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2012




                                                            Session: Open Innovation in Oncology (chairpersons:
Emerging Role of Biomarkers for Success of                  F. BERGER / TBC)
Targeted Cancer Therapies
                                                            • Innovative Cancer Biomarkers: Links Between
Key Note Presentation at BIOVISION EU                          Populations and Patients
                                                               Pierre HAINAUT, International Agency for Research on
                                                                Cancer
                                                             • Emerging Role of Biomarkers for Success of Targeted
                                                                Cancer Therapies
                                                               Saurabh AGGARWAL, Novel Health Strategies, LLC,
                                                                Bethesda, USA
                                                            • Envisioning the Future of Early Anticancer Drug
                                                                Development
                   www.NovelHealthStrategies.com               Johann DE BONO, Institute of Cancer Research, Royal
                                                                Marsden Hospital, UK




Contents                                                    Types of Biomarkers

•   Types of biomarkers                                     Type of Biomarkers       Description

•   Clinical trial design strategies                        Predictive biomarkers    Any measurement associated with response to or lack of 
                                                                                     response to a particular therapy.
•   Past, present and future of biomarkers
                                                            PK/PD biomarkers         PK and PD biomarker data analysis for determination of 
•   New emerging biomarkers: Case studies                                            biologically active dose
    –   T315I                                               Safety/Toxicity          Measurement and monitoring of biomarkers to minimize 
    –   ALK                                                                          toxicity of cancer drugs
    –   Hedgehog                                            Prognostic biomarkers    Provide information on the natural course of disease after 
    –   BRAF                                                                         standard treatments
    –   BRCA                                                Intermediate end‐point   Markers that reflect treatment benefit at an earlier time 
• Implications for discovery and development of targeted                             point than would be required to attain the primary 
                                                                                     objective of the study
  cancer therapies




                                                                                                                                                     1
2012




Factors to Consider for Biomarker and Drug Co‐development                       Clinical Trial Designs for Biomarker Validation


                                                                                 Clinical Design Strategy   Description
   • Characterization and selection of biomarker                                 Enrichment Design          Enrichment studies may be preferred when the biomarker 
       – Specificity                                                                                        is well understood; supporting data suggest little benefit of 
       – Sensitivity                                                                                        the drug in biomarker‐ negative populations or suggest 
                                                                                                            substantial drug toxicity or resistance in biomarker‐positive 
   • Standardize assay methods                                                                              patients
   • Clinical trial design that allows evaluation of predictive                  All‐Comers Designs         Accrual of patients is prospective, the biomarker 
                                                                                                            evaluation may be conducted either prospectively or 
     responsiveness                                                                                         retrospectively
   • Ability to incorporate emerging data and advanced                           Adaptive biomarker         Midtrial modifications are allowed,  based on new interim 
     technology                                                                  enrichment                 information either from inside or outside the trial. 
                                                                                                            Requires specification of Type I and Type II errors




Past, Present and Future of Biomarkers



                                    ALK           Combination biomarkers
     ER                BCR‐ABL      Hedge Hog     Molecular arrays
     Her‐2             C‐Kit        T315I         Biomarkers for monitoring 
     PSA               KRAS         BRAF          Biomarkers for maintenance     Case Study 1: T315I
                                    BRCA          therapy




    1990               2000       2010              2020




                                                                                                                                                                             9




                                                                                                                                                                                   2
2012




Emerging Biomarker Case Study 1: T315I                            Discovery of Ponatinib

• BCR‐ABL targeted agents such as Gleevec have shown                                           • Rationally designed inhibitor 
  remarkable efficacy in CML patients, but still many patients                                   of BCR‐ABL
  relapse due to T315I mutation                                                                • Active against T315I mutant
• Limited benefit of 2nd generation TKIs used as 3rd line                                         – Unique approach to 
                                                                                                    accommodating gatekeeper 
  therapy
                                                                                                    residue
    – Failure‐free survival 20 months
                                                                                               • Potent activity against an 
•   No available therapy for T315I
                                                                                                 array of BCR‐ABL variants
    – Median survival in CP 22 months
                                                                                               • Also targets other 
• There is a need for new agents that can target this mutation 
                                                                                                 therapeutically relevant 
  and provide another treatment option for advanced CML 
                                                                                                 kinases:
  patients
                                                                                               • – Inhibits FLT3, FGFR, VEGFR 
                                                                                                 and PDGFR, and c‐KIT




