Ignyta, Inc. - FORM 8-K - EX-99.1

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Exhibit 99.1

Catalyzing Precision Medicine with Integrated Rx/Dx in Oncology

Investor Day

Palace

Hotel

–

NYC

October 14, 2014

8am

–

9:30am

____ __ ____ _____ ____ ______

_____ _____

____ _____

_____ _____

____ _____

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Second level

Third level

Fourth level

Fifth level

This document contains forward-looking statements, as that term is defined in Section 27A of the Securities Act of 1933 and

Section

21E

the

Securities

Exchange

Act

1934,

about

Ignyta,

Inc.

(“us”

the

“Company”).

Statements

that

are

not

purely historical are forward-looking statements. These include statements regarding, among other things: the clinical and/or

non-clinical data or plans underlying RXDX-101, RXDX-103, RXDX-104 or any of our other development programs; our

ability to design and conduct development activities for RXDX-101, RXDX-103, RXDX-104 and our other development

programs;

our

ability

develop

access

companion

diagnostics

for

our

product

candidates;

our

ability

obtain

and

maintain intellectual property protection for our product candidates; our ability to adequately fund our development programs;

our ability to obtain regulatory approvals in order to market any of our product candidates; and our ability to successfully

commercialize any approved products.

Forward-looking statements involve known and unknown risks that relate to future events or the Company’s future financial

performance, some of which may be beyond our control, and the actual results could differ materially from those discussed

in this document. Accordingly, the Company cautions investors not to place undue reliance on the forward-looking

statements contained in, or made in connection with, this document.

Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements,

include, among others, the potential for results of past or ongoing clinical or non-clinical studies to differ from expectations or

previous results; the interpretation of data from our clinical and non-clinical studies; our ability to initiate and complete clinical

trials and non-clinical studies; the potential advantages of our product candidates; the markets any approved products are

intended to serve; and our capital needs; as well as those set forth under the headings “Special Note Regarding Forward-

Looking Statements,”

“Risk Factors”

and “Management’s Discussion and Analysis of Financial Condition and Results of

Operations”

contained in the Company’s Form 10-K filed with the Securities and Exchange Commission (“SEC”) on February

28, 2014, and similar disclosures made in the Company’s Form 10-Q filings and other SEC filings and press releases.

The forward-looking statements contained in this document represent our estimates and assumptions only as of the date of

this document, and we undertake no duty or obligation to update or revise publicly any forward-looking statements contained

in this document as a result of new information, future events or changes in our expectations.

Third-party

information

included

herein

has

been

obtained

from

sources

believed

reliable,

but

the

accuracy

completeness of such information is not guaranteed by, and should not be construed as a representation by, the Company.

Safe Harbor Statement

Time

Speaker

8:00am

–

8:15am

8:15am –

8:35am

Garrett Brodeur, MD –

Children’s Hospital of

Philadelphia

8:35am –

8:55am

Alexander Drilon, MD –

Memorial Sloan-Kettering

Cancer Center

8:55am –

9:15am

Question & Answer

Jonathan Lim, MD –

Ignyta Chairman and CEO

Agenda

Despite

progress

drug

development,

likelihood

approval

for

early

phase

cancer

drugs is only 6.7%*

*Nature Biotechnology, Jan. 2014; LOA 10.4% for NME’s, all indications

Barriers to precision medicine: challenges with patient selection, market size, sample

procurement, sample prep, tumor heterogeneity, resistance to single agent

therapy….

On the bright side, there are a significant number of new initiatives and technologies

in precision (and personalized) medicine

NCI’s

n-of-1;

Medicine’s

“Manhattan

Project”

other

Big

Data

initiatives;

personalized genomic analyses; “Universal Diagnostics”….

