Agios Pharmaceuticals (AGIO) 8-K Regulation FD Disclosure

October 15, 2014

Agios Pharmaceuticals

2014 Research & Development Day

Exhibit 99.1

2

Today’s agenda

Time

Topic

Presenter

8:30 -

9:00 a.m.

Registration & Breakfast

9:00 -

9:20 a.m.

Welcome and Company Overview

David Schenkein, M.D., CEO

Cancer Metabolism: IDH-Mutant Inhibitors

9:20 –

9:45 a.m.

AG-221 and AG-120 Discovery & Research

Scott Biller, Ph.D., CSO

9:45 –

10:05 a.m.

Overview of AML and Other IDH-Mutant

Diseases

Eyal Attar, M.D.,

Medical Director

10:05 –

10:30 a.m.

Clinical

Development

Strategy

–

Early

Clinical

Evidence

Chris Bowden, M.D., CMO

10:30 -

10:45 a.m.

Break (15 min)

Rare Genetic Disorders of Metabolism: Pyruvate Kinase-R (PKR)

10:45 –

11:15 a.m.

AG-348, Discovery & Research

Scott Biller, Ph.D.

11:15 –

11:35 a.m.

PK Deficiency Disease and Clinical

Development

Sam Agresta, M.D., VP,

Head, Clinical Development

11:35 a.m. –

12:00 p.m.

Closing Remarks & Q&A

David Schenkein, M.D.

12:00 –

1:00 p.m.

Lunch

Agios’

Leadership Team

3

This

“2014

Research

&

Development

Day”

presentation

and

various

remarks

we

make

during

this

presentation contain forward-looking statements of Agios Pharmaceuticals, Inc. within the meaning of The

Private

Securities

Litigation

Reform

Act

of

1995,

including

statements

regarding

Agios’

expectations

and

beliefs about its business, plans and prospects. The words “believe”, “expect”, “could”, “should”, “will”,

“would”, “may”, ”plan”, “intend”, “anticipate”

and similar expressions are intended to identify forward-looking

statements, although not all forward-looking statements contain these identifying words.

The

forward-looking

statements

contained

in

this

presentation

and

in

remarks

made

during

this

presentation

are subject to important risks and uncertainties that may cause actual events or results to differ materially

from

Agios’

current

expectations

and

beliefs,

including

risks

and

uncertainties

relating

to:

Agios’

ability

to

successfully commence and complete preclinical and clinical development of its product candidates; results

of

preclinical

studies

and

clinical

trials;

Agios’

ability

to

maintain

its

collaboration

with

Celgene

on

acceptable

terms; the content and timing of decisions made by regulatory authorities, investigational review boards and

publication

review

bodies;

unplanned

cash

requirements

and

expenditures;

competitive

factors;

Agios’

ability

to

obtain,

maintain

and

enforce

intellectual

property

protection;

Agios’

capital

requirements

and

need

for

funding; and general economic and market conditions. These and other risks are described under the

caption “Risk Factors”

in Agios’

most recent Quarterly Report on Form 10-Q, which is on file with the SEC,

and in other filings that Agios may make with the SEC in the future.

Any forward-looking statements contained in this presentation or in remarks made during this presentation

speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-

looking statements, whether as a result of new information, future events or, except as required by law.

Cautionary Note Regarding Forward-Looking

Statements

October 15, 2014

David Schenkein, M.D., Chief Executive Officer

Building a Great Multi-Product

Biopharmaceutical Company

5

VISION

Agios is passionately committed to

the fundamental transformation of

patients’

lives through scientific

leadership in the field of cancer

metabolism and rare genetic

disorders of metabolism

Driven By Clear Corporate Vision and Values

5

6

Building a Great Multi-Product Biopharmaceutical

Company

Created three first-in-class molecules

Proof of concept for AG-221

Data for AG-120 and AG-348 later this year

~110 employees, OSOP culture

Strong financial position

Celgene partnership

In just six years:

7

Guiding Principles

Follow the science and do what is right for patients

Maintain a culture of incisive decision-making driven by deep

scientific interrogation, edge, and respectful irreverence

Foster collaborative and synergistic spirit that includes all

employees regardless of function or level

Leverage deep strategic relationships with our academic and

commercial partners to improve the quality of our discovery and

development efforts

8

Research

Leader in dysregulated

metabolism of cancer and RGDs

Novel, first-in-class medicines

Incentivize scientists to take smart

risks, challenge dogmas and strive

for answers

Responder identification

necessary to validate a target

Make molecules that have the

properties with potential to go all

the way

Development

Patient safety first

Precision medicine from 1

st

trial

Invest heavily in translational

medicine

Challenge and change the

standards of care

Partner with regulatory agencies

and advocacy groups early

Agios’

Approach to R&D

Decisions Based on Science and Impact on Patients

9

Novel First-in-Class Portfolio: Precision Medicine

Approach

Research

Clinical Development

Primary Commercial

Rights

Development

Programs

AG-221

(IDH2m inhibitor)

AG-120

(IDH1m inhibitor)

AG-348

(Pyruvate kinase (R) Activator)

Research Programs

Cancer Metabolism

Rare Genetic Disorders of

Metabolism

(Multiple Novel Targets)

(Multiple Monogenic Diseases)

US Rts              ex-US Rts

Phase 1

Studies

Hematologic Malignancies

Hematologic Malignancies

Solid Tumors

Phase 1

Studies

PK Deficiency

Phase 1

HV Studies

10

What You’ll Come Away With Today

More confidence that we are leading the disruptive field of dysregulated

metabolism in cancer and in our novel approach to rare genetic diseases

Our commitment to remaining a research driven company with world

class clinical

development and eventually commercial capabilities

Our vision to build one of  the next great independent multi-product companies

Our passion to help patients and a better understanding of the underserved

diseases where we are focused

11

Clinical Pipeline Progress: Building Momentum

Healthy volunteer data

at ASH 2014

Initiate Ph 2 in PK

deficiency patients by

early 2015

AG -

221

AG -

120

AG -

348

Remaining 2014 Potential Product Milestones

2014 Product Milestones Achieved

AG -

221

AG -

120

AG -

348

Ph 1 heme data at

EORTC/AACR

(Nov. 19)

Clear POC

Initiated expansion

cohorts

Fast Track & Orphan

Drug Designations in US

Completed SAD study;

Met primary endpoint in

SAD & MAD studies

Two Phase 1 trials (

IDH1m+ heme and

solid tumors) initiated

and enrolling well

Additional Phase 1

data at ASH 2014

On track to initiate

trial in IDH2m+

solid tumors

12

Today’s Speakers

Eyal Attar, M.D.

Medical Director

Sam Agresta, M.D.

VP, Head of Clinical

Development

Scott Biller, Ph.D.

Chief Scientific Officer

Chris Bowden, M.D.

Chief Medical Officer

13

Agios Leadership Team Here Today

Duncan Higgons

Chief Operating Officer

John Evans

IDH Portfolio Executive, VP

BusinessDevelopment

Glenn Goddard

SVP, Finance

Michael Su, Ph.D.

SVP, Research & Development

Min Wang, Ph.D., J.D.

VP, Legal Affairs

Marion Dorsch, Ph.D.