Ponatinib Phase I Clinical Trial Patient Characteristics          Ponatinib Phase I Clinical Trial Results


                                                                  Chronic Phase CML




                                                                  Advanced Phase CML




                                                                                                                                    3
2012




                                                                          Emerging Biomarker Case Study 2: ALK

                                                                          • Activating mutations or translocations of the anaplastic 
                                                                            lymphoma kinase gene (ALK) have been identified in several 
                                                                            types of cancer
Case Study 2: ALK                                                         • In non–small cell lung cancer, EML4‐ALK is an aberrant fusion 
                                                                            gene that encodes a cytoplasmic chimeric protein with 
                                                                            constitutive kinase activity
                                                                          • EML4‐ ALK is uncommon, occurring in 2 to 7% of all non–
                                                                            small‐cell lung cancers
                                                                          • Preclinical studies have shown that selective ALK inhibition 
                                                                            specifically reduces the proliferation of cells carrying genetic 
                                                                            alterations in ALK


                                                                     14




Discovery of Crizotinib                                                   Crizotinib Clinical Trial Patient Characteristics




• Crizotinib (PF‐02341066, Pfizer) is an oral ATP‐ competitive 
  selective inhibitor of the ALK and MET tyrosine kinases 
• Inhibits tyrosine phosphorylation of activated ALK at nanomolar 
  concentrations.




                                                                                                                                                  4
2012




Crizotinib Clinical Trial Results        Crizotinib Clinical Trial Results




                                                       Shows a Kaplan–Meier curve of estimated progression‐free 
                                                       survival, with the lighter curves above and below the Kaplan–
                                                       Meier curve representing 95% Hall–Wellner confidence limits.




                                         Emerging Biomarker Case Study 3: Hedgehog

                                         • Hedgehog is a key regulator of cell growth and differentiation 
                                           during development, controls epithelial and mesenchymal 
                                           interactions in many tissues during embryogenesis
                                         • Extracellular hedgehog protein binds to patched homologue 
Case Study 3: HedgeHog                     1(PTCH1), a 12‐transmembrane receptor, and prevents 
                                           PTCH1‐mediated inhibition of signaling by smoothened 
                                           homologue (SMO), a 7‐transmembrane protein
                                         • Basal‐cell carcinoma is associated with mutations in 
                                           components of the hedgehog signaling pathway
                                         • Mutations cause constitutive hedgehog pathway signaling, 
                                           which in basal‐cell carcinomas can mediate unrestrained 
                                           proliferation of basal cells of the skin

                                    20




                                                                                                                         5
2012




Discovery of GDC‐0449                                                  GDC‐0449 Clinical Study Patient Characteristics 




• The novel SMO inhibitor GDC‐0449 was discovered by high‐
  throughput screening of a library of small‐molecule compounds and 
  subsequent optimization through medicinal chemistry 
• GDC‐0449 is a selective hedgehog pathway inhibitor with greater 
  potency and more favorable pharmaceutical properties than 
  cyclopamine




GDC‐0449 Clinical Study Patient Characteristics 




                                                                       Case Study 4: BRAF




                                                                                                                          25




                                                                                                                                 6
2012




Emerging Biomarker Case Study 4: BRAF                                   Discovery of PLX4032


• 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an                                                • PLX4032 (also known as RG7204 
  activating mutation in the gene encoding the serine–                                                          or RO5185426), an oral drug 
  threonine protein kinase B‐RAF (BRAF)                                                                         with high affinity for the 
• BRAF mutations are also found in 40 to 70% of papillary or                                                    mutated BRAF
  anaplastic thyroid cancers and in a small percentage of several                                             • Although almost 90% of BRAF 
  other types of tumor                                                                                          mutations constitute V600E 
• BRAF mutation constitutively activates BRAF and downstream                                                    mutations which are targeted by 
  signal transduction in the MAP kinase pathway                                                                 PLX4032, there is mounting 
                                                                                                                evidence that other V600 
                                                                                                                mutations also might be 
                                                                                                                susceptible to selective 
                                                                                                                inhibition




