BIG PHARMA CDX AND THE FUTURE OF PREVENTIVE IMMUNOTHERAPY FOR
EARLY STAGE CANCERS
Luigi Catanzariti, PhD
Founder & Principal - Catanzariti
& Associates
LUIGI CATANZARITI, PHD SWISS RE 7/11/2016 1
DISCLAIMER
The opinions expressed in this presentation and on the following slides are solely those of the presenter.
LUIGI CATANZARITI, PHD SWISS RE 7/11/2016 2
DIAGNOSTIC PARTNERING IS NOW AN INTEGRAL PART OF PHARMA STRATEGY – LESSONS LEARNEDPhase I/II data can potentially be used to seek approval for oncology indications with high unmet clinical need
Rx/CDx co-developments come with considerable clinical, technical, regulatory and commercial challenges.
Both drug and diagnostic development processes have their own rules and regulations. This codependency requires significant adjustments in what can be considered quintessentially clinical (Rx) and technical (Dx) development cultures. These conceptual and organizational differences can be source of significant friction in partnering interactions and are not always understood by management
Large pharmaceutical companies have increasingly internalized these lessons. Biotech startups are generally more inclined to delay regulated CDx development at risk pending more efficacy data
Mutual understanding and integration of “Rx and CDx cultures” early in the development process is important to achieving aggressive development timelines and successful registration of a precision medicine compound
LUIGI CATANZARITI, PHD SWISS RE 7/11/2016 3
HIGH-LEVEL REASONS FOR PHARMA’S OVERALL OPTIMISTIC OUTLOOK
CONVERGENCE OF THREE MAJOR DEVELOPMENTS IN
CANCER:
IMPROVED UNDERSTANDING OF THE HALLMARKS
OF TUMOR GROWTH AND METASTASIS
INTEGRATION OF GENOMIC & LIQUID BIOPSY
TECHNOLOGIES TO ENABLE EARLY DETECTION
AND THERAPEUTIC MONITORING OF RESPONSE
AND RESISTANCE
POTENTIAL FOR IMMUNOTHERAPY TO
SIGNIFICANTLY IMPROVE EFFICACY (BEYOND
PD1/PD-L1 BASED APPROACHES) 4LUIGI CATANZARITI, PHD SWISS RE 7/11/2016
Example: NSCLC
targets:
ALK-translocations
R0S1-translocations
MET
EGFR
BRAF
5
FREQUENCY OF GENETIC ABNORMALITIES IN LUNG CANCER DRIVES COLLABORATION OF PHARMA WITH TECHNOLOGY COMPANIES BEYOND THE TRADITIONAL CD X PROVIDERS
6
Trend to move towards multiplexing
using NGS-based technologies
- Pharma working together with
Technology companies to achieve
approvals for future support of
clinical trials
(Pfizer/Novartis/Thermo-Fisher
‘consortium’ is an example)
IMPLICATIONS OF HIGHLY COMPLEX NGS TESTS
7Pfeifer, FDA workshop on NGS 2/15
NEOANTIGEN DETECTION - NEED FOR IMPROVED SEQUENCING
LUIGI CATANZARITI, PHD SWISS RE 7/11/2016 8From Personalis White Paper 10/15
PHARMA STRATEGIES TARGET DIAGNOSTIC ANDDRUG APPROVAL – WITH CONSTRAINTS Requires early alignment of drug and diagnostic and developments for global clinical study
Regulated diagnostic development is typically not a Pharma strength (focus on ‘biomarker’)
CDx development, configuration is typically driven by countries with high regulatory requirements (ie US, Japan Australia)
US – clinical trial may require first approval of an IDE (Investigational Device Exemption) before patient selection trial allowed to proceed
In the US and Japan device and therapeutic linked via clinical study (concurrent PMA/NDA approvals required for launch)
Need to select CDx technology and partner carefully (approvability, performance, commercial needs, reimbursement ) to avoid regulatory and commercial risks incurred by the diagnostic
EU – implementation of new regulations similar to US by 2019
Not always understood by KOLs who support global drug trials as they generally are more inclined to use latest in-house technology based on best available science (wide-spread NGS discussion)
Impact on clinical trial design to adjust for local testing in clinical trials: FDA has expressed concerns about potential introduction of bias
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LIQUID BIOPSY IN ONGOING BASIC AND APPLIED CANCER RESEARCH
Sampling and analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and extracellular vesicles (EV) for early detection and monitoring
Field has matured with improved sensitivity and detection
Most recent addition are EVs giving access to subsets ofbiomolecules other then DNA found in whole cells for
analysis (will include microRNAs)
Great potential to extend utility through integration with various CDx technologies for therapy selection / monitoring
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Liquid biopsy could
overcome the problem of
tumor heterogeneity
Liquid biopsy for pancreatic cancer. Circulating tumor DNA (ctDNA) can be isolated
from plasma as a liquid biopsy approach. Genomic alterations
detected could then have various clinical applications in pancreatic cancer cases. As
ctDNA is released not only from primary tumors, but also metastases, its analysismight overcome the problem of tumor heterogeneity.