VP, Biology

October 15, 2014

David Schenkein, M.D., Chief Executive Officer

Building a Great Multi-Product

Biopharmaceutical Company

Cancer Metabolism at Agios:

The Discovery of Mutant IDH Inhibitors

Scott Biller, Ph.D., Chief Scientific Officer

16

Today’s Key Points

Breakthrough

work

on

IDH

mutations

-

the

2-HG

story:

-

Discovered that IDH mutations cause a metabolic gain of function

-

Determined IDH inhibitors reverse the block in normal cell

differentiation caused by 2-HG

Developed first investigational medicines to treat IDH mutant cancers

Amazing team of scientists and cutting edge discovery engine

17

Leveraging Our Scientific Competencies: “The Engine”

Three first-in-class

investigational

medicines with

deep pipeline

Cancer Metabolism

100’s of novel targets

Genetic-

or metabolic-biomarker defined patients

Rare Genetic Disorders of Metabolism

Agios Core

Capabilities

“Disruptive Science”

>600 genetic diseases

Orphan market opportunities

Significant unmet need

18

Core Capabilities in Dysregulated Metabolism

Unlocking dysregulated metabolism

-

Expertise in metabolism adds a new dimension

to “systems biology”

approach

-

Unique technology platform allows deep

interrogation of metabolism

-

High level of integration across expertise areas

Rapid translation to clinical proof of

concept

-

Precision medicine:

guided by genomic and

metabolic biomarkers

-

Early POC in well-defined patient populations

to demonstrate clinical benefit:

Higher probability of success

Faster development track

Genetically-Defined

Patient Populations

Metabolic

Enzyme Drug

Discovery

Biochemistry 

Metabolism

Genomics

Cell

Biology

19

Metabolic Flux

Analysis

Enabled by

13

C and

15

N

labeled

nutrients and

informatics

Static view

Flux

Biochemistry

How many metabolites

exist in a single point

at a given moment in

time?

How quickly are

metabolites moving

along enzymatic

pathways?

Which enzyme is the

“Achilles heel”

for a

disease?

VS.

High Throughput

Mass Spec Analysis

Cell

Culture

In house

Vivarium

Patient Samples

Flux

biochemistry

enables

Agios

to

make

groundbreaking

metabolic

insights

Deep Understanding of Metabolic Pathways Drives

Development of Transformational Medicines

20

Metabolome: Untapped Opportunity For Novel

Therapeutic Targets

Combining the metabolome and

genome provide insight into

metabolic vulnerabilities

Mutations in metabolic genes or

metabolic regulators

Tumor specific isoforms

Deletions in metabolic regulators

Fusions of metabolic genes

Genetic

Screens

Metabolomic

Screens

Fold Change

(genotype A vs B)

Cancer

Genomics

Integrated Approach to Metabolic Target Discovery

Identify targets with “locked-in”

metabolic vulnerabilities in tumors

21

22

High Bar for Novel Targets

Cancer

dependency

demonstrated          

in vivo

Precision Medicine

Requirements for oncology drug discovery programs

Patient selection

strategy in place

Robust chemical

starting points

High confidence in being

able to drug the target

We know which patients to

treat using genetic and

metabolic biomarkers

The tumor cares

…

leading

to

higher

probability

of

success

23

First-in-Class Cancer Metabolism Portfolio

Cancer Metabolism

Portfolio

Research

Clinical Development

Development Programs

AG-221

(IDH2m inhibitor)

AG-120

(IDH1m inhibitor)

Research Programs

Cancer Metabolism

Multiple Novel

Targets

Multiple

Phase 1

Studies

Hematologic Malignancies

Hematologic Malignancies

Solid Tumors

Phase

1

Studies

24

Parsons

et

al,

Science

2008

mutations in IDH2 also described (R172)

Subsequently, IDH1 (R132) and IDH2 (R172 and R140Q) mutations found across multiple tumor types.

Recurrent point mutations found at a single residue in one allele of IDH1 or IDH2

Always retains one WT allele and expresses WT protein

Isocitrate Dehydrogenase (IDH) 1/2 Mutations in Cancer

Cytoplasm

Mitochondria

:

Recurrent

IDH1

mutations

(R132)

identified

in

glioma.

Low

frequency

25

A Surprising Biochemical Observation:

NADP+

NADPH

+ CO2

NADP

+

Isocitrate

Time (sec)

Source: Dang L et al. Nature 2009

IDH1

mIDH1

enzyme

generates

and

then

consumes

NADPH

26

Agios Metabolism Platform Identifies 2-Hydroxyglutarate

at High Levels in IDH Mutant Cancer Cells

Unbiased metabolomic study compared IDH1 wt to IDH1 mutant expressing cells

Levels for 850 species were compared across samples

Only

three

species

were

found

to

be

elevated

in

mutant

cells…

all

converge

on 2-HG   

A

B

A

146.50

m/z

149.50

11.50

14.00

time

m/z 147.0299

(expected 147.0299, C5H7O5)

C

WT signal intensity

2-Hydroxyglutarate

(2-HG)

Metabolic mystery solved!

mIDH

NADPH

27

IDH Mutation as a Gain of Function in Cancer:

Normal

IDH

isocitrate

KG

mIDH

isocitrate

KG

Tumor suppressor

loss-of-function

Source: Dang L et al. Nature 2009

2-HG as an Oncometabolite

28

IDH Mutation as a Gain of Function in Cancer:

Normal

IDH

isocitrate

KG

mIDH

isocitrate

KG

Tumor suppressor

loss-of-function

Metabolic

Insight

Oncogene

isocitrate

KG

2-HG

mIDH

gain-of-function

IDH

Source: Dang L et al. Nature 2009

2-HG

as

an

Oncometabolite

29

SPECIFIC

MEASURABLE

CAN BE IMAGED

Brain Tumor Samples

AML Blood Samples

Glu

GABA

2HG

MRI / MRS

*Linda Liau / UCLA

2-Hydroxyglutarate, an Excellent Biomarker:

A Surrogate for Treatment Effect & Clinical Benefit

*S. Gross/JEM

2HG

30

How does 2-HG drive tumors?

A Novel Mechanism

Differentiation

Proliferation

Apoptosis Resistance

Angiogenesis

Migration

Differentiation

Proliferation

Apoptosis Resistance

Angiogenesis

Migration

-KG Dependent

Dioxygenases

Histone demethylases

DNA demethylases

Prolyl hydroxylases

Collagen hydroxylases

Current Model: 2-HG Induces a Block of Differentiation

via Epigenetic Chromatin Remodeling

DNA and Histone

Demethylases

1.

Hypermethylation

2.

Modulation of gene

expression

Oncogene

isocitrate

KG

IDH

Leukemic

Blasts

Cells

Blocked

Differentiation

mt-IDH

31

2-HG

2-HG

Current Model: Mutant IDH Inhibitors Reverse the Block

in Differentiation

DNA and Histone

Demethylases

Active

Demethylation

Oncogene

isocitrate

2-HG

IDH

IDHm

Inhibitor

Differentiated

Myeloid

Cells

Release of

Blocked

Differentiation

mt-IDH

32

33

Potent and reversible inhibitor of

IDH2m (R140Q>172K)

-

Cellular IC

50

= 12 nM (R140Q)

Selective against off-targets

Orally bioavailable, long half-life

Induces differentiation in IDH2m

primary human AML ex vivo

AG-221: A First-in-Class Inhibitor of Mutant IDH2

Differentiation of human IDH2m AML ex vivo

9 Day Treatment with AG-221

AG-221 and 2-HG Concentration Profiles

25 and 50 mg/kg single oral dose

Potently lowers 2-HG levels in

R140Q xenograft models

following a single oral dose

Source: K. Yen, ASH 2013

34

AG-221 Promotes Survival in Primary Human

Leukemia Model

Source: Wang, ASH 2013 poster: AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model