Targeting the right patient with the right drug at the right time can boost success

rates for new patient treatments

Precision Medicine

Harnessing the power of molecularly targeted Rx and Dx

for the benefit of cancer patients everywhere

Ignyta’s Goal Is to Catalyze Precision Medicine

Migrating from 1:1 targeting of single markers for single targets with single drugs to

multi-/combi-Rx/Dx

Multiple alterations: gene rearrangements, SNPs, copy number variants,

overexpression

Multiomic: genomic, epigenomic, proteomic biomarker analyses

Multiplex: signatures or patterns of biomarkers

Combination therapies to combat resistance to single agent treatment

Integrating Rx/Dx solutions to optimize the ability to help patients with low frequency

molecular alterations

Building in-house central diagnostics laboratory

Seamless communication and workflows between Rx drug developers and CDx

developers

Seeking

biomarkers

for

patient

selection

and

for

disease

monitoring

Strong

foundation

biological

understanding

the

targets

and

indications

are pursuing, to underpin both our Rx and Dx efforts

Baseline and longitudinal assessments, including non-invasive methods

Our Approach

Developing and commercializing highly targeted drugs for patients with

low frequency molecular alterations that we assay with our own

companion diagnostics (e.g., RXDX-101)

Repositioning drugs by targeting selected patient populations, instead

of all-comers, using insights from our proprietary database

(Oncolome™) and biomarker development capabilities (e.g., RXDX-

103)

Leveraging Oncolome and our discovery capabilities to identify novel

targets and/or biomarker hypotheses to develop potential first-in-class

cancer therapies (e.g., Spark programs)

Precision Oncology Programs

Ignyta Rx/Dx Pipeline

In-licensed from Nerviano Medical Sciences (NMS); RXDX-102 Pan-Trk inhibitor is a back-up to RXDX-101

Compound

Target

Discovery

Preclinical

Phase 1

Phase 2

Phase 3

RXDX-101

Pan-Trk, ROS1,

ALK

RXDX-103

Cdc7

RXDX-104

RET

Spark-1 Rx/Dx Program

Spark-2 Rx/Dx Program

Spark-3 Rx/Dx Program

Central

Lab

Clinical Sites

Specimens

Platforms

Output

FFPE

Fresh Tissue

FISH

IHC

PCR

NGS

Oncolome®

Trial Enrollment

CDx

Ignyta’s Dx Capabilities Enable Leadership

in Precision Medicine

•

GXP

•

CLIA

•

CNVs

•

Splice variants

•

Mutations

•

Overexpression

•

Rearrangements

Ignyta’s Goal Is to Catalyze Precision Medicine

Harnessing the power of molecularly targeted Rx and Dx

for the benefit of cancer patients everywhere

2030 Vision

2021 –

2025

Scale pipeline revenue

2026 –

2030

Drive sustainable

profitability

Leading precision

medicine

company

2011 –

2015

Advance clinical

pipeline

2016 –

2020

Commercialize RXDX

lead

Speaker Biographies

Garrett Brodeur, M.D.

Associate Chair for Research in the Department of Pediatrics and

Associate Director of the Abramson

Cancer Center in the University of Pennsylvania School of Medicine

Professor of Pediatrics and the Audrey E. Evans Chair in Molecular Oncology at the Children’s Hospital of

Philadelphia. Served as Oncology Division Chief from 1998-2008, during which time he initiated programs

in Cancer Predisposition, Experimental Therapeutics, Palliative Care and Proton Therapy, while expanding

programs in Neuro-Oncology, Cancer Survivorship, and Stem Cell Transplants

Research focuses on identifying the genes, proteins and pathways

responsible for the pathogenesis of

neuroblastoma (NB), including extensive work in examining the role that Trk receptors play in these

tumors

Alexander Drilon, M.D.

Medical Oncologist in the Developmental Therapeutics Clinic and Thoracic Oncology Service at Memorial

Sloan Kettering Cancer Center

Recipient of multiple awards, including an American Society of Clinical Oncology (ASCO) Young

Investigator Award, an ASCO Career Development Award, and an International Association for the Study

of Lung Cancer (IASLC) Fellowship Award

Research focuses on early-phase clinical trials of targeted therapeutics for molecularly-enriched cohorts

of advanced solid tumors. Spearheads research into lung cancers with recurrent gene rearrangements,

including those involving the genes ROS1, NTRK1, and RET

TRK Receptors as Oncogenic Drivers in Pediatric

And Adult Cancers

Garrett M. Brodeur, MD

Children’s Hospital of Philadelphia

University of Pennsylvania

Tumor of the peripheral nervous system

Most common extracranial solid tumor

Accounts for 8% of childhood cancers, and 12%

of deaths from cancer in children

Spontaneous regression in some infants

Maturation to ganglioneuroma in older pts.