Takai E et al . ctRNA used for pancreatic cancer detection (2016)
www.wjgnet.com
SINGLE CELL SEQUENCING IN PHARMA RESEARCH
11http://dx.doi.org/10.1155/2016/9369240
IN SUMMARY
In the short run traditional single gene CDx will be increasingly integratedwith new liquid biopsy sampling technologies (ctDNA, CTC) moving the field potentially towards earlier detection, treatment and monitoring fordrug resistance -> low hanging fruit, 2-5 years time-frame
Select NGS technologies will reach over the next 2 years regulatory approval incountries with strict regulatory requirements and also achieve clinicalvalidation for specific drugs (i.e. lung panels) in conjunction with tissue biopsies, CTCs andctDNA, -> 2-5 years. At this point Pharma will elevate NGS to CDx for specific drugs
Convergence of all these technical developments and the emergence of personalizedtumor vaccines based on novel antigen targets (neo-antigens) could allow to detectand genetically map tumor evolution much earlier and improve efficacy for CDx-based drugtherapies (10 year time-frame – validation in clinical trials will require time)
Early intervention when tumor load and mutational burden is low
Potential to cure cancer
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BACKUPS
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ADVANCES IN IMMUNOTHERAPY SUGGEST POSITIVE CORRELATION BETWEEN CHECKPOINT INHIBITOR BLOCKADE RESPONSE AND MUTATIONAL LOAD
• Immunotherapy is changing the therapeutic landscape in manymalignancies.
• Immune checkpoint inhibitors have already receivedregulatory approval in melanomas, lung, renal and bladdercarcinomas.
• Increased mutational load, seems to potentially increase thenumber of tumor neoantigens that are recognized by theimmune system.
• Neoantigens could also provide early diagnostic andtreatment information for peptide-based personal vaccineapproaches
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HALLMARKS OF CANCER(HANAHAN/WEINBERG, 2000, 2011)
LUIGI CATANZARITI, PHD SWISS RE 7/11/2016 15Luigi Catanzariti, PhD
Swiss Re 7/11/2016
LDTS IN CLIA LABS – INNOVATORS WITH ABILITY TO RAPIDLY VALIDATE NEW TECHNOLOGIES – IN THE US NOT READY FOR FDA APPROVAL YET • Generally faster development / validation cycle compared to established large diagnostic companies
• Significant presence in supporting clinical trials (but not diagnostic filing) with complex but innovative technologies (NGS)
• Some adapting rapidly by implementing QSRs and ability to support regulatory filing of complex, single lab only-based tests (site-specific PMA)
• Generally not preferred big Pharma partners for regulated CDx development and approval (with exceptions)
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THE BIG DIVIDE IN THE US – CLIA VS. FDA APPROVED TESTS
FDA-approved tests developed under QSRs
CDx considered class III (high-risk) devices need FDA approval
Domain of established large diagnostic companies (i.e. Roche Diagnostics, BioMerieux, Abbott Diagnostics, Qiagen etc.)
Laboratory-developed tests (LDTs) developed under CLIA
Generally not developed under QSRs
Cover many new multi-target technologies including NGS increasingly in important to oncology developments
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