Minimal Residual Disease (MRD): a potential surrogate endpoint in AMLAn industry perspective

Sharon McBainSenior Director , Oncology Regulatory AffairsJanssen Research & Development, LLC

Disclaimer

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This presentation is intended for information sharing and discussion purposes, and any views or opinions expressed do not necessarily represent those of Janssen Research and Development LLC, or those of the companies participating in the MRD in AML industry alliance

Topics

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Increasing interest in MRD over past 5 years– Academic/industry focus– Regulatory focus

Looking forward: path to surrogacy?– Early Janssen activities– Industry alliance

Progress so far Next Steps

Global Regulatory Affairs CONFIDENTIAL 4

MRDIs it a thing???

OS and DFS according to MRD by Flow status pre-transplant

0.4

1 2 30

Years after HCT

Prob

abilit

y

0.8

0.04

0.2

0.6

1.0

MRD-, Overall Survival

MRD-, Disease-Free Survival

MRD+, Overall Survival

MRD+, Disease-Free Survival

Walter RB, et al. J Clin Oncol. 2011 Mar 20;29(9):1190-7.5

highly confidential – draft for internal use only6

MRD- status by MFC repeatedly shown to be an independent predictor of relapse and outcomes

San Miguel, 2001, Blood

Terwijn, 2013, JCO

Chen, 2015, JCO

MRD+

MRD-

MRD+

MRD-

Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML

Mojca Jongen-Lavrencic, MD, PhD1, Tim Grob, MD1*, Francois G. Kavelaars1*, Adil S.A. Al Hinai1*, Annelieke Zeilemaker1*, Claudia A.J. Erpelinck-Verschueren1*, Yvette Norden2*, Rosa Meijer, PhD2*, Bart J. Biemond, MD, PhD3*, Carlos Graux4*, Marinus van Marwijk Kooij, MD, PhD5*, Markus G. Manz, MD6, Thomas Pabst, MD, PhD7, Violaine Havelange, MD, PhD8*, Jakob R. Passweg, MD, PhD9*, Gert J. Ossenkoppele, MD, PhD10, Gerrit Jan Schuurhuis, PhD10*, Mathijs A. Sanders, PhD1*, Bob Löwenberg, MD, PhD1 and Peter J.M. Valk, PhD1, ASH Dec 2017

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highly confidential – draft for internal use only8

MRD- CR as a newly recommended response criterion in 2017

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Key regulatory milestones for MRD 2012-2018

2013FDA/ASCO

workshops on MRD in AML

2015EMA release

draft guidance on MRD as endpoint in

CLL

2016Duke M/FDA meeting on

MRD as surrogate in hematologic malignancies

2017FDA analysis of MRD data

in NDA applicationsEMA concept paper to add

use of MRD as EP in MM

2018FDA approves

Blincyto to treat adults and children with ALL in

remission but still have MRD

Medical, academic and industry increased focus

CONFIDENTIAL

Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 2541-2541.

ALLCML CLL AMLMM nHL

34 NDA applications submitted between 2014 and 2016

13 including MRD data

6 MRD data added to PI (46%) 4 not included (31%)3 not proposed (23%)o 5 used PCR testing

o 1 used flow cytometry

Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.

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Global Regulatory Affairs CONFIDENTIAL 11

15th Oct 2018

Janssen early activities for MRD in AML

• Understand current applicability of MRD in clinical practise (e-questionnaire) • Future utility through standardised methods

AML Ad Board Oct 2015

• Outline conceptual plan for pathway to surrogacy• Focus on methods, patient settings and CT designs

MRD Ad Board Dec 2015

• Collaborative effort with Gail Roboz and Gert Ossenkoppele• Review conceptual plan for pathway to surrogacy• Follow-up discussions for SAP and consider partnering

FDA meeting : April 2016MHRA, DKMA : April 2017

• Janssen invited to participate in panel discussion• ‘Call to arms’ for industry collaboration

Duke M/FDA Public meeting Sept 2016

• Ongoing refinement with focus on strength of existing evidence and pathway to surrogacy

MRD Ad BoardDec 2016-2017

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AML Ad Board: Oct 2015

Appreciation of importance of testing MRD, but with great heterogeneity around current utility in clinical practice

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Janssen Pathway to determine MRD as a surrogate for OS in AML

Annual MRD Ad Boards

Define conceptual

plans for methods and

data generation

FDA/EU HA meetings to discuss plans

Development Plan for

prospective evidence

generation to establish surrogacy

Methods: Moving from

multiple methods for Flow to NGS

Submission to HAs

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Preliminary Meta-analysis of published MRD and OS data

Preliminary Meta-Analysis of Published Data

Objective to systematically evaluate strength of ‘signal’ widely reported in the literature– Janssen previously conducted targeted literature review Nov 16– Prognostic association between MRD and OS– Learning exercise for future meta-analysis

Vendor conducted targeted literature review to cross-check previously identified literature and to update the review with recently released literature

– Protocol pre-specified selection criteria for studies to be included, statistical methods etc

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Study Selection Criteria Parameter Selection criteria*

Population 16+ yearsDisease characteristics AML onlyAML Setting (FL, Induction, Maintenance, Other)

All settings

Endpoints Study must report MRD negativity

May also report: CR, OS, EFS, RFS, DFSStudy design RCTs

NRSMethod of MRD detection AllNumber of MRD measurements At least one MRD measurementSample size ≥50 participants