PLX4032 Clinical Trial Patient Characteristics                          PLX4032 Clinical Trial Study Results

                                   •   Patients who had 
                                       melanomas with the V600E 
                                       mutation in BRAF were 
                                       overrepresented because of 
                                       the selective activity of 
                                       PLX4032 against such 
                                       tumors in preclinical testing
                                   •   For the extension cohort, 
                                       eligibility was restricted to 
                                       patients with melanomas 
                                       harboring a V600E BRAF 
                                       mutation
                                                                          PLX4032 induced complete or partial tumor regression in 81% of patients who 
                                                                          had melanoma with the V600E BRAF mutation.




                                                                                                                                                           7
2012




                                                                                   Emerging Biomarker Case Study 5: BRCA


                                                                                   • A germ‐line mutation in one BRCA1 or BRCA2 allele is 
                                                                                     associated with a high risk of the development of a number of 
                                                                                     cancers, including breast, ovarian, and prostate cancer
Case Study 5: BRCA                                                                 • Cells carrying heterozygous loss‐of‐function BRCA mutations 
                                                                                     can lose the remaining wild‐type allele, resulting in deficient 
                                                                                     homologous‐recombination DNA repair, which causes genetic 
                                                                                     aberrations that drive carcinogenesis
                                                                                   • This tumor‐ specific defect can be exploited by using PARP 
                                                                                     inhibitors to induce selective tumor cytotoxicity, sparing 
                                                                                     normal cells


                                                                              30




                                                                                   Implications for Discovery and Development of 
Olaparib Clinical Trial Results
                                                                                   Targeted Cancer Therapies

                                                                                   • Biomarker strategy is becoming critical to demonstrate 
                                                                                     success of targeted cancer therapies

                                                                                   • Biomarker validation remains one of the major challenges for 
                                                                                     success of targeted cancer therapies

                                                                                   • Future clinical trial designs need to integrate biomarker 
  Objective antitumor activity was reported only in mutation carriers, all           evaluation either prospectively or retrospectively
  of whom had ovarian, breast, or prostate cancer and had received 
  multiple treatment regimens




                                                                                                                                                          8
2012




                                                                                                                                                          Developing Oncology HEOR, Marketing, Pricing, Market 
     References                                                                                                                                           Access and Reimbursement Strategy

     •    Envisioning the future of early anticancer drug development, Nature Review Drug 
          Discovery 2010
     •    Inhibition of Mutated, Activated BRAF in Metastatic Melanoma, NEJM, 2010
     •    Inhibition of Poly(ADP‐Ribose) Polymerase in Tumors from BRCA Mutation Carriers, 
          NEJM, 2009                                                                                                                                                         Join Novel Health's Team for Discussion on Key Trends and Emerging Topics for Oncology Products
     •    Crizotinib — Latest Champion in the Cancer Wars?, NEJM 2010                                                                                     Oncology is the highest selling indication for pharmaceutical and biotech products. It is projected that global sales of cancer drugs 
                                                                                                                                                          could reach $75‐$100 billion by 2016‐2020. Currently more than 40% of on‐going clinical trials are for cancer indications. There are 
     •    A Phase 1 Trial of Oral Ponatinib (AP24534) in Patients with Refractory Chronic                                                                 several factors that play a role in clinical and market success of new emerging cancer drugs. Join us for a live discussion on July 10, 
                                                                                                                                                          2012 on the following topics:
          Myelogenous Leukemia (CML) and Other Hematologic Malignancies, ASH 2010                                                                         What is the global outlook for cancer drugs for 2013‐2020?
     •    Saurabh Aggarwal, Targeted Cancer Therapies, Nature Review Drug Discovery 2010                                                                  How is oncology market different from other pharmaceutical and biotech products?
                                                                                                                                                          What are the key factors for clinical and market success of cancer drugs?
     •    Saurabh Aggarwal, What’s fueling the biotech engine‐2010, Nature Biotechnology                                                                  How to develop HEOR evidence generation strategy for oncology products?
                                                                                                                                                          How to develop pricing and reimbursement strategy for new cancer drugs?
                                                                                                                                                          What lessons can be learned from launch price and reimbursement trends for all approved cancer drugs (US, EU and Asia)?
                                                                                                                                                          What is the role of HEOR, QoL and CEA evidence for market access of cancer drugs?
                                                                                                                                                          What is the role of HTAs, comparative effectiveness and CEA for oncology products?
                                                                                                                                                          What are some of new reimbursement models that are emerging for cancer drugs in the US, EU, LatAm and Asian markets?
                                                                                                                                                          How to develop robust budget impact models (Excel, iPad and Android) and CEA for cancer drugs?
                                                                                                                                                          Lessons learned from pricing and reimbursement case studies for CRC, RCC and CML

