56th ASH® Annual Meeting and Exposition
Summary of Data Presentations
Agios Pharmaceuticals, Inc.
Webcast
December 8, 2014
DAVID SCHENKEIN, M.D.
Chief Executive Officer
Agios’ commitment to cancer metabolism and IDHm+ inhibitors
3
Cautionary Note Regarding Forward-Looking
Statements
This 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”, “anticipate,” ”intend,” ”plan,” “potential” 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 clinical trials and preclinical studies; 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 from time to time with the SEC.
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 forwardlooking statements, whether as a result of new information, future events or otherwise.
4
Agenda
Prepared Remarks
Welcome & Overview of Current IDH Programs
 DAVID SCHENKEIN, M.D., Chief Executive Officer
Review of AG-221 (IDH2m+ inhibitor) Oral Presentation at ASH
 EYTAN STEIN, M.D., Lead investigator and attending physician,
Memorial Sloan Kettering Cancer Center
AG-348 Overview and Clinical Development
 CHRIS BOWDEN, M.D., Chief Medical Officer
Question and Answer Session
Joined by:
 MARTIN TALLMAN, M.D., Chief, Leukemia Service, Memorial
Sloan Kettering Cancer Center

SCOTT BILLER, Ph.D., Chief Scientific Officer
5
Clinical Pipeline Progress in 2014: Building Momentum
2014 Product Milestones Achieved
AG - 221
AG - 120
 Clear POC
 Initiated expansion
cohorts
 Fast Track & Orphan
Drug Designations in US
 Initiated trial in IDH2m+
solid tumors
 Two Phase 1 trials (
IDH1m+ heme and
solid tumors) initiated
and enrolling well
 Ph 1 heme data at
EORTC/AACR (Nov.
19)
AG - 348
 Completed SAD study
 Met primary endpoint in
SAD & MAD studies
Remaining 2014 Product Milestones
AG - 221

Additional Phase 1
data at ASH 2014
AG - 348

Healthy volunteer data
at ASH 2014
6
Novel First-in-Class Portfolio:
Precision Medicine Approach
Research
Clinical Development
Primary Commercial
Rights
Development Programs
Advanced Hematologic Malignancies
AG-221
(IDH2m inhibitor)
AG-120
(IDH1m inhibitor)
Phase 1
Studies
Advanced Solid Tumors
Advanced Hematologic Malignancies
Phase 1
Studies
US Rts
Advanced Solid Tumors
AG-348
(Pyruvate kinase (R) Activator)
ex-US Rts
Phase 1
HV Studies
PK Deficiency
Research Programs
Cancer Metabolism
Rare Genetic Disorders of
Metabolism
(Multiple Novel Targets)
(Multiple Monogenic Diseases)
7
ASH Abstracts/Presentations
Topic/Date
AG-221: Oral Presentation
December 7, 4:30 p.m. PST
AG-221: Poster Presentation
Monday, December 8
AG-221: Poster Presentation
Monday, December 8
AG-120: Poster Presentation
Monday, December 8
AG-348: Poster Presentation
Monday, December 8
AG-348: Poster Presentation
Monday, December 8
Lead Author
Title
No.
Eytan Stein
AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the
IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a
Phase I Study in Patients with IDH2 Mutation Positive Advanced
Hematologic Malignancies
#115
Bin Fan
Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD)
Relationship of an Oral, Selective, First-in-Class, Potent IDH2
Inhibitor, AG-221, from a Phase 1 Trial in Patients with Advanced
IDH2 Mutant Positive Hematologic Malignancies
#3737
Cyril Quivoron
AG-221, an Oral, Selective, First-in-Class, Potent IDH2R140Q Mutant Inhibitor, Induces Differentiation in a Xenotransplant
Model
#3735
AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant
IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation
in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient
Samples Treated Ex Vivo
#3734
Phase I Single (SAD) and Multiple Ascending Dose (MAD) Studies of
the Safety, Tolerability, Pharmacokinetics (PK) and
Pharmacodynamics (PD) of AG-348, a First-in-Class Allosteric
Activator of Pyruvate Kinase-R, in Healthy Subjects
#4007
Erica Hansen
Hua Yang
Charles Kung
AG-348 Activation of Pyruvate Kinase in Vivo Enhances Red Cell
Glycolysis in Mice
Abstracts are available online on the ASH conference website: ash.confex.com/ash/2014/webprogram/start.html
#4010
8
Leading the Clinical Development of IDHm+ Inhibitors
Ongoing and Planned Phase I Trials for AG-221 and AG-120
September ‘13
March ‘14
October ‘14
1H 2015
AML + Other Heme Malignancies
AG-221
AG-221 expansion
AG-120
AG-120 Expansion
(planned)
Solid Tumors
AG-120
AG-221
9
AG-120: Summary of Early Phase 1 Data
Data Presented at EORTC-NCI-AACR November 19, 2014
Ongoing Phase 1 Study in IDH1m+ Advanced Hematologic Malignancies




