1

The challenges of achieving early efficacy

in clinical development

Dr. Martin H. Hager, MBA

Cambridge Science Park

August 19, 2016

2Daiichi-Sankyo Co. Ltd. at ASCO 2016

R&D Pipeline as of May 2016

Introduction of Daiichi-Sankyo Co. Ltd.

3

AstraZeneca Investor Day 2013

AstraZeneca Investor Relations General Presentation March 2015

AstraZeneca Official Presentation Material 2013 & 2015

4

Daiichi-Sankyo Co. Ltd.’s new Executive VP

& Global Head of R&D Oncology

Dr. Antoine Yver

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DS-1205: RTK inhibitor → erlotinib-resistant, T790M-negative NSCLC

DS-6051: ROS1/NTRK dual kinase inhibitor → NSCLC

DS-4950: Reptin/Pontin (AAA+ superfamily) inhibitor → CRC

LDC GmbH CDK7 inhibitor → T-ALL, NMC

ArQule Inc. BTK inhibitor → NHL

Overview of Projects

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• Soaring costs, long timelines, and high failure rates result in relatively few

investigational drugs progressing all the way to marketing approval

Are initial candidate selection processes not optimal?

Or is it the way we select treatment dose?

Breitfeld, Groves & Learn: White paper, Quintiles 2014

The reality of drug development

Attrition rate seems to be particularly

high for phase II

Why are so many phase II trials

unsuccessful?

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Why are we so poor at predicting Phase II success?

• For decades, the recommended phase II dose (RP2D) has typically been

determined using the maximum tolerated dose (MTD), a toxicity-based endpoint

• RP2D has been derived independent of efficacy and independent of a significant

safety signal

Dose Escalation1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)

Dose escalation to MTD

All attention focuses on finding the MTD

CRM, mCRM, TITE-CRM, accelerated titration…

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Why are we so poor at predicting Phase II success?

Historical solution: Expansion phase Ib at MTD

• Good approach to reveal additional safety concerns, demonstrating that MTD is not

the appropriate dose. => Efficacy without AEs may have been possible at a lower dose

• Bad approach to assess efficacy, easily confounded by AEs

• Tolerable AEs persist just short of DLT range and limit compliance, => ultimately limit

efficacy

Inherently poor assessment of efficacy and safety in

phase I is contributing to risk

Part A: Dose Escalation1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)

Dose escalation to MTD

Part B: Dose Expansion20 pt cohort at MTD level

Patient population: unselected Patient population: selected

RP2D

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How can we fix this?

First-in-human clinical trials must have 3 objectives:

1. Establish Proof-of-Concept

• Establish a relationship between efficacy and mechanism, i.e. evidence

of target engagement via assessment of PK/PD

2. Recommend a phase II dose

• Establish optimal relationship between efficacy and safety

3. Recommend design for registration studies

• Establish sufficient information regarding indication, patient population,

line of treatment

“Efficacy” is linking all 3 tasks

Efficacy must be a function of dose escalation

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What is needed to obtain early efficacy data?

• Biomarker

• Clearly defined patient population

• Cost-effective and time-efficient approach to screening

How do I use early efficacy data to obtain the right dose?

• Innovative and adaptive trial design

• Early incorporation of intermediate cohorts covering dose range

• Dosing beyond 1st cycle (long term)

• Dose/exposure-response data & models

• Early incorporation of food-effect studies

We need stratified clinical studies!

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DS-6051

ROS1/NTRK dual kinase inhibitor

12Saito et al. Cancer Sci 107 (2016) 713–720

Genomic instability is a hallmark of cancer and can result in chromosomalrearrangements

The resulting gene fusions can lead to the constitutive activation ofoncogenes

Fusions of the tyrosine kinase genes

• ALK (anaplastic lymphoma kinase)• ROS1 (c-ros oncogene 1)• RET (rearranged during transfection)

occur in 1%–6% of lung adenocarcinomas and their products constitutetherapeutic targets for kinase inhibitors

Oncogenic gene fusions in lung cancer

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2011

Saito et al. Cancer Sci 107 (2016) 713–720

United States Patent Guo et al. US 8,383,799 B2

Date: Nov. 5, 2010

2016

ROS1 fusion genes

NTRK fusion genes

FGFR, NRG1 etc.

fusion genes

Beyond ALK: Oncogenic gene fusions now and then

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crizotinib (Xalkori®)Pfizer

ALK inhibitor(ROS1 inhibitory activity)

ceritinib (Zykadia®)Novartis

ALK inhibitor(crizotinib-resistance)

DS-6051Daiichi-Sankyo Co. Ltd.