                                                                                                                                                          Note: Due to proprietary data analyses in this webinar this presentation can be requested only for in‐person live replay
                                                                                                                                                                                                 http://www.novelhealthstrategies.com/oncology.htm




     Targeted Cancer Therapies: Nature Reviews Drug 
                                                                                                                                                          Novel Heath’s Expertise Areas
     Discovery

Oncology has become one of the major               anticancer therapies reached $10.4 billion —        with the FOLFOX4 (oxaliplatin (Eloxatin;
focus areas for pharmaceutical and                 an almost twofold increase since 2005 (FIG.         Sanofi–Aventis) plus leucovorin plus           EXPERTISE AREAS                            RECENT HEOR PROJECTS RECENT MARKET 
biotechnology companies. In 2009, ~16,000          1a)                                                 5‐fluorouracil) chemotherapy regimen2.
of the ~40,000 Phase I, II and III trials listed   — and their sales share increased from 46%          The success of combining one targeted          US & Global Market Access Strategy         HEOR Evidence Development Strategy for Novel  ACCESS PROJECTS
on ClinicalTrials.gov were related to cancer       in 2005 to 56% in 2009.                             drug with chemotherapy has led to the                                                     First in Class Product (Multiple Projects)
(~40%). This large interest stems from the         Antibodies are the market leaders                   hypothesis that efficacy could be enhanced     HEOR Evidence Generation Strategy
existence of high unmet need for improved          Currently, there are 22 FDA‐approved                by adding two or more targeted agents3,                                                   Economic Modeling for Blockbuster Product              40 Country Pricing and Reimbursement 
treatments of multiple types of cancer and         targeted cancer therapies, 9 of which are           especially to combat the resistance            Economic Modeling                          (Multiple Projects)                                    Strategy
the                                                monoclonal antibodies (mAbs), 12 of which           mechanisms used by cancer cells. Although
substantial market success of targeted cancer      are small‐molecule drugs and one of which           such combinations have shown promising         US & Global Pricing Strategy               GVD for Blockbuster Product (Multiple Projects)        2020 P&R Vision for Oncology Market 
therapies launched in the past decade.             is a fusion protein (see Supplementary              efficacy in preclinical models, the results                                                                                                      (Assessment Aided in Acquisition of Cancer 
US oncology market growth                          information S1 (table)). Among these drugs,         in clinical trials so far have not been        Global Value Dossier Development           HTA & Guidelines Review and Strategic                  Biotech for $2.5B)
Although the overall growth in                     four mAbs — bevacizumab (Avastin; Roche),           encouraging in general. For example,                                                      Implications
pharmaceutical sales in the United States          rituximab (Rituxan/MabThera; Biogen Idec/           the CAIRO2 trial showed that addition of       Payer Segmentation Analysis                                                                   P&R Assessment for Ten Fixed Dose 
— the largest pharmaceutical market — has          Roche), trastuzumab (Herceptin; Roche) and          cetuximab to capecitabine (Xeloda; Roche),                                                HEOR & Payer Publication Strategy for Blockbuster  Combinations
been slowing in recent years (to ~2–5% in          cetuximab (Erbitux; Eli Lilly/Bristol‐Myers         oxaliplatin and bevacizumab resulted           Medical Device Reimbursement Strategy      Product
2008–2009; REF. 1), the oncology market            Squibb) — and one small‐molecule drug —             in significantly shorter progression‐free                                                                                                    15 Country Reimbursement Strategy for 
continues to grow at double‐digit rates.           imatinib (Gleevec; Novartis) — constitute           survival and inferior quality of life for      Rare Disease Products                                                                         Novel Medical Device Product
In 2009, the US sales of oncology drugs            86% of the 2009 US sales (FIG. 1b). In 2009,        first‐line treatment of patients with                                                                                                        US & Global Market Access Strategy for Ultra 
(excluding hormonal therapies and vaccines)        the small‐molecule drugs constituted 23%            metastatic colorectal cancer4. Nevertheless,   Value Assessment for M&A or Licensing                                                         Orphan Product
                                                   (~$2.4 billion) of the total US sales of targeted   with further optimization of dose regimens                                                                                                   NPV/DCF Valuation for Neurology Product 
                                                   therapies, with ~50% of those sales being           and greater understanding of biomarker
                                                   derived from imatinib.                              data, it is possible that some patient
                                                                                                       subpopulations could benefit from such
                                                                                                       combinations.