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* Selection Criteria agreed with KOLs at ASH Ad Board Dec 17

Output: 32 publications identified: 31 full papers and 1 conference proceeding

Meta-Analysis MRD studies: preliminary results

MRD-: n=1503, MRD+: n=780

Significantly lower hazard rate of death for MRD- vs. MRD+ patients

Janssen Pathway to determine MRD as a surrogate for OS in AML

Annual MRD Ad Boards

Define conceptual

plans for methods and

data generation

FDA/EU HA meetings to

discuss plans

Development Plan for

prospective evidence

generation to establish surrogacy

Methods: Moving from

multiple methods for Flow to NGS

Submission to HAs

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FDA, MHRA, DKMA 2016-17Duke Margolis/FDA Sept 2016 Call to arms!!Call to arms!!

Preliminary Meta-analysis of published MRD and OS data

MRD in AMLIndustry Alliance

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Partner Industry StakeholdersIntegrated MRD strategy to support surrogacy: 3 Focus Areas

Methods

• Actively collaborate to evaluate potential for core NGS platform as possible future primary method• Share expertise and resources to optimise and harmonise current flow methods

Data

• Harmonise generation of MRD data across portfolios: agree cut-off and schedule/timing of MRD assessments• Build consolidated plan for MRD data read-outs across 4 companies• Determine submission strategy

Stats

• Agree on content of SAP for meta-analysis• Identify 3rd party data gate-keeper and agree scope of work and funding

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2

3

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MRD Industry Alliance: Operational Aspects

1. Form MRD Joint Steering Committee (JSC) to define goals, deliverables and timelines2. JSC to consider key potential confounders (e.g. legal, confidentiality issues, finances,

broader collaborations)3. Assign goals/deliverables to specialist working groups to advance Methods; Data;

Stats4. Meet F2F at least twice yearly (EHA, ASH), and bi-monthly in between as needed.

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Co-Leads: Celgene and Genentech-Roche

Lead: Janssen

Co-Leads: Janssen and Genentech-Roche

MRD Methods Work-stream

Agreement on G&Os

List of Vendors

Assessment of Flow & NGS platforms &

Assays

Pilot Flow & NGS

platforms & assays

Selection of

VendorsContract

discussions

Development of Protocols &

Standards for Clinical Trials

Analytical & Clinical

Validation to Support

Submission

Two work streams - Flow & NGS

Progress

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Data and Stats Work-Stream

Agreement on inclusion criteria for

prospective data analysis

Identification of studies for data analysis

Agreement of studies

selected with data owners

Map timeline for MRD and

OS data readout

Map out vendor

selection criteria and

SoW

Select Vendor

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Draft SAP and obtain feedback from FDA/EMA

Progress

Data to be pooled from industry and academic studies

Global Regulatory Affairs

Will there be a paradigm shift toward MRD as a surrogate?

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By kind permission of Dr G Ossenkoppele

Surrogate endpoint definitions:

1) A validated surrogate endpoint is one that is supported by a clearmechanistic rationale and clinical data providing strong evidence thatan effect on the surrogate predicts a clinical benefit; therefore, suchendpoints can be used to support traditional approval without the needfor additional efficacy information

2) A reasonably likely surrogate endpoint is supported by clearmechanistic and/or epidemiologic rationale but insufficient clinical datato show that it is a validated surrogate endpoint; such endpoints can beused for accelerated approval for drugs or expedited access for medicaldevices

3) A candidate surrogate endpoint is still under evaluation for its abilityto predict clinical benefit

NIH-FDA joint BM team 2015 2

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MRD as endpoint in clinical trials

MRD status to support clinical benefit EP

Data used for labelling (e.g. treatment decisions)

Accelerated approval on MRD status

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Exploratory

Primarysecondary

Potential Surrogate

Validated surrogate

Full approval

Pathway to determine MRD as a surrogate for OS in AML

Annual MRD Ad Boards

Define conceptual

plans for methods and

data generation

FDA/EU HA meetings to

discuss plans

Development Plan for

prospective evidence

generation to establish surrogacy

Methods: Moving from

multiple methods for Flow to NGS

Submission to HAs

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FDA, MHRA, DKMA 2016-17Duke Margolis/FDA Sept 2016 Call to arms!!Call to arms!!

Preliminary Meta-analysis to be published

Dialogue: academia, industry and regulatory community

AREAS FOR INDUSTRY ALLIANCE

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Summary and Next Steps

Growing evidence of the prognostic utility of MRD status in AML between MRD negativity and improved outcome (OS)

Good engagement with regulators with FDA/EMA meetings planned 2019

Moving towards harmonised prospective generation of MRD data

Industry and academic partners in active collaboration to generate and pool patient-level MRD and OS data into meta-analysis assessing predictive nature of correlation

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Questions

Statistical analysis overview

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Milena Sant , Pamela Minicozzi , Morgane Mounier , Lesley A Anderson , Hermann Brenner , Bernd Holleczek , Rafael ... Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: results of EUROCARE-5, a population-based study. The Lancet Oncology, Volume 15, Issue 9, 2014, 931 – 942. http://dx.doi.org/10.1016/S1470-2045(14)70282-7

5-year survival rates across haematology malignancies

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