ROS1/NTRK inhibitor

PF-06463922 lorlatinibPfizer

ROS1/ALK inhibitor

The competitive landscape in 2012

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Comparison of inhibitor performance

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Types of Lung Cancer by Histology

Molecular Profile of

Squamous Cell Carcinoma

Molecular Profile of

Adenocarcinoma

Including large-cell neuroendocrine

carcinoma (LCNEC)

modified from LUNGevity Foundation 2016

Lung Cancer: Histologies and Molecular Profiles (2016)

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A Genomics-Based Classification of Lung and Colorectal Cancer

The Clinical Lung Cancer Genome Project

(CLCGP) and Network Genomic Medicine (NGM)

Thomas R. et al. Science Translational Medicine 30 Oct 2013: Vol. 5, Issue 209, pp. 209

Seshagiri et al. Nature 30 Aug 2012: Vol 488 Issue 7413 pp 660

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DS-6051 points of differentiation

Differentiation from the competition based on:

1. Dual inhibition of ROS1 and NTRK1/2/3 kinases

2. Able to overcome resistance by inhibition of

ROS1 kinase gatekeeper mutation L2026M

ROS1 kinase with crizotinib-resistance mutation G2032R

3. Targeting of

Oncogenic ROS1 / NTRK gene fusions in lung adenocarcinoma

Oncogenic NTRK gene fusions in pulmonary large cell

neuroendocrine carcinoma (LCNEC)

and wild-type KRAS colorectal cancer (CRC) with NTRK gene

fusions (R-spondin dataset)

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Screening is cost-intensive

Assumption:

1. Traditional phase I dose-expansion with molecular subgroup

2. Detection of a chromosomal translocation with 2% incidence

3. Screening cost per patient $1500 (FISH) (kit plus pathology service)

4. Screening failure rate (SFR) 15%

5. Patient drop-out rate 15%

For every single recruited patient

70 patients need to be screened

at $105,000 screening cost

For a 20-patient dose expansion study

1400 patients need to be screened

at $2.1MM screening cost for the sponsor

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Foundation Medicine Investor Relations General Presentation 2014

ROS1NTRK1 NTRK2

FoundationOne screening at clinical sites as part of standard-of-care

An approach to cost-effective screening

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Inclusion Criteria:

• Histologically or cytologically confirmed advanced solid tumors, recurrent or refractory to

standard therapy

• Solid tumors with documented ROS1 or NTRK1/2/3 gene rearrangements

• Neuroendocrine tumors (LCNEC)

50 mg

QD

400 mg

QD

200 mg

QD

100 mg

QD

800 mg

QD

1200 mg

QD

Phase I Study Design

Accelerated Titration Design

Traditional 3+3 Design

Dose e

scala

tion

DS-6051b is orally administered

once daily in 21-day cycles

NCT02279433

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2xSD

SD

4xSD

6xSD

8xSD

10xSD

6mo

12xSD

14xSD

16xSD

18xSD

20xSD

22xSD

24xSD

Predicted Efficacy Threshold

Phase I Dose Escalation

NCT02279433

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• Primary Objective: Determination of MTD and/or RP2D for expansion

• Secondary Objective: Safety, PK/PD and early efficacy

50 mg

QD

400 mg

QD

200 mg

QD

100 mg

QD

800 mg

QD

1200 mg

QD

Dose e

scala

tion

NCT02279433

n=1

n=1

n=3

n=3

n=11

n=3

DLT

MTD

Phase I Dose Escalation

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DS-6051: Treatment-related Adverse Events (≥ 10% )

All Grades

Papadopoulos et al. AACR 2016

Adverse events (AE) were collected throughout the treatment and were graded according to NCI-CTCAE v4 criteria