Relapsed AML with IDH2 R140Q/FLT3-ITD/DNMT3AR882H/NPM1c/CEBPa

insertion

35

AG-221 Induces Differentiation in Primary Human

Leukemia Model

0

20

40

60

80

100

120

Naïve

mice

Ara-C

(2mpk) 

Vehicle

5 mpk

AG-221

15 mpk

AG-221

45 mpk

AG-221 

Bone Marrow Differential

Counts

•

100% blast cells

•

No granules

•

Very little cytoplasm

•

Nuclei have neoplastic lobation

•

More mature cell forms

•

Nuclear lateralization

•

Eosinophilic cytoplasm

•

Coarse chromatin

Mitotic Blast

Neutrophil

Source: Wang, ASH 2013 poster: AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model

36

Potent and reversible inhibitor of

all IDH1 mutants

-

Cellular IC

50

= 8 –

20 nM

Selective against off-targets

Orally bioavailable, long half-life

Induces differentiation in IDH1m

primary human AML ex vivo

AG-120: A First-in-Class Inhibitor of Mutant IDH1

AG-120 and 2-HG Concentration Profiles

50 mg/kg single oral dose

Potently lowers 2-HG levels in

IDH1m+ xenograft models

following a single oral dose

Differentiation of human IDH1m AML ex

vivo 6 Day Treatment with AG-120

0

200000

400000

600000

800000

1000000

1200000

1.0

10.0

100.0

1000.0

10000.0

0.0

20.0

40.0

60.0

Time (hr)

AG-120-50 mpk (single dose)

2HG (single dose)

2HG baseline (vehicle)

37

Normal Hepatocyte Progenitor Differentiation

Source: Adapted from N. Bardessy et al, Cell Cycle, in press

Progenitor

Bile Duct

Hepatocyte

Cholangiocyte

Normal

Differentiation

HNF4

38

Block in Hepatocyte Progenitor Differentiation Leads

to Cholangiocarcinoma

Source: Adapted from N. Bardessy et al, Cell Cycle, in press

Progenitor

Cholangiocarcinoma

Oval Cell

Expansion

IDH Mutant

Progenitor

Bile Duct

Hepatocyte

Cholangiocyte

Normal

Differentiation

HNF4

HNF4

2-HG

2-HG Blocks

Differentiation

39

IDH Mutations Drive Tumorigenesis in a Mouse Model

of Intrahepatic Cholangiocarcinoma

Source: Saha et al, Nature, July 2014

Induction of differentiation along the

hepatocyte lineage with Agios IDH1m

inhibitor AGI-5027

Repression of hepatocyte marker HNF-4

Induction of hepatocyte marker HNF-4

40

IDH1m Inhibitor Blocks Tumor Growth in a

Primary Human Glioma Model

Source: Rohle et al, Science, 2013

2-HG Levels

Tumor growth inhibition observed in subcutaneous neurosphere glioma

model with IDH1m inhibitor AGI-5198

•

Induction of apoptosis indicated via Ki67 staining

150   450

0.0

0.5

1.0

1.5

4.0

4.5

5.0

5.5

6.0

6.5

AGI-5198 [mg/kg]

VEHICLE

AGI-198

450 mg/kg/d

AGI-5198

150 mg/kg/d

Ki67 IHC

-

41

H3K9Me3 IHC

450 mpk

Vehicle

Source: Rohle et al, Science, 2013

H3K9Me3 Levels

Expression of Differentiation Markers

Mechanism in glioma model is

consistent with reversal of

hypermethylation and induction of

differentiation

IDH1m Inhibitor Reverses Epigenetic Changes and

Induces Differentiation

Vehicle

150 mpk

A

GI-5198

450 mpk

AGI-5198

42

Summary

We

have

developed

a

platform

approach

to

the

disruptive

field

of

cancer

metabolism

Agios scientists discovered a novel gain of function with IDH mutations

in cancer

Oncometabolite 2-HG is a tumor driver and an excellent biomarker

AG-221 (IDH2m inhibitor) and AG-120 (IDH1m inhibitor) potently inhibit

2-HG production in IDHm cells and preclinical models

IDH mutations induce a block in differentiation in both hematological

and solid tumors

-

The block in differentiation can be relieved by lowering 2-HG with an

IDHm inhibitor

October 15, 2014

Acute Myeloid Leukemia (AML) and

Other IDH-Mutant Diseases

Eyal C. Attar, M.D., Medical Director

Patients are Inspiring

Source: Singh H and others and Attar E, Blood Cancer Journal, 2013.

2

3

Today’s Key Points

Acute Myeloid Leukemia (AML)

-

Most common leukemia in adults

-

Poor/limited prognosis

-

Few treatment options, with no improvements in decades

-

Molecular mutations are used in prognosis and treatment

IDH inhibitors have the potential to:

-

Change the treatment paradigm

-

Establish new foundations of care

IDH mutations exist in solid tumors and present

opportunities beyond AML

4

AML is a Devastating Blood Cancer

Leukemia

•

RBCs decrease

•

Patient health declines

5

~18K New AML Cases in the U.S. Each Year and

Growing Due to Aging Population

Forecasted  U.S Incidence of AML

Age-Specific U.S. Incidence of AML

Annual incidence of AML in the US is expected to increase by ~24% over the

next 10 years (~ 2% CAGR)

18.9

19.2

19.6

20.0

20.4

20.8

21.2

21.7

22.1

22.5

23.0

0

5

10

15

20

25

2014

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2

1

0

1

1

1

1

1

1

2

2

3

5

7

10

15

20

23

23

0

5

10

15

20

25

Sources: Datamonitor 2014; American Cancer Society; Leukemia and Lymphoma Society

6

AML Incidence and Mortality Remain Unchanged for

>35 Years Due to Lack of Impactful Treatments

* Case rate mortality per year assumes incidence & mortality occurs in same year and does not take into account modest changes in incidence

Sources: American Cancer Society;  Leukemia & Lymphoma Society

AML U.S. Incidence and Mortality, 1975-2010

0

1

2

3

4

5

Incidence

Mortality

7

AML Diagnosis Requires Bone Marrow and Blood Tests

Morphology

Cytogenetics

Molecular

8

Molecular Mutations are Important in Prognosis and

Treatment

Prognosis

Age

Cytogenetics

Molecular

mutations

Comorbidities

> 60 years old

(most patients)

< 60 years old

(better

prognosis)

•

Diabetes

•

Cardiovascular

disease

Three groups:

NPM1

FLT3

CEBPA

IDH1 and IDH2

TET2

TP53

1.

Good

2.

Intermediate

3.

Poor

9

Untreated AML

~18,860 pts

Does the

Patient Have

APML?