Marked first time AG-120 data presented in medical forum
- Clear proof-of-concept
- Validated IDH1 as a potential target
Seven out of 14 evaluable patients achieved investigator assessed
objective responses, including:
- 4 complete remissions
- 2 marrow complete remissions
- 1 partial remission
Early evidence of durability observed
Well tolerated with majority of adverse events mild to moderate
10
10
Planned Clinical Pipeline Progress
2014 Product Milestones Achieved
AG - 221
AG - 120
AG - 348
2015/2016 Potential Product Milestones
AG - 221
AG - 120
 First data from expansion
cohorts (2015)
 Start expansion cohorts
(1H ‘15)
 Initiate global registration
program in heme
malignancies (2015)
 Initiate combination trials
for frontline AML (2015)
 Initiate combination trials
for frontline AML (2015)
 Ongoing solid tumor
Phase 1 study (2015)
 First Ph 1 solid tumor
data (2015)
AG - 348
 Phase 2 trial in PK
deficiency patients
(1H ‘15)
 First data from Natural
History study (2015)
 Initiate global registration
program in heme
malignancies
(by early 2016)
11
AG-221 Clinical Development Considerations in
Hematologic Malignancies
Ongoing Phase 1
Ongoing Dose
Escalation
Advanced Heme
Malignancies
Data at
ASH 2014
Expansion
Cohorts
Initiated
October
2014
Potential Future Directions in Collaboration with Celgene
SPEED
Relapsed/Refractory AML
Options informed by:
• Clinical data
• Regulatory input
BREADTH
Front-Line | Unfit Patients
Front-Line | Fit Patients
Maintenance (Post BM Transplant)
Additional heme malignancies (e.g. MDS)
12
Cancer Metabolism Program:
IDH Mutations Found in AML, MDS, NHL and Range of Solid Tumors
Indication
IDH1m
Low grade glioma & 2ary GBM
68-74
Chondrosarcoma
40-52
Acute Myeloid Leukemia (AML)
6-10
MDS/MPN
Intrahepatic Cholangiocarcinoma
IDH2m
% IDHm
3
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
Based on literature analysis. Estimates will continue to evolve with additional future data.
** Includes “basket” of emerging unconfirmed indications.
13
AML is a Devastating Blood Cancer

Acute Myeloid Leukemia (AML)
- Most common leukemia in adults
- ~ 18K new cases annually in US
- Poor/limited prognosis
- Few treatment options, with no improvements in decades
- 5-year survival rate is 20-25%
- Majority of AML patients age 60 and older and many cannot tolerate
standard of care chemotherapy

IDHm+ inhibitors have the potential to:
- Change the treatment paradigm
- Establish new foundations of care