                                      http://www.novelhealthstrategies.com/Targeted_Cancer_Therapies.pdf




                                                                                                                                                                                                                                                                                                        9
2012




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Aggarwal Biomarker Presentation Lyon France 2011

  • 1. 2012 Session: Open Innovation in Oncology (chairpersons: Emerging Role of Biomarkers for Success of F. BERGER / TBC) Targeted Cancer Therapies • Innovative Cancer Biomarkers: Links Between Key Note Presentation at BIOVISION EU Populations and Patients Pierre HAINAUT, International Agency for Research on Cancer • Emerging Role of Biomarkers for Success of Targeted Cancer Therapies Saurabh AGGARWAL, Novel Health Strategies, LLC, Bethesda, USA • Envisioning the Future of Early Anticancer Drug Development www.NovelHealthStrategies.com Johann DE BONO, Institute of Cancer Research, Royal Marsden Hospital, UK Contents Types of Biomarkers • Types of biomarkers Type of Biomarkers Description • Clinical trial design strategies Predictive biomarkers Any measurement associated with response to or lack of  response to a particular therapy. • Past, present and future of biomarkers PK/PD biomarkers PK and PD biomarker data analysis for determination of  • New emerging biomarkers: Case studies biologically active dose – T315I Safety/Toxicity Measurement and monitoring of biomarkers to minimize  – ALK toxicity of cancer drugs – Hedgehog Prognostic biomarkers Provide information on the natural course of disease after  – BRAF standard treatments – BRCA Intermediate end‐point Markers that reflect treatment benefit at an earlier time  • Implications for discovery and development of targeted  point than would be required to attain the primary  objective of the study cancer therapies 1
  • 2. 2012 Factors to Consider for Biomarker and Drug Co‐development Clinical Trial Designs for Biomarker Validation Clinical Design Strategy Description • Characterization and selection of biomarker Enrichment Design Enrichment studies may be preferred when the biomarker  – Specificity is well understood; supporting data suggest little benefit of  – Sensitivity the drug in biomarker‐ negative populations or suggest  substantial drug toxicity or resistance in biomarker‐positive  • Standardize assay methods patients • Clinical trial design that allows evaluation of predictive  All‐Comers Designs Accrual of patients is prospective, the biomarker  evaluation may be conducted either prospectively or  responsiveness retrospectively • Ability to incorporate emerging data and advanced  Adaptive biomarker  Midtrial modifications are allowed,  based on new interim  technology  enrichment information either from inside or outside the trial.  Requires specification of Type I and Type II errors Past, Present and Future of Biomarkers ALK Combination biomarkers ER BCR‐ABL Hedge Hog Molecular arrays Her‐2 C‐Kit T315I Biomarkers for monitoring  PSA KRAS BRAF Biomarkers for maintenance  Case Study 1: T315I BRCA therapy 1990 2000 2010 2020 9 2
  • 3. 2012 Emerging Biomarker Case Study 1: T315I Discovery of Ponatinib • BCR‐ABL targeted agents such as Gleevec have shown  • Rationally designed inhibitor  remarkable efficacy in CML patients, but still many patients  of BCR‐ABL relapse due to T315I mutation • Active against T315I mutant • Limited benefit of 2nd generation TKIs used as 3rd line  – Unique approach to  accommodating gatekeeper  therapy residue – Failure‐free survival 20 months • Potent activity against an  • No available therapy for T315I array of BCR‐ABL variants – Median survival in CP 22 months • Also targets other  • There is a need for new agents that can target this mutation  therapeutically relevant  and provide another treatment option for advanced CML  kinases: patients • – Inhibits FLT3, FGFR, VEGFR  and PDGFR, and c‐KIT Ponatinib Phase I Clinical Trial Patient Characteristics Ponatinib Phase I Clinical Trial Results Chronic Phase CML Advanced Phase CML 3