Age, Perf Status,

Comorbidities

~60-70%

~30-40%

NO

~89% (~17K pts)

~10-12K pts

Unfit for

Induction

Chemotherapy

~5-7K pts

Relapse

Sources: market research

Treatment Remains Unchanged With Limited Options

Differentiation

Therapy

Fit for

Induction

Chemotherapy

YES

~11%

(~2K

pts)

10

Case Study: Even Low Intensity Treatments Carry

Significant Burden and Result in Poor Outcomes

72-year-old male

Retired, enjoys spending time with his wife and being outdoors

Felt increasingly tired for 3 months and red “spots”

on his lower legs for last 2 weeks

Referred to a hematologist, diagnosed with AML

Transfusion requirements

Patients’

health

10.5 months

Outpatient azacitidine X 6 cycles

10

11

Case Study: Intensive Treatments Carry Significant

Burden and Have Limited Success

•

62-year-old male

•

Admitted to local hospital with fever, cough, sputum production

•

Pneumonia and low blood counts

•

Hematologist diagnosed AML

•

After a week of antibiotics, leukemia therapy was initiated

Induction

chemotherapy

6 wk hospitalization

Hair loss

Mouth sores

Fevers

Transfusions

Consolidation

chemotherapy

Stem cell

transplant

4 wk hospitalization

Near-fatal central

line infection

Fevers

Transfusions

4 wk hospitalization

Fevers

Transfusions

Immunosuppressive

medications to prevent

GVHD

5 months

12

Case Study: Relapsed AML has Limited Treatment Options

with Poor Chance of Success

•

63-year-old male

•

1 year after completing induction, consolidation, transplant

-

Developed low blood counts

-

Recurrent AML diagnosed

6 week hospitalization

Hair loss

Mouth sores

Fevers

Transfusions

Stable disease for 2 months

Returned to clinic 2X/week for

transfusions

Hospitalized for fever

No remission

Progressive

leukemia

4 months

types of patients enrolled in AG-221 study

Re-induction

chemotherapy

Outpatient clinical trial

Goal: To Change the Treatment Paradigm for AML

Chemotherapy

Stem Cell Transplantation

(select eligible patients)

AML

IDHm+

AML

IDHm inhibitor

Potential to establish a new foundation in AML care

13

14

IDH Represents a Novel Target for Precision Medicine

Found in

approximately 20%

of AML

Occur early in the

disease

Result in elevated

2-HG levels

Elevated 2-HG

modifies proteins

that turn genes on

and off

Mutations in IDH

15

AML with IDH Mutations Demonstrate Elevated 2-HG

Source: Fathi AT, et al., Blood, 2012

AML

IDH1/2 wild type

IDH1/2 mutant

16

IDH Mutations Also Found in MDS, NHL and Range of

Solid Tumors

Indication

% IDHm

Low grade glioma & 2

ary

GBM

68-74

Chondrosarcoma

40-52

Acute Myeloid Leukemia (AML)

6-10

MDS/MPN

3

Intrahepatic Cholangiocarcinoma

11-24

Ollier/Maffucci

80

Others* (colon, melanoma, lung, prostate)

1-3

Acute Myeloid Leukemia (AML)

9-13

MDS/MPN

3-6

Angio-immunoblastic NHL

30

Intrahepatic Cholangiocarcinoma

2-6

Giant Cell Tumor of the Bone

80

D2HG Aciduria

100

Others* (melanoma, glioma)

3-5

IDH1m

IDH2m

Based on literature analysis.  Estimates will continue to evolve with additional future data.

** Includes “basket” of emerging unconfirmed indications.

Tumors with IDH Mutations Demonstrate Elevated 2-HG

Cholangiocarcinoma

Source: Borger D R et al. Clin Cancer Res 2014;20:1884-1890;

Glioma

Source: Choi C et al. Nature Medicine 1012; 18, 624–629

Tumor

Control

17

IDH Mutations Observed in Hematologic Malignancies

AML

MDS

Non-Hodgkin

Lymphoma

Bone marrow

Bone marrow

AITL

Incidence

(cases/year US)

18K

15K

1.4K

Prevalence (US)

25K

>60K

3K

IDH1m frequency

6-10%

3%

ND

IDH2m frequency

9-13%

3-6%

30%

Treatment Options

Chemotherapy

Stem cell transplant

Chemotherapy

Stem cell transplant

Chemotherapy, XRT

Stem cell transplant

5-year overall

survival

20-25%

~30%

~36%

Multiple sources, including market research and SEER. Estimates will continue to evolve with additional future data

18

IDH Mutations Observed in Solid Tumors With Limited

Treatment Options

Multiple sources, including market research and SEER. Estimates will continue to evolve with additional future data

*excludes primary GBM

Gliomas

Cholangiocarcinoma

Chondrosarcoma

Low grade and

2ary

GBM

Bile ducts

Cartilage

Incidence

(cases/year US)

5K

2K –

4K

700-1000

Prevalence (US)

24K

5K

--

IDH1m frequency

68-74%

11-24%

40-52%

IDH2m frequency

3-5%

2-6%

6-11%

Treatment Options

Surgery, XRT

Chemotherapy

Surgery, Chemotherapy

Liver transplantation

Surgery, XRT

Chemotherapy

5-year overall

survival

~32–

68%*

~9%

~10-90%

19

Points to Remember

AML

-

poor prognosis and high morbidity

-

no new treatments for > 35 years

-

5-year survival rates*

•

~38% adults < 65 years

•

~5% adults >= 65 years

IDH mutations:

-

found in approximately 20% of adults with AML

-

result in elevated 2-HG

IDH mutations are also found in MDS, NHL, and solid tumors

There is a tremendous need for a safe and effective targeted molecular

medicine for these patients

*Source: SEER data

20

IDH-Mutant Inhibitors

Clinical Development Strategy –

Early Clinical Evidence

October 15, 2014

Chris Bowden, M.D., Chief Medical Officer

22

Today’s Key Points

Focus on genetically defined patient populations

Precision medicine approach may provide higher probability and shorter

development timelines

Early AG-221 Phase 1 results support potential rapid development

Advancing AG-221 and AG-120 in a broad range of tumor types

Indication

% IDHm

Low grade glioma & 2

ary

GBM

68-74

Chondrosarcoma

40-52

Acute Myeloid Leukemia (AML)

6-10

MDS/MPN

3

Intrahepatic Cholangiocarcinoma

11-24

Ollier/Maffucci

80

Others* (colon, melanoma, lung, prostate)

1-3

Acute Myeloid Leukemia (AML)

9-13

MDS/MPN

3-6

Angio-immunoblastic NHL

30

Intrahepatic Cholangiocarcinoma

2-6

Giant Cell Tumor of the Bone

80

D2HG Aciduria

100

Others* (melanoma, glioma)

3-5

IDH1m

IDH2m

IDH1m and IDH2m: Distinct Genetically Defined

Populations

23

Based on literature analysis.  Estimates will continue to evolve with additional future data.

** Includes “basket” of emerging unconfirmed indications.

Phase I Trials for AG-221 and AG-120

Leading the Clinical Development of IDH Inhibitors

AG-221

AML + Heme

malignancies

Solid Tumors

2014

March

2013

September

2014

October

Study start

AG-120

AG-221 (planned 4Q)

AG-120

AG-221 expansion

24

IDH Inhibitors: AML Clinical Development Paradigms

Diagnostically Defined Population

Demonstrate Clinical Benefit

Acute Myeloid Leukemia (AML)

IDH1m+

AML

IDHm+

AML

IDH2m+

AML

Precision

Magnitude

Efficacy

Decrease disease

morbidity

Safety and

convenience

25

26

AG-221: Phase 1 Data Presented at European

Hematology Association (EHA),  June 14, 2014

AN UPDATE OF THE CLINICAL SAFETY AND

ACTIVITY IN A PHASE I TRIAL OF AG-221, A

FIRST IN CLASS, POTENT INHIBITOR OF THE

IDH2-MUTANT PROTEIN, IN PATIENTS WITH

IDH2 MUTANT POSITIVE ADVANCED

HEMATOLOGIC MALIGNANCIES

Eytan M. Stein

1

, Martin S. Tallman

1

, Daniel A. Pollyea

2

, Ian W. Flinn

3

, Amir T. Fathi

4

,

Richard M. Stone

5

, Ross L. Levine

1

, Samuel Agresta

6

, Hua Yang

6

, Bin Fan

6

, Kate Yen

6

,

Stéphane de Botton

7

1

Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center,

Weill

Cornell

Medical

College,

New

York,

New

York;