Most patients are over 1 year of age with

metastatic disease and a poor prognosis

Neuroblastoma—An Enigmatic Pediatric Cancer

Low-

and intermediate-risk NB patients: cure rate 90%

High-risk NB patients: cure rate 40-50%

Improvements in cure of HR-NB patients has plateaued

Intense, multimodality therapy has many acute toxicities

Multimodality therapy has many long-term toxicities:

Growth, sterility, hearing, endocrine, dental, cardiac,

second malignancies

Thus, more effective, less toxic therapy is needed

Therapy targeted to specific genes, proteins and

pathways is likely to provide a selective advantage

Unmet Need #1: More Effective, Less Toxic Therapy

TrkA Signaling

Survival

Brodeur GM: CCRes, 2009

Survival

Differentiation

Gab1/2

SOS

Grb2

Ras

Raf

MEK

MAPK

PDK1

PI3K

Bad Bcl2

Akt

APS

SH2B

Frs2

Shc

PLC

PKC

mTor

RSK

Cytoplasm

NGF

Transcription

Factors

Nucleus

TrkB Autocrine Pathway

Brodeur GM: CCRes, 2009

BDNF

•

Inactive

•

Decoy receptor

TrkB-Shc

BDNF+

•

PI3K+

•

Metastasis

•

Chemoresistance

•

Angiogenesis

TrkB-full

BDNF+

TrkB-T1

BDNF+

•

Inactive

•

Decoy receptor

Role of TRK Receptors in Human Neuroblastomas

Brodeur GM: CCRes, 2009

Features

TrkA (NTRK1) TrkB (NTRK2)

Clinical group

Favorable

Unfavorable

Ligand (expr.)

NGF (No)

BDNF (Yes)

Cell Survival

Yes

Differentiation

Yes

Invasion

Inhibits

Promotes

Metastasis

Inhibits

Promotes

Angiogenesis

Inhibits

Promotes

Drug resistance

Inhibits

Promotes

NTRK

Gene Activation in Pediatric and Adult Cancers

Unmet Need #2: Potent TRK Receptor Inhibitor

There

are

relatively

few

actionable

targets

oncogenic

drivers

MYCN is amplified in 22%, but it is difficult to target

ALK is activated by mutation, duplication, amplification in 8-10%

TrkB/BDNF autocrine activation occurs in 50-60% of HR-NB

Phase 1 trial with Lestaurtinib was promising, but it was discontinued

Efficacy of CEP-2563* in NB Xenografts

P=0.0025

Control

Treatment

*CEP-2563 is an alanyl-lysinyl prodrug of CEP-701 (Lestaurtinib)

Apoptosis in NB Tumors After CEP-2563 Treatment

DAPI Staining TUNEL Staining

Control

Tumor

CEP-2563

Treated

Effect of Lestaurtinib ±

Topo-Cyclo on NB xenografts.

Lestaurtinib enhances the efficacy of chemotherapy

Tested with Topo-Cyclo (below) and Irino-TMZ (not shown)

TRK inhibition also enhances effect of radiation therapy

Effects are at least additive, if not synergistic

Tumor Growth Life-table Analysis Linear Mixed Effects Model

Day

Trough Levels

= CEP-701 BID

Lestaurtinib Phase I Trial: Clinical Trial Design

Minturn JE, Can. Chemo. Pharm, 2011

Conventional dose-

and toxicity/MTD finding study

Nine dose levels from 25-195 mg/m2/dose BID

Bioassay performed to assess therapeutic efficacy

Lestaurtinib Phase I Trial: Target Inhibition

Adult Phase 2 Dose

Minturn JE, Can. Chemo. Pharm, 2011

Dose Levels

Dose of C

EP –

701

(mg/M

/dos

B.I.D.)

Dose Level 1

Dose Level 2

Dose Level 3

Dose Level 4

Dose Level 5

Dose Level 6*

Dose Level 7#

115

Dose Level 8#

150

Dose Level 9#

195

CEP-701 Clinical Trial: Conclusions

Lestaurtinib is tolerated in pediatric patients at doses above those

used in adults. Mild hepatotoxicity encountered, but MTD not reached.