IDH mutations exist in solid tumors and present opportunities beyond
hematologic malignancies and AML
Tremendous need for a safe and effective targeted molecular medicine for
these patients
Source: SEER data, market research
14
Goal: To Change the Treatment Paradigm for AML
AML
Chemotherapy
Stem Cell Transplantation
(select eligible patients)
IDHm+
AML
IDHm+ inhibitor
Potential to establish a new foundation in AML care
15
EYTAN STEIN, M.D.
Lead investigator and attending physician,
Memorial Sloan Kettering Cancer Center
AG-221 Phase 1 clinical data Presented at ASH 2014
16
AG-221, an Oral, Selective, First-in-Class, Potent
Inhibitor of the IDH2 Mutant Enzyme, Induces
Durable Reponses in a Phase 1 Study of IDH2
Mutation Positive Advanced Hematologic
Malignancies
Eytan M Stein1, Jessica K Altman2, Robert Collins3, Courtney DiNardo4, Daniel J DeAngelo5,
Amir T Fathi6, Ian Flinn7, Arthur Frankel3, Ross L Levine1, Bruno C Medeiros8, Manish Patel9,
Daniel A Pollyea10, Gail J Roboz11, Richard M Stone4, Ronan T Swords12, Martin S Tallman1,
Sam Agresta13, Caroline Almon13, Bin Fan13, Meredith Goldwasser13, Hua Yang13, Katharine
Yen13, Stéphane de Botton14
1Memorial
Sloan Kettering Cancer Center, New York, NY; 2Robert H. Lurie Comprehensive Cancer Center,
Chicago, IL; 3University of Texas Southwestern, Dallas, TX; 4University of Texas MD Anderson Cancer Center,
TX; 5Dana-Farber Cancer Institute, Boston, MA; 6Massachusetts General Hospital Cancer Center, Harvard
Medical School, Boston, MA; 7Sarah Cannon Research Institute, Nashville, TN; 8Stanford Comprehensive
Cancer Center, Stanford University, Stanford, CA; 9Florida Cancer Specialists/SCRI, Sarasota, FL; 10University
of Colorado Cancer Center, Aurora, CO; 11Weill Cornell Medical College, New York Presbyterian Hospital, New
York, NY; 12Sylvester Comprehensive Cancer Center, University of Miami Hospitals, Miami, FL;
13Agios Pharmaceuticals, Cambridge, MA; 14Institut Gustave Roussy, Villejuif, France
IDH Mutations as a Target in AML


Isocitrate dehydrogenase (IDH) is a critical
enzyme of the citric acid cycle
IDH mutations occur in a spectrum
of solid and hematologic tumors1
– IDH2 mutations: 9–13% of AML and 3–6% of
MDS
– IDH1 mutations: 6–10% of AML and 3% of
MDS
Tumor cell
Mitochondrion
Citrate
Citrate
Isocitrate
Isocitrate
IDH1
KG
IDH2
NADPH
IDH1
mutant
KG
IDH2
mutant

IDH1/2 mutations confer a gain-of-function2:
– increased histone and DNA methylation
– impaired cellular differentiation
2-HG
NADPH
Epigenetic changes
Impaired cellular
differentiation
1Based
2Dang
on literature analysis. Estimates will continue to evolve with future data.
et al. Nature 2009;462:739-44.
AML = acute myeloid leukemia; MDS = myelodysplastic syndrome
18
IDH Mutations as a Target in AML
 Isocitrate dehydrogenase (IDH) is a critical enzyme of the citric acid cycle
 IDH mutations occur in a spectrum of solid and hematologic tumors
 IDH1/2 mutations confer a gain-of-function
 Inhibition of the mutation promotes appropriate cellular differentiation
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. [Power Point Slides] Retrieved from www.agios.com.
19
AG-221 Phase 1 Study Design and Status
Ongoing, first-in-human, dose escalation study:

AG-221: First-in-class, oral, potent, reversible, selective inhibitor of mutated IDH2

IDH2 mutation-positive hematologic malignancies, including relapsed or refractory
AML, MDS, or untreated AML

AG-221 in continuous oral dosing QD or BID daily, 28-day cycles
Key outcome measures:

Safety and tolerability, DLTs

MTD and recommended phase 2 dose

PK and PD (2-HG)

Characterize differentiation effect and preliminary clinical activity

Response assessed by investigator using IWG AML and MDS criteria
Update since EHA presentation:

Treated 38 additional patients, 73 total

Explored four additional dose cohorts (highest cumulative daily dose of 300 mg)

Initiated four expansion cohorts at 100 mg PO QD in October 2014

In-parallel dose escalation continues in QD regimen
MTD = maximum tolerated dose; DLT = dose limiting toxicity; PK = pharmacokinetics; PD = pharmacodynamics
20
Disposition by Cumulative Daily Dose Level*

73 patients treated, 38 remain on study drug treatment

Months of treatment, median (range) = 1.90 months (0.1‒8.8)