DS-6051 was tolerated at dose of up to 800 mg QD with mostly

Grade 1 or 2 adverse events

No signs of neuropathy or visual disturbances

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Pharmacokinetics of DS-6051

• Peak exposure occurred between 2 and 5 h post-dose

• Preliminary PK analysis showed that the exposure increased with dose in a

dose proportional manner between 100 mg QD and 1200 mg QD

• Target concentration for ROS1 mutant (G2032R) which was estimated from

non-clinical studies was achieved at 400 mg QD

Papadopoulos et al. AACR 2016

Steady State Kinetics at C1D15

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Efficacy of DS-6051

64-year old male, never smoker with ROS1 gene fusion-positive NSCLC

Extensive liver metastases

1200 mg QD

Partial Response

(PR) on DS-6051

max. 58% decrease

in tumor size

Subject had progressed on crizotinib (BOR:SD) and ceritinib (BOR: PD)

Papadopoulos et al. AACR 2016

Tumor assessments were performed

at baseline and every 3 cycles

thereafter using RECIST 1.1 criteria

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Efficacy of DS-6051

Patient with LCNEC and extensive liver metastases

800 mg QD

Partial Response

(PR) on DS-6051

max. 41% decrease

in tumor size

Papadopoulos et al. AACR 2016

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Results

Enrolled Subjects and Dose

• As of the data cut-off date (March 23, 2016), 23 subjects were enrolled in the

dose escalation portion at 50–1200 mg dose levels

• Enrolled population included 19 subjects with advanced solid tumors, 1 large

cell neuroendocrine carcinoma, 2 subjects with ROS1 fusion-positive

NSCLC, and 1 subject with leiomyosarcoma with a ROS1 point mutation in

the extracellular domain

Safety

• Nineteen (86.4%) subjects experienced treatment-related AE, mostly Grade 1

or 2

• Most frequent treatment-related AEs (≥20%) were nausea, diarrhea, vomiting,

and dehydration

• 2 DLT cases (Grade 3 transaminase increase) occurred in 2 subjects at 1200

mg, which resulted in incomplete dosing for Cycle 1 (<16 of planned 21

doses)

• The MTD was 800 mg QD

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• Primary Objective: Determination of MTD and/or RP2D for expansion

• Secondary Objective: Safety, PK/PD and early efficacy

Dose escalation (solid tumors)

NCT02279433

Dose expansion (ROS1+ or NTRK+)

800 mg

Phase I Dose Expansion

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New Screening Approaches

Umbrella Trial

Multiple drugs targeting multiple mutations

in a single tumor type

Basket Trial

Single drug targeting a single mutation

in a variety of tumor types

Same tumor type Different tumor types

Modified from Kummar S. et al. J Natl Cancer Inst (2015) 107 (4)

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LC-SCRUM JapanLung Cancer Genomic Screening Project for Individualized Medicine

• 186 institutions participating

in 46 prefectures (Sep 2015)

• > 2000 patients enrolled

New Screening Approaches: LC-SCRUM Japan

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New Screening Approaches: LC-SCRUM Japan

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New Screening Approaches: LC-SCRUM Japan

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DS-1205

Combating erlotinib-resistance

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Pre-clinical xenograft model

Camidge R. et al. Nature Reviews Clinical Oncology 11, 473–481 (2014)

DS-1205 is able to re-sensitize a subset of erlotinib-

resistant tumors

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Part A: Dose Escalation1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)

Dose escalation to MTD

Dose Confirmation12-15 pt cohorts to explore MED, BED, MTD

dose range / regimen

Patient population: selected

MTD

MED

BED

Phase I/II design to support better assessment of

efficacy and safety

Exposure-Response relationship for efficacy Exposure-Response relationship for safety

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1. The traditional MTD approach is not suitable for oncology drug dose selection

2. Demonstration of efficacy is crucial

3. Use biomarker-defined target population during dose escalation

4. Test more than one dose

5. Use dose/exposure-response models to integrate all available data

6. Integrate target inhibition data if MOA is well understood

7. Establish long-term safety/tolerability for chronic use

8. Integrate food-effect studies early in development

Lessons Learned