2

University

of

Colorado

Cancer

Center,

Aurora,

CO;

3

Sarah

Cannon

Research

Institute,

Nashville,

TN;

4

Massachusetts

General

Hospital

Cancer

Center,

Harvard

Medical

School,

Boston,

MA;

5

Dana-Farber

Cancer

Institute,

Boston,

MA;

6

Agios

Pharmaceuticals,

Cambridge,

MA;

7

Institut

Gustave

Roussy,

Villejuif,

France

27

CR = Complete Response

CRp = Complete Response, Incomplete Platelet Recovery

CRi  = Complete Response, Incomplete Hematologic Recovery

PR = Partial Response (>50% Decrease in Bone Marrow Blasts)

30 mg BID

N=7

50 mg BID

N=7

75 mg

BID

N=6

100 mg

QD

N=5

100 mg

BID

N=5

150 mg 

QD

N=5

Total

N=35

CR

2

3

-

1

-

-

6

CRp

1

-

-

-

1

-

2

CRi

-

1

-

-

-

-

1

PR

1

1

1

-

1

1

a

5

SD

-

1

2

1

-

1

5

PD

-

1

1

3

1

-

6

b

ORR

4/4

5/7

1/4

1/5

2/3

1/2

14/25

NE

3

-

2

-

2

3

d

10

a

PR at C1D15

b

3 Subjects with Clinical PD/Clinical Deterioration (No Day 28 Marrow Assessment).

c

Subjects did not have a Day 28 Marrow Assessment (Off Study).

d

Subjects on study (<28 days at data cut).

SD = Stable Disease

PD = Progressive Disease

NE = Not Evaluable

ORR = CR + CRp + CRi + PR

AG-221 Phase 1 Early Data: Efficacy and Response

Measured by IWG Criteria per Investigator

Data Presented at European Hematology Association (EHA) on June 14, 2014

Note: Based on unaudited data from live clinical database

c

c

c

28

C2

C3

C4

C5

C6

C7

Bone Fracture,

Death Unrelated

Neutrophil counts

increase by

C1D15. Counts

are in normal

range by C2D15

in  responders.

AG-221 Phase 1 Early Data: Summary of Objective

Responses (as of May 23, 2014 data cut )

Data Presented at European Hematology Association (EHA) on June 14, 2014

C1

30 MG

BID

50 MG

BID

75 MG

BID

100 MG

QD

100 MG

BID

150 MG

QD

Transplant

CR

CRp

CR

PR

PR

CRp

PR

CR

PR

CR*

CR

PR

CRi

CR**

On Study

Off Study

Response

Bone Marrow

*Bone marrow blasts 7% at C51. Dose escalated to 75 mg BID on study in CR, **Bone marrow blast increase to 11% at C3D1. Dose escalated to 75 mg BID. On study

  Note: Based on unaudited data from live clinical database

AG-221: Evidence of Cell Differentiation Leading to

Potential Paradigm Shift in Treatment

Data Presented at European Hematology Association (EHA) on 6/14/2014

29

AG-221: Cellular Differentiation Leads to a CR  

Data Presented at AACR, April 2014

C1D15 bone marrow demonstrates unique differentiation effect of AG-221

therapy

CR=complete response; C1D15=Cycle 1, Day 15; C3D1=Cycle 3, Day 1; C4D1=Cycle 4, Day 1.

30

Stein EM et al. (2014) Clinical safety and activity in a Phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant 

positive advanced hematologic malignancies. 

Total Subjects* (N=18) n (%)

MedDRA Preferred Term:

Grade 1 or 2

Grade

3

All Events

Nausea

4 (22.2)

0

4 (22.2)

Pyrexia

4 (22.2)

0

4 (22.2)

Thrombocytopenia

1 (5.6)

3 (16.7)

4 (22.2)

Anemia

2 (11.1)

1 (5.6)

3 (16.7)

Dizziness

3 (16.7)

0

3 (16.7)

Febrile neutropenia

0

3 (16.7)

3 (16.7)

Peripheral edema

3 (16.7)

0

3 (16.7)

Sepsis

0

3

3 (16.7)

Cough

2 (11.1)

0

2 (11.1)

Diarrhea

1 (5.6)

1 (5.6)

2 (11.1)

Fatigue

1 (5.6)

1 (5.6)

2 (11.1)

Leukocytosis

0

2 (11.1)

2 (11.1)

Neutropenia

1 (5.6)

1 (5.6)

2 (11.1)

Petechia

2 (11.1)

0

2 (11.1)

Rash

1 (5.6)

1 (5.6)

2 (11.1)

*Based

on

number

of

subjects

with

AE

data

reported

in

database

as

of

25

April

2014

AG-221 Phase 1 Early Data: Most Common Side Effects

Data Presented at European Hematology Association (EHA) on June 14, 2014

31

Total Subjects* (N=18) n (%)

32

Phase 1

ASH 2014

Initiated

October

2014

AG-221 Phase I Trial in AML & Other Heme Malignancies

Expansion

Cohorts

Advanced Heme

Malignancies

Ongoing Dose

Escalation

Phase 1

Ongoing Dose

Escalation

Initiated

October

2014

Safety-dose limiting toxicity, dose modifications,

chronic toxicity

Pharmacokinetics-exposure, half-life, variability

Pharmacodynamics-2-HG reduction

Clinical activity: remissions and durability

Dose Selection Criteria

Dose Selected for Start of Expansion Cohorts: Multiple

Factors Considered

100 mg

Single Daily Dose

IDH2m+ AML and Heme malignancies

Dose Selected

ASH 2014

Expansion

Cohorts

Advanced Heme

Malignancies

AG-221: Phase I Expansion Cohorts:

Homogenous patient populations

Phase 1

Ongoing Dose

Escalation

Initiated

October

2014

AG-221: Four Expansion Cohorts

Cohort 2

R/R AML <60 yrs

n=25

Cohort 4

Basket Heme

n=25

Cohort 3

AML –decline SOC

chemotherapy

n=25

Cohort 1

R/R

AML

60

yrs

(transplant ineligible)

n=25

Dose Selected

ASH 2014

Advanced Heme

Malignancies

Expansion

Cohorts

BREADTH

Phase 1

Initiated

October

2014

AG-221 Clinical Development Considerations

Relapsed/Refractory AML

Front-Line | Unfit Patients

Maintenance (Post BM Transplant)

Front-Line | Fit Patients

SPEED

ASH 2014

Additional heme malignancies (e.g. MDS)

Potential Future Directions in Collaboration with Celgene

Options informed by:

Advanced Heme

Malignancies

Ongoing Dose

Escalation

Expansion

Cohorts

•

Clinical data

•

Regulatory input

36

Accelerated Pathway:

-

Response rates

-

Duration of response

-

Reduction in transfusions

& Infections

Standard Pathway:

Potential Endpoints for Regulatory Approval in Heme

and Solid Tumor Cancers with an IDH Mutation

U.S. Regulatory Approval

Global Regulatory Approval

Potential Regulatory Pathways

Primary endpoint

Secondary endpoints

Overall survival

Relapse free survival

Improvement in disease

related symptoms

37

Untreated

AML

-

(no

APML)