≤75 mg
(n=19) (%)
100 mg
(n=22) (%)
≥150 mg
(n=32) (%)
All patients
(N=73) (%)
On therapy, n
9 (47%)
10 (45%)
19 (59%)
38 (52%)
Discontinued, n
10 (53%)
12 (55%)
13 (41%)
35 (48%)
Progressive disease
2
6
6
14
Death
2
1
3
6
Transplant
1
2
2
5
Adverse event
2
2
0
4
Withdrawal of consent
1
-
2
3
Investigator decision
2
-
-
2
Clinical deterioration
-
1
-
1
AEs leading to study drug discontinuation:
– Grade 5 sepsis (1), Grade 4 febrile neutropenia (1), hypoxia (1), Grade 3
bacteremia (1)
* Categorized by initial dose assigned
21
Patient Characteristics
All treated patients
(n=73)
Age in years, median (range)
67 (33–90)
Diagnosis, n*
RR AML
55
MDS
6
Untreated AML
5
Other (5 CMML, 1 Myeloid sarcoma)
6
Men/women, n
39/34
ECOG performance status, n**
0
18 (25%)
1
39 (53%)
2
14 (19%)
Number of prior regimens, median (range)
RR AML
Prior BMT, n
2 (1‒11)
13 (18%)
IDH2 mutations, n***
R140
54 (74%)
R172
13 (18%)
Abnormal cytogenetics, n
*Missing for 1 patient; **Missing for 2 patients; ***Missing for 6 patients
21 (29%)
22
Safety Summary

Therapy has been well tolerated to date:
– MTD not reached
– Most common AEs: nausea, pyrexia, diarrhea, fatigue
– DLT: 1 Grade 5 hypoxia (100 mg BID) in a patient with unrelated fungal
pneumonia and sepsis
– 30-day all cause mortality 4.1%; 60-day all cause mortality 13.7%

Majority of SAEs are disease-related:
– 13 patients experienced 21 possibly or probably treatment related SAE’s
– Most common (2 patients): leukocytosis (n=3), DIC (n=2), tumour lysis
syndrome (n=2)
– Notable treatment-related SAEs: leukocytosis (n=3)

11 deaths reported:
– 9 unrelated: acidosis, cardiac arrest, leukocytosis, respiratory distress
syndrome, respiratory failure (n=2), sepsis (n=3)
– 2 possibly related: sepsis/hypoxia and atrial flutter
DIC = disseminated intravascular coagulation SAE = serious adverse events
23
Adverse Events by Cumulative Daily Dose & Overall
≤75 mg (n=19)
100 mg (n=22)
≥150 mg (n=32)
All patients (N=73)
16 (84.2)
17 (77.3)
26 (81.3)
59 (80.8)
Nausea
5 (26.3)
7 (31.8)
5 (15.6)
17 (23.3)
Pyrexia
2 (10.5)
8 (36.4)
4 (12.5)
14 (19.2)
Diarrhea
4 (21.1)
2 (9.1)
7 (21.9)
13 (17.8)
Fatigue
3 (15.8)
4 (18.2)
5 (15.6)
12 (16.4)
Anemia
0
5 (22.7)
6 (18.8)
11 (15.1)
3 (15.8)
3 (13.6)
5 (15.6)
11 (15.1)
0
6 (27.3)
4 (12.5)
10 (13.7)
Decreased appetite
1 (5.3)
4 (18.2)
5 (15.6)
10 (13.7)
Dyspnea
4 (21.1)
5 (22.7)
1 (3.1)
10 (13.7)
Constipation
3 (15.8)
1 (4.5)
5 (15.6)
9 (12.3)
Cough
1 (5.3)
7 (31.8)
1 (3.1)
9 (12.3)
Febrile neutropenia
3 (15.8)
4 (18.2)
2 (6.3)
9 (12.3)
Leukocytosis
2 (10.5)
4 (18.2)
3 (9.4)
9 (12.3)
Thrombocytopenia
0
5 (22.7)
4 (12.5)
9 (12.3)
Neutropenia
0
2 (9.1)
6 (18.8)
8 (11.0)
Sepsis
3 (15.8)
1 (4.5)
4 (12.5)
8 (11.0)
Vomiting
2 (10.5)
3 (13.6)
3 (9.4)
8 (11.0)
0
2 (9.1)
5 (15.6)
7 (9.6)
1 (5.3)
2 (9.1)
4 (12.5)
7 (9.6)
Any AE, n (%)
Most common AEs, n (%)
Peripheral edema
Asthenia
Blood bilirubin increased
Mucosal inflammation
 Notable Grade ≥3 AEs (≥5%): petechiae (7%), pneumonia (7%), respiratory
failure (6%), tumor lysis syndrome (6%)
24
PK/PD Analysis