  • 4. 2012 Emerging Biomarker Case Study 2: ALK • Activating mutations or translocations of the anaplastic  lymphoma kinase gene (ALK) have been identified in several  types of cancer Case Study 2: ALK • In non–small cell lung cancer, EML4‐ALK is an aberrant fusion  gene that encodes a cytoplasmic chimeric protein with  constitutive kinase activity • EML4‐ ALK is uncommon, occurring in 2 to 7% of all non– small‐cell lung cancers • Preclinical studies have shown that selective ALK inhibition  specifically reduces the proliferation of cells carrying genetic  alterations in ALK 14 Discovery of Crizotinib Crizotinib Clinical Trial Patient Characteristics • Crizotinib (PF‐02341066, Pfizer) is an oral ATP‐ competitive  selective inhibitor of the ALK and MET tyrosine kinases  • Inhibits tyrosine phosphorylation of activated ALK at nanomolar  concentrations. 4
  • 5. 2012 Crizotinib Clinical Trial Results Crizotinib Clinical Trial Results Shows a Kaplan–Meier curve of estimated progression‐free  survival, with the lighter curves above and below the Kaplan– Meier curve representing 95% Hall–Wellner confidence limits. Emerging Biomarker Case Study 3: Hedgehog • Hedgehog is a key regulator of cell growth and differentiation  during development, controls epithelial and mesenchymal  interactions in many tissues during embryogenesis • Extracellular hedgehog protein binds to patched homologue  Case Study 3: HedgeHog 1(PTCH1), a 12‐transmembrane receptor, and prevents  PTCH1‐mediated inhibition of signaling by smoothened  homologue (SMO), a 7‐transmembrane protein • Basal‐cell carcinoma is associated with mutations in  components of the hedgehog signaling pathway • Mutations cause constitutive hedgehog pathway signaling,  which in basal‐cell carcinomas can mediate unrestrained  proliferation of basal cells of the skin 20 5
  • 6. 2012 Discovery of GDC‐0449 GDC‐0449 Clinical Study Patient Characteristics  • The novel SMO inhibitor GDC‐0449 was discovered by high‐ throughput screening of a library of small‐molecule compounds and  subsequent optimization through medicinal chemistry  • GDC‐0449 is a selective hedgehog pathway inhibitor with greater  potency and more favorable pharmaceutical properties than  cyclopamine GDC‐0449 Clinical Study Patient Characteristics  Case Study 4: BRAF 25 6
  • 7. 2012 Emerging Biomarker Case Study 4: BRAF Discovery of PLX4032 • 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an  • PLX4032 (also known as RG7204  activating mutation in the gene encoding the serine– or RO5185426), an oral drug  threonine protein kinase B‐RAF (BRAF) with high affinity for the  • BRAF mutations are also found in 40 to 70% of papillary or  mutated BRAF anaplastic thyroid cancers and in a small percentage of several  • Although almost 90% of BRAF  other types of tumor mutations constitute V600E  • BRAF mutation constitutively activates BRAF and downstream  mutations which are targeted by  signal transduction in the MAP kinase pathway PLX4032, there is mounting  evidence that other V600  mutations also might be  susceptible to selective  inhibition PLX4032 Clinical Trial Patient Characteristics PLX4032 Clinical Trial Study Results • Patients who had  melanomas with the V600E  mutation in BRAF were  overrepresented because of  the selective activity of  PLX4032 against such  tumors in preclinical testing • For the extension cohort,  eligibility was restricted to  patients with melanomas  harboring a V600E BRAF  mutation PLX4032 induced complete or partial tumor regression in 81% of patients who  had melanoma with the V600E BRAF mutation. 7