~

17K pts

Fit for Induction

Chemotherapy

Unfit for Induction

Chemotherapy

Age/

Comorbidities

~10%

Age 80+; poor

status; severe

comorbidities

Consolidation

HSCT

~40%

Success

Age/MRD/

Cytogenetics

Refractory

High

Low or

Intermediate

Induction and

Consolidation

Relapsed Patients

Yes

No

Front-Line

Refractory

Patients

Clinical Setting Landscape

1

Line

Treatment

~60%

Source: Market research

Willingness to

receive tx

Supportive

care

“Gentle”

regimen

Clinical

Trial

~60-70%

~30-40%

st

38

AG-120: Potent & Selective Inhibitor of IDH1 Mutations

•

Current Status: Two Phase 1 studies initiated in March 2014

•

What’s

new:

Early

data

from

Phase

1

Heme

at

EORTC/AACR

in

November

Multiple expansion cohorts

IHCC, chondrosarcoma,

glioma, others

Phase 1 Trials

Advanced hematologic

malignancies

Study Designs

“3 + 3”

design

All patients IDH1m+

Assess safety, PK

Assess 2HG levels,

Advanced Solid Tumors

Current Status

•

AML

MDS

MPD

Potential Future Directions in Collaboration with Celgene

Expansion Studies

Full Development

Potential for rapid entry

into definitive efficacy

trials in IDH1m+ patients

Hematology:

“Speed”

and “Breadth”

options in

AML/MDS, similar to AG-

221 program

Rare IDH disorders

Solid

tumors:

fast

path

opportunities

•

•

Multiple expansion cohorts

differentiation, efficacy

39

IDH Inhibitors as Potential Foundation of Therapy for

IDH Mutant Cancers

Early Development

-

IDH mutation positive patients only

-

Partner with research for strong correlative science

Speed

-

Data driven expansion cohorts

-

High unmet medical need populations

Breadth

-

In-depth understanding of entire IDHm+ population indication

-

Randomized trials targeting global registration and reimbursement 

Keys to Success in Clinical Development

IDH-Mutant Inhibitors

Clinical Development Strategy –

Early Clinical Evidence

October 15, 2014

Chris Bowden, M.D., Chief Medical Officer

Rare Genetic Disorders of Metabolism:

Pyruvate Kinase Deficiency and PKR Activator, AG-348

Scott Biller, Ph.D., Chief Scientific Officer

October 15, 2014

2

Today’s Key Points

By leveraging our scientific excellence in cellular metabolism, we have 

defined a transformative approach to small molecule therapies for rare

genetic disorders

AG-348, our first RGD therapy:

-

is an allosteric activator of pyruvate kinase

-

corrects the metabolic dysregulation in PK deficiency patient blood

ex vivo

A suite of biomarkers have been implemented in our healthy volunteer

trials and will be included in patient trials

This is very cool science!

3

Rare Genetic Disorders of Metabolism

Archibald Garrod

>1900’s

>1980’s-00’s

Novel Agios approach to rare genetic disorders of metabolism:

Identify optimal intervention points in dysregulated metabolic pathways

Correct metabolic defect using small molecules

-

Potential to correct brain phenotypes

>2010’s

Enzyme Replacement Therapies

(mostly Lysosomal Storage

Disorders)

600 RGDs described

featuring inherited

mutation in single

metabolic enzyme

Unaddressed rare disorders

of metabolism

Significant unmet need

4

Scientific Approach to Rare Genetic Disorders of

Metabolism

Severe clinical presentation

Potential to be transformative        

High unmet need

Amenable to

SM approach

Agios rare genetic disorders of

metabolism portfolio

Detailed

Mutational &

structural

analysis

Biology/clinica

l feasibility

Monogenic

Diseases

(RGD-M)

Multiple genes

causing disease

= Gene

= Disease condition

Gene

causing

multiple

diseases

Agios analysis of databases of genetic disorders:

>600 Rare Genetic Disorders of Metabolism

Systematic Disease Selection

Frequency

5

Agios Approach to Correct Metabolic Pathway Defects

Metabolite A pool

Enzyme 1

Metabolite B pool

Metabolite C pool

Enzyme 2*

(mutant)

6

Alternative Pathway

Pathway modulation:

Reduce toxic metabolites or bypass

metabolic defect by targeting

upstream/adjacent pathway

Allosteric modulation:

Restore metabolic flow by directly

modulating biochemical activity or

stabilizing the protein

Metabolite B pool

Metabolite C pool

Metabolite A pool

Agios Approach to Correct Metabolic Pathway Defects

Enzyme 1

Enzyme 2*

(restored)

7

Pyruvate Kinase (PK) Deficiency:

Rare Hematological Genetic Disorder

Caused by >160 hypomorphic mutations in PKR

Autosomal recessive disorder characterized by chronic hemolytic anemia

Poor prognosis

-

Presents in infancy or childhood with severe hemolytic anemia and jaundice

-

No disease-altering therapies

-

Transfusions and splenectomy common to manage symptoms

-

Lifelong risks from chronic hemolysis and iron overload

Blood smear in PK

Deficiency

Disease Characteristics

Agios’

Therapeutic Approach

PKR enzyme catalyzes the final step in glycolysis in red blood cells

In PK Deficiency, low PKR activity leads to low ATP levels and high rate of hemolysis in red

blood cells

Agios has developed AG-348, a small molecule activator that restores activity of mutant

PKR

8

Glycolysis

Glycolysis

Glycolysis

Glycolysis

ATP

ATP

ATP

ATP

PKR

PKR

mPKR

mPKR

PKR mutations lead to low pyruvate kinase activity and ATP levels

Low ATP levels result in decreased red cell life span, hemolysis

and anemia

Red Blood Cells are Highly Dependent on Glycolysis

for ATP Generation

Normal Red Cell

PK Deficient Red Cell

9

Glycolysis

Glycolysis

Glycolysis

Glycolysis

ATP

ATP

mPKR + AG 348

mPKR + AG 348

AG-348 Restores PKR Activity and Corrects the

Metabolic Deficiency

PK Deficient Red Cell

PK Deficient Red Cell + AG-348

mPKR

mPKR

ATP

ATP

10

AG-348

Active Site

PKR Enzyme: Active Tetramer Indicating Mutations and AG-348 Binding Site

AG-348 binds at the PKR dimer-dimer

interface, distal to common mutations

associated with PK deficiency

AG-348 is Designed to Activate a Wide Variety of

Mutant PKR Enzymes

11

Enzyme thermal stability of the most

common unstable mutant R510Q

AG-348 activates PKR WT and nearly

all PKR mutant enzymes tested

AG-348 increases the thermal stability    

of unstable mutant enzymes

AG-348 activates 10 of 11 common

mutants, as well as WT PKR

AG-348 Increases Catalytic Efficiency and Improves

Stability of Mutant Enzymes

Source: Kung, ASH poster 2013

12

Two Mechanisms for AG-348 Action

Increased catalytic efficiency

ATP

Glycolysis

Glycolysis

ATP

13

Degradation

Glycolysis

Two Mechanisms for AG-348 Action

Increased protein stability

ATP

14

PK Deficient Red Cells Have Metabolic Defects That

Result in Chronic Hemolysis

Glucose

1,3-DPG

3-PG

PEP

Pyruvate

PKR

2,3-DPG

`

ATP

Glucose

1,3-DPG

3-PG

PEP

Pyruvate

mPKR

`

ATP

WT PKR

Mutant PKR

WT

PKD

2,3-DPG

ATP

2,3-DPG

Source: Kung, ASH poster 2013

2,3-DPG levels are elevated

and ATP levels reduced in

PK deficient red cells

15

AG-348 Restores Metabolite Levels in PK Deficient

Patient Blood to That of Normal Red Cells

Patient A

(R510Q/G511R)