Excellent exposure to AG-221

High accumulation after multiple doses

Mean plasma half-life > 40 hours
Plasma AG-221 exposure

Sustained plasma 2-HG inhibition after
multiple doses
–
Up to 98% in IDH2-R140Q subjects
Plasma 2-HG inhibition in
IDH2-R140Q subjects
25
Best Overall Response by Cumulative Daily Dose*
≤75 mg
(n=9)
100 mg
(n=14)
≥150 mg
(n=22)
Total
(n=45 efficacy evaluable)
CR
3
3
-
6
CRp
1
1
2
4
mCR
-
2
2
4
CRi
-
-
1
1
PR
-
3
7
10
SD
5
3
9
17
PD
-
1
1
2
Disease Not
Evaluable
-
1
-
1
Overall
Response
Rate**
4/9 (44%)
9/14 (64%)
12/22 (55%)
25/45 (56%) 95% CI (40%, 70%)
CR = complete response
CRp = complete response, incomplete platelet recovery
Marrow CR = ≤5% blasts in BM; no hematological recovery
CRi = complete response, incomplete hematologic recovery
PR = partial response
SD = stable disease
PD = progressive disease
* Includes patients with a Day 28 response assessment as of October 1, 2014. Excludes 12 on-going
patients with Day 28 not yet available and 16 patients off study without a Day 28 assessment.
** ORR = CR + CRp + mCR + CRi + PR
26
Duration of Treatment and Best Overall Response
N = 25 responders
Estimate Duration of Response: 3-month 90%*
All responding patients on study treatment as of 1 October 2014 *censored at last response assessment
27
Patient with a Partial Remission
 69 year old diagnosed with AML with an IDH2 R140Q mutation
 Induction chemotherapy with 7+3  Persistent Disease  Started AG-221
 Patient on study for > 5 months and now in CR
Cycle 2, Day 1 12% Blasts
Screening 44% Blasts
Hgb
Platelets
ANC
Hgb
Platelets
ANC
10.9
29
0.1
11.2
106
1.3
28
Conclusions
 AG-221 is well tolerated in patients with advanced hematologic
malignancies.
 2-HG inhibition of >90% in patients with an IDH2-R140 mutation.
 Consistent with preclinical models, AG-221 treatment leads to 2-HG
lowering and differentiation of leukemic blasts cells.
 Overall response rate is 25/45 (56%) including 6 complete
remissions.
– Responses are durable, with a duration on study as long as 8+ months.
 Dose expansion at 100 mg PO QD in 4 cohorts of 25 patients in AML
and advanced hematologic malignancies each initiated in October
2014.
 These data provide continued validation of mutant IDH2 as a
therapeutic target in AML and MDS.
29
Acknowledgements
We would like to thank the principal
investigators, their institutions and most
importantly the patients who volunteered to
take part in this study.
30
CHRIS BOWDEN, M.D.
Chief Medical Officer
Review of AG-348 clinical development
31
Two Abstracts Accepted for Poster Presentation
Related to AG-348
Topic/Date
AG-221: Oral Presentation
December 7, 4:30 p.m. PST
AG-221: Poster Presentation
Monday, December 8
AG-221: Poster Presentation
Monday, December 8
AG-120: Poster Presentation
Monday, December 8
AG-348: Poster Presentation
Monday, December 8
AG-348: Poster Presentation
Monday, December 8
Lead Author
Title
No.
Eytan Stein
AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the
IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a
Phase I Study in Patients with IDH2 Mutation Positive Advanced
Hematologic Malignancies
#115
Bin Fan
Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD)
Relationship of an Oral, Selective, First-in-Class, Potent IDH2
Inhibitor, AG-221, from a Phase 1 Trial in Patients with Advanced
IDH2 Mutant Positive Hematologic Malignancies
#3737
Cyril Quivoron
AG-221, an Oral, Selective, First-in-Class, Potent IDH2R140Q Mutant Inhibitor, Induces Differentiation in a Xenotransplant
Model
#3735
AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant
IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation
in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient
Samples Treated Ex Vivo
#3734
Phase I Single (SAD) and Multiple Ascending Dose (MAD) Studies of
the Safety, Tolerability, Pharmacokinetics (PK) and
Pharmacodynamics (PD) of AG-348, a First-in-Class Allosteric
Activator of Pyruvate Kinase-R, in Healthy Subjects
#4007
Erica Hansen
Hua Yang
Charles Kung
AG-348 Activation of Pyruvate Kinase in Vivo Enhances Red Cell
Glycolysis in Mice
Abstracts are available online on the ASH conference website: ash.confex.com/ash/2014/webprogram/start.html
#4010
32
Pyruvate Kinase (PK) Deficiency:
Rare Hematological Genetic Disorder
Disease Characteristics



