Companion & Complementary Diagnostics: Clinical and Regulatory Perspectives Workshop on Companion Diagnostics January 31, 2017 Jan Trøst Jørgensen, M.Sc.Pharm., Ph.D. Dx-Rx Institute Fredensborg, Denmark E-mail: jan.trost@dx-rx.dk Disclosures: Jan Trøst Jørgensen has worked as a consultant for Dako, Agilent Technologies and Euro Diagnostica and has given lectures at meetings sponsored by AstraZeneca, Merck Sharp & Dohme, and Roche. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 1
Companion & Complementary Diagnostics Introduction and History Definitions Drug-Diagnostic Co-Development What can be achieved? Regulatory Aspects Conclusion and Future Perspectives Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 2
Disease Heterogeneity In order to achieve a more effective pharmacotherapy we need to recognize that most diseases are heterogeneous and thus develop drugs accordingly. 1 1. Jørgensen JT. A challenging drug development process in the era of personalized medicine. Drug Discov Today 2011;16: 891-897 Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 3
Drug-Diagnostic Combinations Oncology A high degree of correlation between response and positive estrogen-receptor assay suggests the value of the diagnostic test as a means to select patients for tamoxifen treatment Lerner HJ et al. Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer. Cancer Treat Rep. 60,1431-1435 (1976). Tamoxifen Breast Cancer HER2 Breast Cancer FDA Approves: Trastuzumab + HercepTest Imatinib, Gefitinib, Vemurafenib, Crizotinib, Pertuzumab, Ceritinib, Pembrolizumab and more 1970 1980 1990 2000 2010 Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 4
Companion Diagnostics (CDx) US Definition 1 A CDx assay is an in vitro diagnostics device that provides information that is essential for the safe and effective use of a corresponding therapeutic product: 1. Identify patients who are most likely to benefit from the therapeutic product 2. Identify patients likely to be at increased as a result of treatment with the therapeutic product risk for serious adverse reactions 3. Monitor response to treatment with the therapeutic product for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness 4. Identify patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective, i.e., there is insufficient information about the safety and effectiveness of the therapeutic product in any other population 1. In Vitro Companion Diagnostic Devices. Guidance Document. FDA, August 6, 2014. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262327.pdf Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 5
Companion Diagnostics (CDx) Proposed EU Definition 1 A device which is essential for the safe and effective use of a corresponding medicinal product: 1. Identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or 2. Identify, before and/or during treatment, patients likely to be at increased risk for serious adverse reactions as a result of treatment with the corresponding medicinal product; 1. Council of the European Union. (2016) Proposal for a Regulation of the European Parliament and of the Council on in vitro diagnostic medical devices. 911663/16. August 31, 2016. (http://data.consilium.europa.eu/doc/document/st-11663-2016-init/en/pdf) Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 6
Complementary Diagnostics (CDx) Preliminary US Definition 1 A test that identify a biomarker-defined subset of patients that respond particularly well to a drug and aid risk/benefit assessments for individual patients, but that are not pre requisites for receiving the drug. Drugs with US FDA approved complementary diagnostic: Nivolumab for NSCLC and Melanoma (PD-L1 IHC 28-8 pharmdx) Atezolizumab for NSCLC and Urothelial Carcinoma (VENTANA PD-L1 (SP142) assay) 1. Theoret M. Biomarkers for PD-1/L1 inhibitors: Regulatory Considerations. Presentation at the EMA-CDDF Joint Meeting, London February 4-5, 2016. (http://www.ema.europa.eu/docs/en_gb/document_library/presentation/2016/04/wc500204586.pdf) Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 7
Companion & Complementary Diagnostics 1 1. Jørgensen JT. Companion and Complementary Diagnostics: Clinical and Regulatory Perspectives. Trends Cancer 2016; 2: 706-712. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 8
Drug-Diagnostic Co-Development 1,2 Phase I to III Clinical Development Drug Development Discovery Research Pre-clinical Clinical Phase I Clinical Phase II Clinical Phase III Regulatory Approval Post Approval Phase Strong Biomarker Hypothesis Cut-off Selection Parallel Development & Analytical of Drug and Diagnostic & Validation Clinical Validation Clinical Utility Biomarker Selection Feasibility Studies Prototype Assay(s) Analytical Validation Clinical Validation & Utility Regulatory Approval Post Approval Phase CDx Development 1. Olsen D, Jørgensen JT. Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Front Oncol 2014; 4: 105. 2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016. (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm510824.pdf) Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 9
Drug-Diagnostic Co-Development 1,2 Phase I/II Clinical Development Drug Development Discovery Research Pre-clinical Clinical Phase I Clinical Phase II Regulatory Approval Post Approval Phase Strong Biomarker Hypothesis Cut-off Selection Parallel & Development Analytical of Drug & and Diagnostic Validation Clinical Validation Clinical Utility Biomarker Selection Feasibility Studies Prototype Assay(s) Clinical Analytical Validation Validation & Utility Regulatory Approval Post Approval Phase CDx Development 1. Olsen D, Jørgensen JT. Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Front Oncol 2014; 4: 105. 2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016. (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm510824.pdf) Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 10