Doses

mg/M

twice

daily

was

required

for

significant

target

inhibition

8 of 16 NB patients treated at effective dose respond: 2 PR’s, 2

MR’s and 4 SD (median 10 mo, 4-28+ mo) 50% ORR

Preclinical data support a follow-up phase 1/2 study combining a TRK

inhibitor with other agents

However, Cephalon was taken over by TEVA and the R&D for

Lestaurtinib ended

Minturn JE, Can. Chemo. Pharm, 2011

RXDX-101 is a Potent, TRK-Selective Multikinase Inhibitor

RXDX-101 inhibits TrkA, TrkB, TrkC, ALK and ROS1 at

low nanomolar concentrations

RXDX-101 has shown promise in a Phase 1 dose

escalation study in Italy

The TrkB/BDNF autocrine pathway is important in 50-

60% of high-risk NB patients

We tested the antitumor efficacy of RXDX-101 in vitro

and in our SY5Y-TrkB xenograft model

RXDX-101 Is a Potent Inhibitor of TRK Phosphorylation

RXDX-101 and SY5Y-TrkB Growth Inhibition in Vitro

RXDX-101 and SY5Y-TrkB Growth Inhibition in Vivo

We have tested ~12 different TRK inhibitors from 8 companies over

the past 20 years

RXDX-101 is the most potent TRK receptor inhibitor we have tested

We are planning a Phase 1/2 industry-sponsored, study of RXDX-101

in recurrent/refractory tumors at CHOP, pending an adult Phase 2

dose, a pediatric formulation, and regulatory agency concurrence

We are planning phase 2 expansion cohorts for NB and brain tumors

We are performing studies to identify mechanisms of RXDX-101

resistance

We are also performing combination studies with RXDX-101 and 1)

conventional chemotherapy, 2) other RTK inhibitors, 3) signaling

inhibitors, and 4) other targeted agents in the pediatric pipeline

RXDX-101: Conclusions

General Mechanisms of Resistance to RTK Inhibitors

Target-dependent mechanisms:

Mutations/rearrangement/

alternate

splicing

that

block

inhibitor

binding

Amplification, overexpression of target RTK

Target-independent mechanisms: bypass pathways

Activation of another RTK

Activation of downstream signaling: Ras/Raf/Mek/Erk, PI3K/Akt, mTOR

Target-independent

mechanisms:

EMT,

differentiation

Target-independent mechanisms: resistance to apoptosis

Targeted Therapy for Patients with Genomic Alterations

Involving NTRK 1/2/3, ROS1, ALK, and RET

Alexander Drilon, MD

Attending

Physician,

Thoracic

Oncology

Service

and

Developmental

Therapeutics

Memorial Sloan-Kettering Cancer Center, New York, NY

Targeted Therapy In Oncology

A Rapidly Expanding Field

1999

2004

2009

Timeline of Driver Discovery in Lung Cancers

Drilon Am J Hematol Oncol 2014

Targeted Therapy in Lung Cancers

NCCN Guidelines NSCLC 2014

ALK-

•

recurrent gene rearrangements

•

varying upstream partners

•

intact ALK

TK domain

•

oncogenic in vivo and in vitro,

expression in transgenic mouse

model

multiple lung

adenocarcinomas

•

3-5% of NSCLCs, commonly in

adenocarcinomas from never or

former light smokers

•

efficacy of ALK inhibition is well-

established

Shaw Oncogene 2014

Rearranged

Lung Cancers

ALK

•

ALK-

rearranged

cancers

–

5% NSCLCs (EML4-ALK)

–

50% adult ALCL (NPM-ALK)

–

50% inflammatory myofibroblastic

tumor (TPM3-ALK)

–

10% spitzoid neoplasms (TPM3-ALK)