Glucose

1,3-DPG

3-PG

PEP

Pyruvate

PKR

2,3-DPG

`

ATP

AG-348

Patient B

(R486W/D390N)

Patient C

(A495V/E241stop)

2,3-DPG

ATP

PKR

Activity

DMSO

AG-348 (2 uM)

Source: Kung, ASH poster 2013

16

AG-348 Activates WT PKR and Effects Metabolite

Biomarkers in Preclinical Models

WT Mouse single dose

WT Mouse 13 doses (BID)

Dose-dependent increase in ATP levels and decrease in 2,3-DPG levels

seen in mice dosed BID with AG-348

-

Single dose results in 2,3-DPG response but minimal ATP response

-

Multiple doses lower 2,3-DPG and raise ATP levels

Source: Agios internal research

17

AG-348 Increases Glycolytic Flux in Preclinical Models

1.8-fold increase in glycolytic flux

upon AG-348 treatment in wt mice

time (min)

DMSO      AG-348

13C

3

labeled

Unlabeled

+AG-348

13C

3

labeled

Unlabeled

Vehicle

Source: Agios internal research

18

Robust Suite of Metabolic Biomarkers in Place for

Healthy Volunteer and Patient Trials

Glucose

FBP

1,3-DPG

3-PG

PEP

Pyruvate

PKR

2,3-DPG

`

ATP

AG-348

Ex Vivo

PKR

Activity Assay

ATP & 2,3-DPG

levels

Pharmacodynamic

Biomarkers

Glycolytic Flux

Source: Kung, ASH poster 2013

19

Summary

AG-348 Profile

Potent activator of PKR mutant and wild-type enzymes

Excellent pharmaceutical properties, oral dosing

Functions by increasing catalytic efficiency and stabilizing unstable mutant

proteins

Corrects the metabolic phenotype in blood from multiple PK deficient patients

Biomarkers incorporated into the healthy volunteer studies to evaluate WT

PKR activation and metabolic response

Rare Genetic Disorders of Metabolism:

Pyruvate Kinase Deficiency and PKR Activator, AG-348

Scott Biller, Ph.D., Chief Scientific Officer

October 15, 2014

Sam Agresta, MD, MPH & TM

VP, Head of Clinical Development

Pyruvate Kinase-R (PKR) Program

Disease Background & Clinical Development Strategy

October 15, 2014

22

Today’s Key Takeaways

PK deficiency is a serious disease with life-

long hemolytic anemia

Current therapy is supportive and does not

address underlying disease

AG-348 targets mutated enzyme which

drives pathogenesis

Natural history and clinical evaluation of

AG-348 is underway

University of Milan

Stanford

23

Source: Zanella. Blood Rev. 2007; 21(4):217;, Blood and Bone Marrow Pathology; Wintrobe’s Clinical Hematology; Physician Interviews; Market Research.

Pyruvate Kinase (PK) Deficiency 

A Destructive Red Blood Cell Disease

Disease Pathophysiology

Description

•

Rare genetic disease often

presenting at birth

Etiology

•

Caused by mutations in PK-LR

gene coding for Erythrocyte

Pyruvate Kinase

Clinical

Presentation

•

Lifelong hemolytic anemia and

associated morbidities

Diagnosis

•

PKR enzyme activity and

genetic testing

Disease Overview

PK deficiency

Normal

Red Blood Cell

Blood Smear

24

Disease Progression from Infants to Adults

Splenectomy

Jaundice

Iron Overload

Pyruvate kinase deficiency is the most common enzyme abnormality

of

the glycolytic pathway

25

Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research

Hb: Hemoglobin.

Majority of Patients Have Moderate to Severe Disease

Adult and Pediatric Diagnosed PK Deficiency Population

Mild

(20 –

30%)

Moderate

(20 –

30%)

Severe

(40 –

50%)

Description

•

Transfusion typically

required during

stressors: pregnancy

or infection

•

Patients are often

diagnosed in 30s and

40s after suffering

from aplastic crisis

•

Severity and symptoms

range

•

Diagnosed at all ages

•

Seek treatment and

diagnosis when

intolerant of low Hb

Annual

Transfusions

> 12    

0     

2  

<1Transfusions Per Year

4

6     

8

10  

> 12   

0    

2    

1 –

4 Transfusions Per Year

4

6   

8    

10   

> 12 

0    

2      

>4 Transfusions Per Year

4

6    

8    

10 

•

Present at an early age

and diagnosed in

childhood

•

Require aggressive

blood transfusion

management

•

Disease severity may

attenuate

26

Sources: Wintrobe’s Clinical Hematology; Physician Interviews; Market Research

PK Deficiency Diagnosis Currently Requires Many

Steps to Confirm

Step

Key Details

•

Initial symptoms of anemia may include pallor, fatigue, weakness, or

reduced exercise tolerance

•

Complete blood count confirms anemia

•

Blood smear is often performed concurrently to evaluate cell morphology

•

Reticulocyte count demonstrates reticulocytosis which is indicative of

hemolytic anemia

•

An enzyme assay for the activity of PKR or a genetic test can confirm

disorder

•

Tests

may

also

be

performed

to

differentiate

against

other

forms

of

hemolytic anemia

Presentation and

Symptom Evaluation

Evaluation for

Anemia

Evaluation for Hemolytic

Anemia

Evaluation for PK

Deficiency

27

Description

Distribution of Patient Age at Time of Diagnosis

•

Seek diagnosis due to 

inability to function with

current level of anemia

•

Diagnosis occurs when

growth and activity are

closely monitored

•

Most common in severe

patients or those with

siblings who are also

afflicted

Age Group

Source: Market Research

Majority of Patients are Diagnosed due to Symptoms

Pediatric

~50%

Adult

~40%

~10%

Neonatal

Pediatric

1 Month –

18

years

Adult

> 18 years

Neonatal

< 1 Month

28

Availability

of

a

therapy

may

increase

awareness

and

willingness

to

diagnose

patients

Estimated PK Deficiency Patient Population

(U.S. and EU5)

Estimate  

Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research

Estimates based on

genetic modeling

Severe

(40 –

50%)

Similar to Other Rare Genetic Diseases, PK Deficiency is Largely

Undiagnosed

Diagnosed Patients

(~2.4 K)

Total U.S. and EU5 Population

(~32 K)

Mild

(20 –

30%)

Moderate

(20 –

30%)

5 –

10%

diagnosed with PK deficiency

29

PK Deficiency is an Inherited Disease

Autosomal recessive inheritance

-

More than 160 different causative

mutations have been identified

Most affected individuals are compound

heterozygous for two different mutant

alleles

Acquired PK deficiency rarely occurs as

a result of acute leukemia, pre-leukemia

Chemotherapy may cause a more

common and milder form of PK

deficiency

Source: Etiemble et al, 1980 

30

Clinical Presentation and Morbidity

PK deficiency results in severe and systemic disease throughout life

Source: Segel et al, 2011

Death in utero from hydrops fetalis

Transfusion-requiring anemia (Can be life threatening)

Pallor, icterus, and splenomegaly

Hepatosplenomegaly

Pigmented (bilirubin) gallstones

Transient aplastic anemia caused by infection

Folic acid deficiency secondary to increased

requirements

Clinically significant iron overload

Growth delay, frontal bossing, skin ulcers

Chronic Hemolysis

•

•

•

•

•

•

•

•

•

31

Source: Zanella et al, 2005

Anemia

Jaundice

Splenomegaly

90%

70%

81%

Splenectomy

30%

Neonatal Jaundice

59%

Exchange Transfusion

45%

Median number of Transfusions 15 (1

100)

