big pharma cdx and the future of preventive …84de918c-58a6-4505-8382... · 2019. 6. 4. · big...

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.


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


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


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


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


BACKUPS


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

14

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)


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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©2016 This presentation is copyright protected. All rights reserved. You maydownload or print out a hard copy for your private or internal use. You are notpermitted to create any modifications or derivatives of this presentation without the prior written permission of the copyright owner.

This presentation is for information purposes only and contains non-bindingindications. Any opinions or views expressed are of the author and do notnecessarily represent those of Swiss Re. Swiss Re makes no warranties orrepresentations as to the accuracy, comprehensiveness, timeliness or suitability of this presentation for a particular purpose. Anyone shall at its own risk interpret and employ this presentation without relying on it in isolation. In no event will Swiss Re be liable for any loss or damages of any kind, including any direct, indirect or consequential damages, arising out of or in connection with the use of this presentation.

big pharma cdx and the future of preventive …84de918c-58a6-4505-8382... · 2019. 6. 4. · big...

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