Immune Checkpoint Inhibitors 1 st Line Treatment in NSCLC Pembrolizumab/PD-L1 IHC 22C3 pharmdx (KEYNOTE-024) PD-L1 IHC 22C3 pharmdx is approved as a companion diagnostic Assay cut-off: 50% PD-L1 expression 1 Treatment: Pembrolizumab (P) vs platinum-based chemotherapy (C), N=305 2 PFS: Median 10.3 mo (P) vs 6.0 mo (C); (HR 0.50, 95% CI 0.37-0.68, P<0.001) Nivolumab/PD-L1 IHC 28-8 pharmdx (CheckMate 026) PD-L1 IHC 28-8 pharmdx is approved as a complementary diagnostic Assay cut-off: 5% PD-L1 expression Treatment: Nivolumab (N) vs platinum-based chemotherapy (C), N=541 3 PFS: Median 4.2 mo (N) vs 5.9 mo (C); (HR 1.15, 95% CI 0.91-1.45, P=0.25) 1. Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372:2018-28. 2. Reck M al. LBA8_PR - KEYNOTE-024. Abstract presented at ESMO 2016 Congress, October 7-11, 2016, Copenhagen, Denmark. (https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5286/2016-10-09#2z94t0v3) 3. Socinski M et al. LBA7_PR - CheckMate 026. Abstract presented at ESMO 2016 Congress, October 7-11, 2016, Copenhagen, Denmark. (https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5286/2016-10-09#2z94t0v3) Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 11
Drug-Diagnostic Co-Development Enrichment Designs 1,2,3 Traditional Randomized Design Enrichment Design (Randomized) Enrichment Design (Single Arm) 1. Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. Draft Guidance. FDA, December 2012. (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf) 2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016. (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm510824.pdf) 3. Jørgensen JT. Companion Diagnostics and Clinical Utility in Oncology - Current Status and Future Aspects. Oncology 2013; 85: 59-68. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 12
Approved ALK & ROS1 Inhibitors in NSCLC Regulatory Submissions Efficacy Data 1,2,3 No. of Patients Crizotinib - ALK (US)/2011 255 Ceritinib (US)/2014 163 Alectinib (US)/2015 225 Crizotinib - ROS1 (US)/2016 50 0 50 100 150 200 250 300 1. Gandhi S, Chen H, Zhao Y, et al. First-line treatment of advanced ALK-positive non-small lung cancer. Lung Cancer: Targets and Therapy 2015; 6: 71-82. 2. McKeage K. Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. Drugs 2015 ; 75: 75-82. 3. Jørgensen JT. The importance of predictive biomarkers in oncology drug development. Expert Rev Mol Diagn. 2016;16: 807-809. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 13
Drug-Diagnostic Combinations Objective Response Rates Oncology 1 1. Jørgensen JT. Clinical application of companion diagnostics. Trends Mol Med. 2015; 21: 405-7. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 14
Companion Diagnostics (CDx) Regulatory Aspects 1,2,3 Classification of CDx assays US: Class III (high risk IVD devices) EU: General IVD (low risk IVD devices). In the near future Class C* Documentation of analytical and clinical validity US: Review by FDA EU: Self-certification and CE marking. In the near future review by independent notified body and national competent authorities and/or EMA *Class C: High individual risk or moderate public health risk, where an erroneous result would put the patient in an imminent life-threating situation or would have major negative impact on outcome 1. US FDA. Guidance for Industry and FDA Staff. In Vitro Diagnostic (IVD) Device Studies -Frequently Asked Questions. June 25, 2010 (http://www.fda.gov/downloads/medicaldevices/.../ucm071230.pdf). 2. Council of the European Union. (2016) Proposal for a Regulation of the European Parliament and of the Council on in vitro diagnostic medical devices. 911663/16. August 31, 2016. (http://data.consilium.europa.eu/doc/document/st-11663-2016-init/en/pdf) 3. Pignatti F. et al. Cancer drug development and the evolving regulatory framework for companion diagnostics in the European union. Clin. Cancer Res. 2014; 20: 1458-1468. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 15
Drug-diagnostics Codevelopment Future Perspectives Percentage of company pipeline relying on biomarker in late clinical development 1 65% 60% 55% 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Oncology Other Diseases Oncology will continue to dominate Other therapeutic areas: Central nervous system diseases Cardiovascular diseases Autoimmune diseases Drug and biomarker R&D will become a more flexible and iterative process 1. Milne CP et al. Market watch: Where is personalized medicine in industry heading? Nat Rev Drug Discov. 2015;14: 812-3. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 16
Summary & Conclusion The drug-diagnostic codevelopment model: Increased drug efficacy Reduction in time and resources spent 1,2,3 Increased development success rate 1,2,3 Oncology drug development is currently undergoing major changes Key requirements for CDx assay development: A clear intended us Analytical validity Clinical validated and demonstrated clinical utility 1. Falconi A. et al.. Biomarkers and receptor targeted therapies reduce clinical trial risk in non-small-cell lung cancer. J Thorac Oncol 2014; 9: 163-169. 2. Rubinger D.A. et al. Biomarker use is associated with reduced clinical trial failure risk in metastatic melanoma. Biomark Med 2015; 9: 13-23. 3. Jørgensen JT. The importance of predictive biomarkers in oncology drug development. Expert Rev Mol Diagn 2016; 16: 807-809. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 17
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A bad tumor biomarker test is as bad as a bad drug Current president of ASCO, Daniel F. Hayes 1 1. Hayes D., Raison C. Lessons for tumor biomarker trials: vicious cycles, scientific method & developing guidelines. Expert Rev Mol Diagn 2015; 15:165-169. Jan Trøst Jørgensen Workshop on Companion Diagnostics - January 31, 2017 19