Companion Diagnostics in Pharmaceutical Development. Robert C Newton, Ph.D. VP, Drug Discovery Biology Incyte Corporation

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1 Companion Diagnostics in Pharmaceutical Development Robert C Newton, Ph.D. VP, Drug Discovery Biology Incyte Corporation

2 Why the Interest in Companion Diagnostics? Personalized Medicine using diagnostics to identify the members of a population that will best benefit from a targeted therapy Qualifiers Compound is directed to a specific target trastuzumab/her2 vs. taxol or cisplatin Target is only expressed by a subset of patient (<50%) HER2 in 20% of invasive breast cancer, 6-8% of gastric cancer EML4-ALK mutation in 3-5% of NSCLC/crizotinib BCR-Abl mutation in 90% of CLL Benefit is associated with modulating the specific target Benefits to Drug Development Faster proof of concept Higher response rates Smaller trials, lower cost, faster recruitment

3 Technical Options for Companion Diagnostics are Varied Blood, plasma or serum biomarker PSA in prostate cancer CA125 in ovarian cancer Circulating tumor cells Genetic test (PCR, FISH, etc.) of tumor EGFR mutation in lung and colon cancer ALK mutation in lung cancer BRAF mutation in melanoma KRAS mutation in colon cancer Immunohistochemistry of tumor Estrogen receptor in breast cancer Herceptest in breast cancer Broader Profile of tumor Gene expression pattern

4 Normal Progression of Assay Development in Drug Development Preclinical - Biomarker Discovery and Hypothesis Generation Phase 1 Dose escalation for safety and early signs of efficacy Feasibility: include a wide range of diagnostic assays to look for limitations and associations Define and finalize key reagents (antibodies, primers, etc.) Develop prototypes Phase 2a Proof of Concept Design optimization: Include assays as research kits in their final form Assay all comers to identify the correct population to target Phase 2b Dose ranging to optimize the therapeutic window Design verification: Finalize assay SOP and define target population Phase 3 Validation of efficacy and safety Design validation: Validate assay and the association of efficacy with targeting the population

5 Example: Assay Development in Trastuzumab Development Preclinical - Biomarker Discovery Her2 was identified as a therapeutic target in a subset of breast cancer Phase 1 Dose escalation for safety and early signs of efficacy Assayed for HER2 levels by IHC using trastuzumab antibody as both therapeutic and diagnostic Identified polyclonal antibody characteristics that yielded better and more reproducible detection (intracellular target) Phase 2a Proof of Concept IHC assay was used under a standard protocol with the polyclonal antibody Population was categorized a 0 through 3+ Phase 2b Dose ranging to optimize the therapeutic window Trastuzumab dose set and response rates compared in different populations. Her2 set at 2+ or 3+ as the target population Phase 3 Validation of efficacy and safety Validated that 3+ HER3 positive patient population derived the most benefit from trastuzumab.

6 Clinical Trials with vs. without Selection To screen or not to screen: gefitinib in NSCLC Gefitinib trial in all comers N = 210, RR of 18%, ~3 month PFS, ~8 month OS in Phase 2 N = 1093, no advantage over placebo, p = N = 1037, no advantage over placebo, p = 0.64 Gefitinib in EGFR mutation positive patients N=264, HR = 0.77, p =0.13 using IHC N=114, HR = 0.61, p = using FISH The right screen: tivantinib vs onartuzumab in NSCLC Tivantinib in c-met genetically amplified patients Phase II: N = 167, HR = 0.81; p =.24 using no selection Patients with MET copy number 2, 3, 4, and 5 revealed PFS HRs of 0.92 (N = 125), 0.75 (N = 68), 0.71 (N = 37), and 0.42 (N = 20), respectively All NS The Phase III MARQUEE trial in NSCLC in patients with c-met amplification was suspended at interim analysis due to lack of efficacy Onartuzumab in c-met overexpression by IHC N=65, >50% of tumor cells 2+ or 3+ for c-met IHC; HR=0.37; p=0.002

7 Crizotinib A Recent Example of the Benefits of Patient Selection An activating ALK fusion is expressed in 3-5% of NSCLC. Study A (N = 136 patients) and Study B (N = 119 patients) in ALK positive individuals resulted in a statistically significant average increase of 7 months in PFS and median response duration of 48 weeks Objective response rates of 51% in phase II vs. current standard, single-agent therapy ORR of less than 10%. A 1,000 patient study of all comers would result in an average increase of ~1 month in PFS and a median response duration of ~6 weeks. Crizotinib received accelerated approved based on this data and approval of a companion diagnostic using the Vysis ALK Break Apart FISH Probe Kit Approved by the FDA for the treatment of anaplastic lymphoma kinase (ALK)-rearranged NSCLC in August 2011, 4 years after the first publication of ALK-rearranged NSCLC Companion diagnostic assay was not specified in approval