65% exchange transfusion newborns require multiple transfusions and/or a splenectomy

30% patients are transfusion-dependent in childhood or until splenectomy

Gallstones

Cholecystectomy

30%

25%

Transfusions

64%

Clinical Data in 61 Patients with PK Deficiency

Median Age at Diagnosis 16 yrs  (1 day-

65 yrs)

32

Transfusion Requirements in an Infant with PK

Deficiency

Source: Smiers et al, 2007

33

Splenectomy Offers Minimal Disease Impact

Spleen intact

Spleen removed

Source: Zanella et al. 2005

Normal level

•

34

Extra-Medullary Hematopoiesis

Abnormal bone marrow

production

Source: Pratt et al. 2005

60 year old woman with PK Deficiency

with spinal cord compression

35

Iron Overload Impacts Mortality

Iron Deposition in the Liver

Liver Pathology

Clinical Symptoms

Source: Morton et al. 2011 

Normal Portal and Central Veins

No Signs of Fibrosis

36

AG-348: Clinical Development

Current: Supportive only

Future: Targeting enzyme defect

Bone

Marrow

Transplant

Transfusion

Iron

chelation and

Phototherapy

Lifelong

Antibiotics

Chole-

cystectomy

Folic acid

Splenectom

y

AG-348

Agios Approach to PK Deficiency

Clinical Trials

•

Healthy Volunteer Studies

•

Phase 2 Trial in Patients

Biology & Chemistry

•

PKR Protein Interactions and

Biologic Effect

•

Pharmacodynamic Correlates

Disease Understanding

•

Natural History Study

•

Translational Research with

Disease Experts

37

38

PK Deficiency Natural History Study Designed to

Inform Registration Path

Study will capture retrospective and prospective clinical data, annual quality of life 

measures, and genetic diagnostic information 

Understanding the Disease & Identifying Patients and Treatment Centers

Study Design

Longitudinal cohort with retrospective, baseline, and annual collection of data from routine care visits for

PK deficiency and its complications

Participants will be followed for at least 2 years

Population:

Participants of any age with PK deficiency

Approximately 100 participants

Objectives:

Increase

understanding

of

range

of

symptoms

and

complications

of

PK

deficiency

Transfusion burden in splenectomized and non-splenectomized PK deficiency

Association of patient reported outcome measures with clinical parameters

Incidence and timing of splenectomy

Prevalence and treatment of iron overload

Prevalence of co-morbidities

Determine pregnancy outcomes

Description of Genotypic/Phenotypic variation

Natural History Study has Identified Global Treatment

Centers

-Does not include 3 sites open in Canada

As of September 2014:

23 sites open

>50 patients enrolled

12 additional global sites identified

39

40

AG-348: Clinical Development Status

Status Today

Single ascending dose study in healthy volunteers

Dosing completed; met primary endpoint

Multiple ascending dose study in healthy volunteers ongoing

Met primary endpoint

Phase 2 start-up activity initiated

Expect to enroll by early 2015

Data from healthy volunteer studies at ASH 2014

Natural History Study: 23 sites and >50 patients enrolled

AG-348: Profile

Activator of the PK enzyme

Orally dosed

Corrects underlying metabolic defect in preclinical models

41

Phase 1

Phase 2 to Late Development

AG-348 Clinical Development Status

Single ascending dose 

(SAD) escalation

(Healthy Volunteer Clinical Studies)

Current Status

Potential Future Directions

Study Designs

Multiple ascending dose

(MAD) escalation

Randomized double blind placebo

controlled trials

Single experienced U.S. site

Assess safety, PK and PD

Potential for activation of wild type

PK enzyme and effect on

metabolites

Select dose range for Phase 2

study in PK deficiency patients

Plan to initiate Phase 2 trial in adults

with PK deficiency by early 2015

Development in pediatric patients

based on POC in adults

42

Phase 2 Study Considerations

Potential Open-label Global (US, EU) Single-Arm Phase 2

End of Treatment

Treatment:

-

Dose/Schedule decided by healthy volunteer studies

Clinical endpoints:

-

Safety

-

Efficacy

•

Hemoglobin: stabilization and/or increase

•

Transfusion frequency and amount

-

Quality of life (endpoints evaluated in NHS)

PK/PD Markers

Screening/Observati

on Period

Hemoglobin Set Point

Transfusion Requirements*

Hemolysis Markers

Reticulocytes

QOL’s

AG-348 Treatment

43

Potential Regulatory Endpoints for Approval

Key clinical endpoints:

-

Reduction in transfusion(s)

-

Avoid splenectomy

-

Change in hemoglobin

-

QOL assessments

PILOT (Phase II)

TRIUMPH (Phase III)

SHEPHERD (Phase III)

Patient

Enrollment

11 transfusion-

dependent PNH patients

4 transfusions in past

year

87 transfusion-dependent

PNH patients

4 transfusions in past

year

97 transfusion-dependent

PNH patients

1 transfusion in past 2

years, but    3 in past year

Length

~12 week

~26 week

52 week

Primary

and

Secondary

Endpoints

Pharmacokinetics

Evaluated reduction in

incidence of

intravascular hemolysis,

hemoglobinuria and

transfusion requirements

Determine efficacy via

stabilization of hemoglobin

and number of packed

RBCs transfused

Compared transfusion

requirements and LDH

against placebo

Evaluated primary efficacy

endpoints of hemolysis as

determined by LDH

Secondary endpoints:

Fatigue and quality of

life as determined by

survey

Soliris®

(Eculizumab) in PNH may provide regulatory precedent

44

Source: Market Research

AG-348: Potential Benefit Across All of PK Deficiency

Patients

•

Patients receiving transfusions

suffer from anemia, poor QOL,

and potentially severe adverse

events

•

Although rarely transfused,

underlying hemolytic anemia

causes morbidity

ILLUSTRATIVE

Potential Addressable Population Expansion

All Other Patients with

Poor Quality of Life

Patients with >4

Annual

Transfusions

Patients with >1

Annual Transfusion

45

Summary

Potential for AG-348 to be first medicine to target underlying defect

PK deficiency is a serious disease with life-long hemolytic anemia

Current therapy is supportive and does not address underlying disease

AG-348 targets mutated enzyme which drives pathogenesis

Natural history and clinical evaluation of AG-348 is underway

Sam Agresta, MD, MPH & TM

VP, Head of Clinical Development

Pyruvate Kinase-R (PKR) Program

Disease Background & Clinical Development Strategy

October 15, 2014

October 15, 2014

David Schenkein, M.D., Chief Executive Officer

Closing Remarks

&

Q&A

48

Clinical Pipeline Progress: Building Momentum

Healthy volunteer data

at ASH 2014

Initiate Ph 2 in PK

deficiency patients by

early 2015

AG -

221

AG -

120

AG -

348

Remaining 2014 Potential Product Milestones

AG -

221

AG -

120

AG -

348

Ph 1 heme data at

EORTC/AACR

(Nov. 19)

Clear POC

Initiated expansion

cohorts

Fast Track & Orphan

Drug Designations in US

Two Phase 1 trials (

IDH1m+ heme and

solid tumors) initiated

and enrolling well

Additional Phase 1

data at ASH 2014

On track to initiate

trial in IDH2m+

solid tumors

2014 Product Milestones Achieved

Completed SAD study;

Met primary endpoint in

SAD & MAD studies