  • 8. 2012 Emerging Biomarker Case Study 5: BRCA • A germ‐line mutation in one BRCA1 or BRCA2 allele is  associated with a high risk of the development of a number of  cancers, including breast, ovarian, and prostate cancer Case Study 5: BRCA • Cells carrying heterozygous loss‐of‐function BRCA mutations  can lose the remaining wild‐type allele, resulting in deficient  homologous‐recombination DNA repair, which causes genetic  aberrations that drive carcinogenesis • This tumor‐ specific defect can be exploited by using PARP  inhibitors to induce selective tumor cytotoxicity, sparing  normal cells 30 Implications for Discovery and Development of  Olaparib Clinical Trial Results Targeted Cancer Therapies • Biomarker strategy is becoming critical to demonstrate  success of targeted cancer therapies • Biomarker validation remains one of the major challenges for  success of targeted cancer therapies • Future clinical trial designs need to integrate biomarker  Objective antitumor activity was reported only in mutation carriers, all  evaluation either prospectively or retrospectively of whom had ovarian, breast, or prostate cancer and had received  multiple treatment regimens 8
  • 9. 2012 Developing Oncology HEOR, Marketing, Pricing, Market  References Access and Reimbursement Strategy • Envisioning the future of early anticancer drug development, Nature Review Drug  Discovery 2010 • Inhibition of Mutated, Activated BRAF in Metastatic Melanoma, NEJM, 2010 • Inhibition of Poly(ADP‐Ribose) Polymerase in Tumors from BRCA Mutation Carriers,  NEJM, 2009 Join Novel Health's Team for Discussion on Key Trends and Emerging Topics for Oncology Products • Crizotinib — Latest Champion in the Cancer Wars?, NEJM 2010 Oncology is the highest selling indication for pharmaceutical and biotech products. It is projected that global sales of cancer drugs  could reach $75‐$100 billion by 2016‐2020. Currently more than 40% of on‐going clinical trials are for cancer indications. There are  • A Phase 1 Trial of Oral Ponatinib (AP24534) in Patients with Refractory Chronic  several factors that play a role in clinical and market success of new emerging cancer drugs. Join us for a live discussion on July 10,  2012 on the following topics: Myelogenous Leukemia (CML) and Other Hematologic Malignancies, ASH 2010 What is the global outlook for cancer drugs for 2013‐2020? • Saurabh Aggarwal, Targeted Cancer Therapies, Nature Review Drug Discovery 2010 How is oncology market different from other pharmaceutical and biotech products? What are the key factors for clinical and market success of cancer drugs? • Saurabh Aggarwal, What’s fueling the biotech engine‐2010, Nature Biotechnology How to develop HEOR evidence generation strategy for oncology products? How to develop pricing and reimbursement strategy for new cancer drugs? What lessons can be learned from launch price and reimbursement trends for all approved cancer drugs (US, EU and Asia)? What is the role of HEOR, QoL and CEA evidence for market access of cancer drugs? What is the role of HTAs, comparative effectiveness and CEA for oncology products? What are some of new reimbursement models that are emerging for cancer drugs in the US, EU, LatAm and Asian markets? How to develop robust budget impact models (Excel, iPad and Android) and CEA for cancer drugs? Lessons learned from pricing and reimbursement case studies for CRC, RCC and CML Note: Due to proprietary data analyses in this webinar this presentation can be requested only for in‐person live replay http://www.novelhealthstrategies.com/oncology.htm Targeted Cancer Therapies: Nature Reviews Drug  Novel Heath’s Expertise Areas Discovery Oncology has become one of the major anticancer therapies reached $10.4 billion — with the FOLFOX4 (oxaliplatin (Eloxatin; focus areas for pharmaceutical and an almost twofold increase since 2005 (FIG.  