/Celsentri • Maraviroc only functions against CCR5-tropic viruses and has no effect on CXCR4 so clear need to differentiate between the virus in an individual patient • Pfizer commissioned Monogram Biosciences (San Francisco) to develop a test (Trofile) that would differentiate the two strains • Assay used intensively during the trials and was fully operational when drug was launched • Assay only run in California so local operators were appointed in specific regions to facilitate sample logistics©Lab21 May 2012
  23. 23. What are LDTs ?• Assays or “kits” developed and “validated” by a laboratory/institution• Currently regulated by CLIA, HCFA and/or state (if in the U.S.) but not the FDA• No official requirements for design control, clinical trials, QSR(GMP)manufacture and quality control nor review and approval by a recognized regulatory body of a 510(k) submission and product “labeling”• No requirement for clinical validation• Pricing is typically low ( $200-450)
  24. 24. Laboratory Developed Tests: Pre-marketing requirements• For a test system developed in-house or, where the performance specifications are not provided by the manufacturer, the lab has to establish: • Accuracy • Precision • Analytical sensitivity • Analytical specificity • Reportable range of the test system • Reference intervals (normal values) • Other performance criteria required
  25. 25. US: Unequal Regulation of IVDs IVD Manufacturer CLIA Certified Lab IVD Kit Laboratory Developed Test (LDT) FDA FDA Enforcement Discretion
  26. 26. Vertically Integrated Diagnostics • Independent and platform agnostic • Can develop assays for appropriate biomarker • Has accredited laboratories in key global locations • Fully optimise and validate assay • Run clinical trials (GCLP) • Run assays as LDTs (CLIA, CPA, CAP) • Support clinical validation • Full regulatory and manufacturing capability (GMP) • CE mark (ISO) • 510(K) • PMA • Global sales and marketing/distributor network to cover all geographies©Lab21 May 2012
  27. 27. Conclusion • Pharma/Dx partnership is extremely important to maximise efficiency of stratified medicine • It is critical that all parties adopt a far more stringent approach to protection of IP, regulatory compliance and quality control • Many lessons to be learnt from therapeutic areas where personalised medicine has been in place for many years • Diagnostic companies may not differentiate a companion diagnostic from any other of their diagnostic tests within their business model • All parties: healthcare providers, government agencies, pharma, diagnostic companies and, most important, patients should be able to maximise value from stratified medicine©Lab21 May 2012