8 Tying The Legal Knot Most pharmaceutical companies do not have a diagnostics business, so there is a need for a partnership Strong interdependency is necessary for the pharmaceutical company to guarantee the codevelopment of the diagnostic If the diagnostic is not used, the drug may not be prescribed Promotion of the diagnostic is tied to the drug label Pharmaceutical company requires global reach for diagnostic to match pharmaceutical marketing (limits vendors to global companies) Diagnostic Partner must also have compliant design control and quality systems along with registration capacities that match the Pharma registration plans Development of the diagnostic is significantly more valuable to the pharmaceutical company than the diagnostic company

9 The Health Care Cost Differential Herceptin vs. Herceptest in breast cancer Herceptin = $3200/month (1 yr. = $38,400) Herceptest = $35 ($175/eligible patient) Tarceva vs. EGFR Mutation Test in NSCLC Tarceva = $8,000 (3 mo. = $24,000) EGFR = $650 ($4,333/eligible patient) Vemurafenib vs. Cobas 4800 BRAF V600 in melanoma Vemurafenib = $9,400/month (6 mo. = $56,400) BRAFV617F Assay = $660 ($1,320/eligible patient) Crizotinib vs. ALK Mutation test in NSCLC Crizotinib = $9,600/month (1 yr. = $115,200) Vysis ALK Break Apart FISH = $250 ($5,000/eligible patient) Diagnostic test costs will be cumulative (EGFR + ALK)

10 The Pace of Companion Diagnostics is Accelerating but Far From Steady 1998 Herceptin and Herceptest Currently 4 IHC assays and 6 gene amplification assays EGFR mutation assay (not a companion) 2005 c-kit amplification assay (not a companion) Vemurafenib and BRAF testing 2011 Crizotinib and ALK testing KRAS mutation assay (not a companion) Additional examples in Phase 3 Development Pertuzumab and trastuzumab-dm1 and HER2 Dabrafenib and BRAF Ontartuzumab and c-met

11 Diagnostics Partnerships in 1-2Q 2012 Diagnostics Partner Pharmaceutical Partner Disease Area Deal Date Foundation Medicine Novartis (NVS) Cancer-Multiple 12-Jun PrimeraDx Eli Lilly (LLY) Cancer-Multiple 12-Jun Genomic Health (GHDX) OncoMed Pharmaceuticals Cancer-Undisclosed 12-May Dako Genetech Cancer-Breast 12-May Roche/Ventana (RHHBF.PK) Millennium/Takeda (TKPHF.PK) Cancer-lymphoma 12-Apr Roche/Ventana Seattle Genetics (SGEN) and Cancer-lymphoma Millennium 12-Apr HTG Molecular Diagnostics Sanofi (SNY) Cancer-Undisclosed 12-Mar Meso Scale Discovery Bristol-Myers Squibb (BMY) Neurology-Alzheimers 12-Mar Abbott Molecular (ABT) Merck & Co (MRK) Cancer-Undisclosed 12-Mar Myriad Genetics (MYGN) Cephalon (CEPH) Cancer-ovarian and breast 12-Mar Biodesix Inc. Kadmon Corporation Cancer-Lung 12-Feb Dako Amgen (AMGN) Cancer-Undisclosed 12-Feb Siemens AG (SI) GSK/ViiV (GSK) Infection-HIV 12-Feb Siemens AG Tocagen Cancer-Brain 12-Feb Foundation Medicine Sanofi Cancer-Multiple 12-Jan Roche/Ventana Aeterna Zentaris Inc. Cancer-Multiple 12-Jan Xenon Genetech Pain 12-Jan Roche/Ventana Bayer (BAYZF.PK) Cancer-Undisclosed 12-Jan Roche/Ventana Pfizer (PFE) Cancer-Lung 12-Jan Roche/Ventana Syndax Cancer-lung 12-Jan

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13 BATTLE Study Prototype The complexity lurking behind companions On-going study in NSCLC at MD Anderson Biopsy-mandated study in 255 elderly pre-treated NSCLC patients Markers assessed: EGFR, KRAS, BRAF/M (PCR); EGFR, Cyclin D1 (FISH); VEGF, VEGFR, 3 RXR receptors + Cyclin D (IHC) Patients adaptively randomized based on biomarker analysis to four different treatments Tumor biomarker analysis demonstrates sex and age variations, and is hypothesis-generating.