Novel Test for Improving Patient Outcomes in Hematologic Cancers. predictive test that determines sensitivity to therapeutic options

Transcription

1 Novel Test for Improving Patient Outcomes in Hematologic Cancers predictive test that determines sensitivity to therapeutic options

2 Implementing A Surrogate Functional Biomarker Practical application of a fundamental biological principle to Guide Treatment Praedicare Dx: A predictive, functional biomarker platform that: Probes key cell death/survival mechanism cancer cells Measures function of Bcl-2 family onco-proteins ex vivo Provides CLIA validated test (LDT) headed towards IDE Demonstrated clinical utility in hematologic cancer Predictive Biomarker for AML, CLL, MM therapies Matches FDA paradigm for approval May provide Cdx for multiple therapies 2

3 Biomarker for Apoptosis-Inducing Therapies Test determines cancer cell proximity to programmed death Apoptosis Cell 1 Cell 2 Cell 3 Cell viability d x d y d z BCL Distinguishes Between: Sensitive cells Normal cells Resistant cells Cancer cells BCL Test readout (% priming [d x, d y, d z ] ) 3

4 Mitochondrial Profiling: Surrogate Functional Biomarker NORMAL CELL TUMOR CELL (addicted to anti-apoptotic proteins) Pro-apoptotic sensitizers and mimetic compounds are sequestered. Anti-apoptotic... Pro-apoptotic and sequester sensitizers proteins pro-apoptotic are and overexpressed mimetic activators, halting compounds tumor apoptosis. cells... displace activators, re-establishing the apoptotic pathway. LEGEND X APOPTOSIS Loss of Checkpoint Control DNA Damage Anaploidy X APOPTOSIS Mitochondrion Anti-Apoptotic Protein Pro-Apoptotic Protein Activator BH3 Protein Sensitizer BH3 Protein BH3 Mimetic Compound

5 Enhanced Decision Making in Hematologic Malignancy Apoptosis Drug Targets BCL2 AKT Mcl-1 PARP1 p53 PI3Kinase HDAC CDK Btk Proteasome Other SOC chemotherapies PraediCare Dx Hematological Malignancies MM AML ALL CLL NHL MCL DLBCL Broad Cdx Applications Improved Clinical Outcomes >450,000 US patients; >570,000 in EU 5

6 Complex Therapeutic Decision Making with Uncertain Efficacy and Certain Toxicity Objective: Make First Treatment the Best Treatment Identify non-responder patients and provide predictive value for alternative treatment option. AML Treatment Algorithm Age <60? Yes No Induction Standard Induction OR CR Transplant CR Consolidation Induction Failure Low-Intensity Therapy OR Intermediate- Intensity Therapy Induction Failure Retreatment OR Transplant Retreatment OR Transplant OR OR Best Supportive Care Transplant OR Best Supportive Care Best Supportive Care Adapted from NCCN Guidelines, Version , AML Today we have limited tools to predict patient outcomes in hematologic malignancy. A predictive diagnostic would have immediate and meaningful medical utility. - K. Anderson, MD Dana Farber Cancer Institute 6

7 Clinical Diagnostic: Establishing Evidence of Utility Acute Myeloid Leukemia Cytarabine - 62 patient Validation set completed Cytarabine patient Verification set started HMA - 28 patient Test set completed HMA patient Verification set started Alvocidib patient Validation study started Prospective study protocol to FDA AML - Cytarabine Response Predictor Multiple Myeloma Bortezomib - 25 patient Test set completed Carfilzomib patient (SWOG study started) Chronic Lymphocytic Leukemia Alvocidib - 65 patient Test set completed Ibrutinib+Alvocidib patient Validation study started Rituxan-125 patient Test set completed 7

8 PraediCare Dx development of test platform readout correlate to hypomethylating agent treatment In collaboration with Dr. Raoul Tibes at Mayo Scottsdale