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
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 & high rate of hemolysis in red cells

Agios has developed AG-348, a small molecule activator that restores activity of mutant PKR
33
Disease Progression from Infants to Adults
Adults
Adolescents
Infants
Iron Overload
Splenectomy
Jaundice
Pyruvate kinase deficiency is the most common enzyme abnormality of
the glycolytic pathway
34
Majority of Patients Have Moderate to Severe Disease
Adult and Pediatric Diagnosed PK Deficiency Population
Mild
(20 – 30%)
Annual
Transfusions
0
2
4
6
8
Moderate
(20 – 30%)
10
<1Transfusions Per Year
• Transfusion typically
required during
stressors: pregnancy
or infection
Description
• Patients are often
diagnosed in 30s and
40s after suffering
from aplastic crisis
> 12
0
2
4
6
8
Severe
(40 – 50%)
10
> 12
1 – 4 Transfusions Per Year
• Severity and symptoms
range
• Diagnosed at all ages
• Seek treatment and
diagnosis when
intolerant of low Hb
Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research
0
2
4
6
8
10
> 12
>4 Transfusions Per Year
• Present at an early age
and diagnosed in
childhood
• Require aggressive
blood transfusion
management
• Disease severity may
attenuate
Hb: Hemoglobin.
35
Red Blood Cells are Highly Dependent on Glycolysis
for ATP Generation
Normal Red Cell
Glycolysis
PKR
PK Deficient Red Cell
Glycolysis
mPKR
ATP
ATP
 PKR mutations lead to low pyruvate kinase activity and ATP levels
 Low ATP levels result in decreased red cell life span, hemolysis and anemia
36
AG-348 Restores PKR Activity and Corrects the
Metabolic Deficiency
PK Deficient Red Cell
PK Deficient Red Cell + AG-348
Glycolysis
Glycolysis
mPKR + AG 348
mPKR
ATP
ATP
 PKR mutations lead to low pyruvate kinase activity and ATP levels
 Low ATP levels result in decreased red cell life span, hemolysis and anemia
37
Estimated PK Deficiency Patient Population
(U.S. and EU5)
Similar to Other Rare Genetic Diseases, PK Deficiency is Largely Undiagnosed
Estimate
Total U.S. and EU5 Population
(~32 K)
Estimates based on
genetic modeling
5 – 10% diagnosed with PK deficiency
Diagnosed Patients
(~2.4 K)
.
Mild
Moderate
Severe
(20 – 30%)
(20 – 30%)
(40 – 50%)
Availability of a therapy may increase awareness and willingness to diagnose patients
Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research
38
AG-348: Clinical Development Status
AG-348: Profile




Activator of the PK enzyme
Orally dosed
Corrects underlying metabolic defect in patient blood ex vivo
Agios has WW rights
Status Today
 Single ascending dose (SAD) study in healthy volunteers