Sanofi–Aventis) plus leucovorin plus EXPERTISE AREAS RECENT HEOR PROJECTS RECENT MARKET  biotechnology companies. In 2009, ~16,000 1a) 5‐fluorouracil) chemotherapy regimen2. of the ~40,000 Phase I, II and III trials listed — and their sales share increased from 46% The success of combining one targeted US & Global Market Access Strategy HEOR Evidence Development Strategy for Novel  ACCESS PROJECTS on ClinicalTrials.gov were related to cancer in 2005 to 56% in 2009. drug with chemotherapy has led to the First in Class Product (Multiple Projects) (~40%). This large interest stems from the Antibodies are the market leaders hypothesis that efficacy could be enhanced HEOR Evidence Generation Strategy existence of high unmet need for improved Currently, there are 22 FDA‐approved by adding two or more targeted agents3, Economic Modeling for Blockbuster Product  40 Country Pricing and Reimbursement  treatments of multiple types of cancer and  targeted cancer therapies, 9 of which are especially to combat the resistance Economic Modeling (Multiple Projects) Strategy the monoclonal antibodies (mAbs), 12 of which mechanisms used by cancer cells. Although substantial market success of targeted cancer are small‐molecule drugs and one of which such combinations have shown promising US & Global Pricing Strategy GVD for Blockbuster Product (Multiple Projects) 2020 P&R Vision for Oncology Market  therapies launched in the past decade. is a fusion protein (see Supplementary efficacy in preclinical models, the results (Assessment Aided in Acquisition of Cancer  US oncology market growth information S1 (table)). Among these drugs, in clinical trials so far have not been Global Value Dossier Development HTA & Guidelines Review and Strategic  Biotech for $2.5B) Although the overall growth in four mAbs — bevacizumab (Avastin; Roche), encouraging in general. For example, Implications pharmaceutical sales in the United States rituximab (Rituxan/MabThera; Biogen Idec/ the CAIRO2 trial showed that addition of Payer Segmentation Analysis P&R Assessment for Ten Fixed Dose  — the largest pharmaceutical market — has Roche), trastuzumab (Herceptin; Roche) and cetuximab to capecitabine (Xeloda; Roche), HEOR & Payer Publication Strategy for Blockbuster  Combinations been slowing in recent years (to ~2–5% in cetuximab (Erbitux; Eli Lilly/Bristol‐Myers oxaliplatin and bevacizumab resulted Medical Device Reimbursement Strategy Product 2008–2009; REF. 1), the oncology market Squibb) — and one small‐molecule drug — in significantly shorter progression‐free 15 Country Reimbursement Strategy for  continues to grow at double‐digit rates. imatinib (Gleevec; Novartis) — constitute survival and inferior quality of life for Rare Disease Products Novel Medical Device Product In 2009, the US sales of oncology drugs 86% of the 2009 US sales (FIG. 1b). In 2009, first‐line treatment of patients with US & Global Market Access Strategy for Ultra  (excluding hormonal therapies and vaccines) the small‐molecule drugs constituted 23% metastatic colorectal cancer4. Nevertheless, Value Assessment for M&A or Licensing Orphan Product (~$2.4 billion) of the total US sales of targeted with further optimization of dose regimens NPV/DCF Valuation for Neurology Product  therapies, with ~50% of those sales being and greater understanding of biomarker derived from imatinib. data, it is possible that some patient subpopulations could benefit from such combinations. http://www.novelhealthstrategies.com/Targeted_Cancer_Therapies.pdf 9
  • 10. 2012 Recent Media Coverage Contact Us www. NovelHealthStrategies.com 10