–

breast CA, esophageal SCC, renal cell

CA, colorectal CA, DLBCL

•

ALK-mutated cancers

–

10% anaplastic thyroid

–

10% sporadic NBL

–

100% hereditary NBL

–

missense, kinase domain

•

ALK inhibition

–

ORR 60-80%, PFS 8 months in ALK-

rearranged NSCLCs

–

phase 3: superior to chemo

–

responses in ALK-rearranged ALCL

–

CR in ALK-mutated neuroblastoma

Mosse Lancet Oncol 2013, Butrynski NEJM 2010, Rikova J Clin Oncol 2007, Shaw NEJM 2013

44/M IMT

containing

RANBP2-

ALK

with

PR to

crizotinib

ALK inhibition with crizotinib in ALK-fused NSCLC

Alterations

ALK

Alterations

cBio Portal, accessed 9/2014

ROS1-

•

fusion biology similar to ALK

•

ROS1

TK domain intact, partners

w/ transmembrane & coiled-coil

domains

•

oncogenic in vivo and in vitro

•

1-2% of NSCLCs: adenoCA, never

or former light smokers

•

strong efficacy data for ROS1

inhibition

Shaw Oncogene 2014, Gu PLoS One 2011, Bergethon JCO 2012

Lung Cancers

Rearranged

ROS1 Alterations

Charest Genes Chrom Cancer 2003, Gu PLoS One 2011, Bergethon JCO 2012, Shaw ASCO 2012

•

ROS1-rearranged cancers

–

1-2% NSCLCs (CD74-ROS1)

–

9% cholangiocarcinoma (FIG-ROS1)

–

17% spitzoid neoplasms (TPM3-ROS1)

–

1-2% glioblastoma (FIG-ROS1)

–

ovarian CA, gastric CA, colorectal CA,

IMT, angiosarcoma, epithelioid

hemangioendothelioma

•

ROS1 inhibition

–

response rate ~60%

–

comparable to efficacy in ALK

fusion-

positive lung cancers

ROS1-rearranged cholangioCA

TAE64

apoptosis

ROS1 inhibition with crizotinib in ROS1-fused NSCLC

ROS1

Alterations

cBio Portal, accessed 9/2014

For Cancers With NTRK, ROS1,

and ALK Alterations

RXDX-101

RXDX-101 (NMS-E628)

•

oral multikinase

inhibitor

•

activity against TRKA,

TRKB, TRKC, ROS1, and

ALK

•

ongoing Trials

–

Phase I First-In-Human Trial

(Italy)

–

Phase I/II Trial of

Continuous Dosing (US)

Kinase

IC50 nM

TRKA

1.7

TRKB

0.1

TRKC

0.1

ROS1

0.2

ALK

1.6

RET, VEGFR, IGF1R,

FGFR1, FLT3

>10 fold

selectivity

RXDX-101 (NMS-E628) Preclinical Activity

EML4-ALK

in vivo (NCI-H228 lung cancer xenografts)

ALK C1156Y

and L1196M

in vivo (Ba/F3 in SCID mice)

crizotinib

in vitro (Ba/F3 expr TEL-ROS1)

TEL-ROS1

SLC34A2-ROS1

in vivo (Ba/F3 in SCID mice)

in vitro (HCC78 lung cancer cell line)

TPM-TRKA

in vivo (KM12 colorectal xenograft)

in vitro (KM12 colorectal cell line)

RXDX-101

RXDX-101 and Blood Brain Penetration

ALKA-372-001:

First-in-Human (FIH) Study of RXDX-101

Break

Week

Figure 1a. Schedule A

Dose

Break

Week

Figure 1c. Schedule C

Week

Figure 1b. Schedule B

phase 1, open-label

study of RXDX-101

-evaluating the safety,

PK, antitumor activity

advanced/metastatic

solid tumors that harbor

a ROS1, ALK, or NTRK

molecular alteration

Dose

ALKA First-in Human Study

75/F, NTRK1-rearranged colorectal cancer, s/p chemotherapy and cetuximab

RXDX-101 1600 mg/m

, PR via RECIST, 4 month duration

RXDX-101: Clinical Activity

as a TRK Inhibitor

Baseline, 3/2014

Week 4, 4/2014

Data as of ESMO September 2014

Baseline, 7/2014

Week 4, 8/2014

RXDX-101: Clinical Activity

as a ROS1 Inhibitor

ALKA First-in Human Study

ROS1-

partial response via RECIST, ongoing benefit at 3+ months

Data as of ESMO September 2014

rearranged NSCLC: RXDX-101 400 mg/m

ALKA First-in Human Study

63/F ALK-rearranged NSCLC

(s/p 4 cycles chemo, crizotinib)

