Panel 1 Discussion. Capitalizing on the Totality of Evidence to Streamline Approvals for Supplemental Indications. #FriendsAM17

Panel 1 Discussion Capitalizing on the Totality of Evidence to Streamline Approvals for Supplemental Indications #FriendsAM17

Panel 1 Participants Moderator: George Demetri, Dana-Farber Cancer Institute, Harvard Medical School Shanthi Ganeshan, Novartis Pharmaceuticals Marian Johnson-Thompson, Komen Patient Advocate Amy McKee, U.S. FDA Pratik Multani, Ignyta Jordan Schecter, Janssen #FriendsAM17 2

Working Group Objectives and Goals George Demetri, MD Dana-Farber Cancer Institute, Harvard Medical School #FriendsAM17 3

The Patient Perspective Marian Johnson-Thompson, PhD Komen Patient Advocate #FriendsAM17 4

Rethinking supplemental approvals in FDA Amy McKee, M.D. Office of Hematology and Oncology Products Office of New Drugs Center for Drug Evaluation and Research FDA

Current status Initial approval for a new cancer treatment can be accelerated approval or regular approval www.fda.gov Depends on trial design (randomized vs. single-arm), endpoints, disease context, etc. Regular approval does not require additional clinical trials to demonstrate efficacy and safety Common endpoints: Overall survival, disease-free survival, progression-free survival Accelerated approval may require additional clinical trials to verify/describe efficacy and safety Common endpoints: Response rate, progression-free survival 6

Current status Approvals for second, third, nth indication (supplemental marketing applications) for a product also can be regular approval or accelerated approval Depends on disease context, available therapies, endpoints/trial design, ability to conduct confirmatory trial In select situations, should the FDA grant regular approval for supplements based on trial design/endpoints that typically would support an accelerated approval? 7

Initial approval 11/2015 Example #1: Daratumumab Accelerated approval as monotherapy for 4 th -line treatment of patients with multiple myeloma (MM) based on response rate (RR) in single-arm trial Second indication approval 11/2016 Regular approval in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for 2nd-line treatment of patients with MM based on PFS in two randomized trials Both trials also demonstrated statistically and clinically significant improvement in RR Third indication approval 6/2017 Regular approval in combination with pomalidomide/dexamethasone for 3rd-line treatment of patients with MM based on RR in single-arm trial 8

Framework Need Data Unmet clinical need Rare disease Equipoise Natural history of disease Relatedness to other indication(s) MOA and performance Dose & regimen Safety, Efficacy, benefit:risk profile Contribution in combination therapy Endpoint Diagnostic 9

Example #2: Crizotinib Initial approval 8/2011 Accelerated approval for treatment of patients with metastatic ALK-positive nonsmall cell lung cancer (NSCLC) based on response rate (RR) in single-arm trial Regular approval 11/2013, additional study added to labeling 9/2015 Regular approval in metastatic ALK-positive NSCLC based on PFS in randomized trial (second-line setting) versus chemotherapy Data from randomized trial in first-line metastatic ALK-positive NSCLC versus chemotherapy based on pfs PFS Both trials also demonstrated statistically and clinically significant improvement in RR Second indication approval 3/2016 Regular approval for treatment of patients with metastatic ROS-1-positive NSCLC based on RR in single-arm trial 10

Summary FDA already is using this framework in select situations for supplemental indications Is this the appropriate framework for all supplements? All stakeholders? Can this framework be applied across diseases? 12

Capitalizing on the Totality of Evidence to Streamline Approvals for Supplemental Indications Industry Perspective Shanthi Ganeshan, PhD, Novartis

Disclaimer The opinions expressed in this presentation and on the following slides are solely those of the presenter and not necessarily those of Novartis. 14

Benefits of the Framework Provides a streamlined and systematic approach Possible for rapid full approvals and expedited availability of drugs for patients in diseases with unmet medical need Require fewer patients likely single-arm studies requiring less time to complete No requirement for confirmatory studies, saving considerable time/resources No pre-clearance for promotional materials required for full approvals Encouraging more supplemental applications which could further support patient care 15

Examples: could these have been full approvals? Pembrolizumab: MSI-H, dmmr CRC Microstatillite instability-high (MSI-H); mismatch repair deficient (dmmr); colorectal cancer (CRC) Unmet clinical need Rare disease Equipoise Natural history Safety profile Efficacy Benefit:risk ratio Relatedness Study endpoint Diagnostics Pembrolizumab: Classical Hodgkin Lymphoma Unmet clinical need Rare disease Equipoise Natural history Safety profile Efficacy Benefit:risk ratio Relatedness Study endpoint? Long-term safety Imatinib: Adjuvant GIST Gastrointestinal stromal tumor (GIST) Unmet clinical need Rare disease Equipoise Natural history Safety profile Efficacy Benefit:risk ratio? Dosage & regimen Relatedness Study endpoint? Long-term safety 16

Other considerations Global authorities Companion diagnostics Level of evidence in submissions Full approvals for NMEs 17

Disease Interception: The Next Frontier Jordan Schecter, MD, Senior Medical Director 15 November 2017 Janssen Research & Development, LLC Artwork: Cliff Enright, Star Cradle Artwork from The Creative Center at University Settlement

Source: Paramount via Wired.com

Imagine Going beyond a cure To a time when no one ever gets a cancer diagnosis 20

How do we get there? Disease Interception 21

What Is Cancer? Cancer Develops Over Many Years Decades of progression, increasing genetic complexity http://www.hopkinscoloncancercenter.org/cms/cms_page.aspx?currentudv=59&cms_page_id=0b34e9be-5de6-4cb4-b387-4158cc924084 22

-Founding Principles- Cancers develop over many years, often decades A cancer diagnosis is preceded by premalignancy Cancers become more complex over time Complexity makes cancers more adaptable Adaptable cancers are harder to eradicate Early disease is less complex and therefore less adaptable Treating cancer and premalignancy earlier leads to better outcomes for patients 23

What Is Disease Interception? Why Is it Different? Onset of observable symptoms of disease Spectrum of disease HEALTHY PREDICT & PREEMPT DIAGNOSE & TREAT Beginning of disease-causing processes Disease Interception 24

Multiple Myeloma: A Case Study in Disease Interception Malignancy of plasma cells 10-15% of all hematological cancers Prevalence >185,000 patients Incidence >47,000 new cases estimated in U.S., EU-5 and Japan in 2019 Despite new treatments, multiple myeloma remains incurable Lytic bone lesions, renal failure, bone marrow failure 25

Multiple Myeloma: The Problem and the Opportunity Disease interception: MGUS and SMM MM premalignancy = 3.2% of people over 50 years of age MGUS and SMM = 92% MGUS; 8% SMM (high risk MGUS) Opportunity = prevent 20,000 new MM cases (U.S./year) Korde et al. 2011, Blood. 26

Multiple Myeloma: The Problem and the Opportunity Identify patients at high risk for development of MM Risk factors: M-protein >1.5 g/dl Non IgG MGUS Free light-chain ratio <.26 or >1.65 27

MM Disease interception: POC study for SMM Need Surrogate Endpoint to show clinical benefit Co-Primary Endpoints: CR Rate PFS/Death 28

Multiple Myeloma: Design a confirmatory Phase 3 SMM study Objective: To determine if treatment with daratumumab as monotherapy prolongs progression-free survival (PFS) compared to active monitoring in subjects with high-risk SMM (PFS is primary endpoint) 29