9 Recent Eutropics Publications Demonstrate Medical and Pre-clinical Development Utility 9

10 PraediCare Dx Discriminates Positive and Adverse Response in CLL Hrk peptide readout predicts CLL patient response to alvocidib Bad peptide readout predicts adverse CLL patient response (TLS) to alvocidib AUC Bad =. 75 (p =.0007) AUC Bad+Age+ECOG =.85 (p <.0001) AUC Hrk =. 73 (p =.0002) AUC BIM(0.1) =. 73 (p =.0004) AUC Hrk+Trisomy12 =.83 (p <.0001) In collaboration with Dr. John Byrd and Dr. Amy Johnson Ohio State University, Division of Medical Oncology 10

11 Clinical Diagnostic: Guiding treatment decisions for SOC, SOC+, New treatments Report Date 08/22/13 Patient name John A. Smith Diagnosis Acute Myelogenous Leukemia Date of Birth 01/15/43 Client MD Anderson Sample Received 08/20/13 Gender Male Physician Dr. Jones Collection Method Whole blood ID# AB12345 Pathologist Dr. Springer Sample Date 08/19/13 Patient Results BIM BIM(.1) PUMA PUMA(10) PUMA 2A NOXA BMF BAD HRK Therapeutic Implications 65% Therapy #1 65% Likelihood of response 0% 100% 33% Therapy #2 33% Likelihood of response 0% 100% 85% Therapy #3 85% Likelihood of response 0% 100% 65% Therapy #4 65% Likelihood of response 0% 100% 15% Therapy #5 15% Likelihood of response 0% 100% 11

12 Utility of Predictive Test Clinical Therapeutic Medical utility for a range of indications MM AML CLL DLBCL NSCLC Garner Patient advocacy group support, uptake with KOLs, MolDx, reimbursement, NCCN, et.et. + Companion Diagnostic Benefit to Pharma Partners Clinical Development Speed development Regulatory Approval FDA compliance Commercial Competitive advantage Reimbursement Improve cost effectiveness, clinical outcomes 12

13 Path to Cdx Strategic plan to Cdx: Staged approach to building clinical product, Development Milestones CLIA(RUO) Relapsed/refractory patients IDE PMA: time frame Bridge study towards PMA (to be determined) True Cdx Concerns? Define risk mitigation strategy, Third party CLIA lab with larger footprint Deployment; commercialization and global distribution, with third party (could be required) Alignment on scalability and global footprint; 13

14 Will CDx Test Require IDE? Draft Guidance - In Vitro Companion Diagnostic Devices, August 2014 Investigational status: Use in clinical trials is typically considered investigational Does not matter even if already being previously provided as LDT (e.g., PraediCareDx) When a test is to be in a clinical study constitutes a significant risk study, an IDE must be filed For CDx, determination of significant risk relates to: Selection trial is considered a likely significant risk (SR) Stratification Trial: Likely non-significant risk (NSR) FDA (CDRH/OIR) is currently developing a Guidance Document on Use of Investigational Devices in Therapeutic Trials 14

15 Determining Risk in Drug-CDx studies CDRH Questions to Consider 1. Will use of the investigational test results lead to some trial subjects foregoing or delaying a treatment that is known to be effective? 1. Will use of the investigational test results expose trial subjects to safety risks that exceed the risks encountered with control therapies or non-trial standard of care? 2. Is it likely, based on a priori information about the investigational therapy, that incorrect test results would degrade the safety or efficacy of subjects treatment? 3. Does specimen acquisition, done for investigational testing and outside the standard of care, require an invasive sampling procedure that presents significant risk? Yes to any of the above questions results in the study be SR. No to all is NSR 15

16 Staged Cdx Development Praedicare Dx (AML): evidence based Path to CTA, Cdx; Perform test and training sets to establish correlation to response Perform verification in larger retrospective/prospective studies Perform Pilot prospective study in phase ½ or phase 2 clinical trial Lock down algorithm and analytics Perform Risk assessment, discussion with FDA; CEDR and CDRH Engage third party lab, transfer CLIA test (option) Select patients into phase 3 study 16

17 Reimbursement Considerations: Dx Evidence driven Coverage Coding Payment Analytical Validity: Accuracy, precision, and reproducibility Clinical Validity: Clinical Utility: Evidence Facilitate NCCN Guideline reference to support coverage) Use of Misc Chemistry code (84999) initially Multianalyte Assay with Algorithmic Analysis (MAAA) code once test is established Establish value-based list price (charges) for the test 17