RXDX-101 1200 mg/m

PR via RECIST

11 months on therapy with

continued disease control

Baseline, 11/2013

Week 8, 1/2014

Week 20, 5/2014

RXDX-101: Clinical Activity

as an ALK Inhibitor

Data as of ESMO September 2014

Clinical Antitumor Activity in Each of

TrkA, ROS1 and ALK Patients

PD at C11

PD at C4

* Unconfirmed

** All

PRs

were

Schedule

except

patient

with

ROS1+

NSCLC

Schedule

*** CR was in Schedule C

Timing of PR

Timing of CR

Data as of ESMO September 2014

Dose

(mg/m²)

Treatment Cycles / Months

200

400

800 1200

200

400

800

400

800

1200

800

1200

1600

400**

400***

CR*

Neuroblastoma

(ALK)

NSCLC

(ALK)

Pancreatic

(ROS1)

NSCLC

(ALK)

NSCLC

(ROS1)

CRC

(TrkA)

NSCLC

(ROS1)

NSCLC

(ROS1)

Tumor type

(Alteration)

Best

Response

Responders Tend to Have Higher Exposure than

Non-Responders Throughout the Entire Dosing Cycle

Note:

Analysis

includes

patients

the

800,

1200

and

1600

mg/m

cohorts;

mean

represented

square,

and

standard error of the mean is represented by error bars

Dose

Week

Non-responders

(n = 6)

Responders

(n = 3)

Day 18, T

96h

RXDX-101 Exposure Levels of

Responders and Non-Responders

Intermittent Dosing Schedule (Schedule A, fasted)

(4 days on, 3 days off, 1 week break)

The following may further increase

RXDX-101 exposure:

•

Additional PK Optimization

Break

Fed (vs. fasted) state

New formulation

Continuous dosing schedules

without breaks

STARTRK-1

Dose Escalation

•

n = 20-30 patients

•

Advanced solid tumors

•Genetic alterations in

NTRK1/2/3, ROS1, ALK

Expansion

•

Patients treated at

RP2D

•

n = 20 patients per

expansion cohort

ALK+ pre-treated

ROS1+ cohort

TRKA+ cohort

TRKB/C+ cohort

Endpoints

Primary:

I -

MTD/RP2D, DLTs

Secondary: Safety, PKs, PFS, OS, RR

3+3 Design

ALK+ TKI naïve

Dose

Week

Continuous Daily

Schedule

Dose

Escalation

Study Targeting ALK, ROS1, TRKA/B/C

RET

Alterations in Cancer

Drilon et al

Cancer Disc 2013;3:630, Saito et al Carcinogenesis 2014

•

Ranged

–

20-40% papillary thyroid

cancers

–

60-80% radiation-induced

papillary thryoid cancers

–

1-2% of NSCLCs

–

chronic myelomonocytic

leukemia

–

Oncogenic in vitro

and in

vivo:

multiple

lung

cancers

transgenic mice expressing

KIF5B-RET

•

RET-mutant

cancers

–

medullary thyroid CAs:

–

MEN2A 100%

–

MEN2B 100%

–

FMTC 100%

•

RET-

•

RET-

rearranged cancers

mutant cancers

RET

Alterations

cBio Portal, accessed 9/2014

RXDX-104: A

Potent RET

Inhibitor

•

RET inhibition

–

pre-clinical activity of various RET

inhibitors, documented clinical

responses to RET inhibition

–

issues with tolerance secondary

to VEGFR activity of RET TKIs and

associated adverse events

•

RXDX-104

–

potent, highly-selective RET

inhibitor (2 nM)

–

Good selectivity in panel of 54

tyrosine/serine-threonine kinases

–

active against RET-mutated and

RET-rearranged cell lines

•

LC-2/ad (CCDC6-RET lung)

•

MZ-CRC1 (M918T CRC)

•

TT (C634W thyroid)

Attached files

Ignyta, Inc. Reports

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