Dosing completed; met primary endpoint
 Multiple ascending dose (MAD) study in healthy volunteers ongoing
 Enrollment complete; met primary endpoint
 Phase 2 start-up activity initiated
 Expect to initiate trial in first half of 2015
 First data from healthy volunteer studies at ASH 2014
39
Robust Suite of Metabolic Biomarkers in Place for
Healthy Volunteer and Patient Trials
Glucose
FBP
Pharmacodynamic
Biomarkers
1,3-DPG
2,3-DPG
ATP & 2,3-DPG
levels
3-PG
Glycolytic Flux
PEP
PKR `
Ex Vivo PKR
Activity Assay
AG-348
ATP
Pyruvate
Source: Kung, ASH poster 2013
40
AG-348 Restores Metabolite Levels in PK Deficient
Patient Blood to That of Normal Red Cells Ex Vivo
Patient A
(R510Q/G511R)
Patient B
Patient C
(R486W/D390N) (A495V/E241stop)
DMSO
AG-348 (2 uM)
Glucose
1,3-DPG
2,3-DPG
PKR
Activity
3-PG
2,3-DPG
PEP
`
PKR
AG-348
ATP
Pyruvate
Source: Kung, ASH poster 2013
ATP
41
Phase 1 SAD/MAD Healthy Volunteer Study Designs
Study designs: SAD- 1 dose, MAD- 14-day, Twice Daily Dosing
Phase 1 SAD/MAD Healthy Volunteer Studies:
Summary of Results
SAD (Single Ascending Dose):
 Completed six cohorts (30 mg – 2500 mg
single dose) in 48 healthy volunteers:
 36 people received AG-348; 12 people
received placebo
MAD (Multiple Ascending Dose):
 Data reported from first two completed
cohorts (120mg and 360mg BID) in 16
healthy volunteers:
 Favorable safety profile thru highest dose
 No serious adverse events have been
reported in the blinded analysis
 No serious adverse events or early
withdrawals
 Enrollment complete; several additional
cohorts undergoing analysis
 Did not reach MTD
 No food effect observed
Pharmacodynamics data:
Pharmacodynamics data:
 Up to a 49% mean decrease in blood
2,3-DPG levels were observed.
 ATP levels were not predicted to change
after single dose of AG-348
 Up to a 48% mean decrease in blood
2,3-DPG levels were observed
 Up to a 52% mean increase in blood ATP
levels were observed
43
Mean Blood Concentration-time Profiles
(2,3-DPG) – SAD Study
Mean Blood Concentration-Time Profiles of 2,3-DPG Following a Single Oral Dose of AG-348
 A dose-dependent decrease in blood 2,3-DPG concentration (up to 49%) was
observed over 24 hour following AG-348 dosing
 Increasing the dose to >360 mg did not result in additional decreases in blood
2,3-DPG
44
Mean blood concentration-time profiles
(2,3-DPG) – MAD Study
Mean Blood Concentration-Time Profiles of 2,3-DPG Following Multiple Oral Doses of AG348 (cohorts 1 and 2 only)
 After dosing for 2 weeks (MAD study), 2,3-DPG levels are reduced up to 48%
 The duration of 2,3-DPG response was longer than in pre-clinical animal studies
45
ATP Levels: MAD Study
Mean Blood Concentration-Time Profiles of ATP Following Multiple Oral Doses of AG-348
(cohorts 1 and 2 only)
 Substantial increase in blood ATP levels ranging up to 52%
 Levels remained elevated through 72 hour after the last dose
 The duration of ATP elevation is much longer than observed in preclinical species
46
AG-348 Clinical Development Status
Current Status
Phase 1
Single ascending dose
(SAD) escalation
Multiple ascending dose
(MAD) escalation
Potential Future Directions
Phase 2 to Late Development
Plan to initiate Phase 2 trial in adults
with PK deficiency in first half of 2015
(Healthy Volunteer Clinical Studies)
Study Designs

Randomized double blind
placebo controlled trials

Assess safety, PK and PD

Assess activation of wild type
PK enzyme and effect on
metabolites

Guide dose range for Phase
2 study in PK deficiency
patients
Development in pediatric patients
based on POC in adults
47
Phase 2 Study in PK Deficient Patients:
Study Considerations
Global (US, EU) Single-Arm Phase 2
AG-348 Treatment
End of Treatment
Screening/Observati
on Period
Hemoglobin
Set Point
Transfusion Requirements*
Hemolysis Markers
Reticulocytes
QOL’s


PK/PD Markers
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)
48
PK Deficiency Natural History Study Designed to
Inform Registration Path
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 two years
Population:

Participants of any age with PK deficiency
As of December 2014:
 >20 sites open
 ~100 patients enrolled
Study will capture retrospective and prospective clinical data, annual quality of life
measures, and genetic diagnostic information
49
AG-348: Potential to be First Medicine to Target the
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:
- Ex-vivo proof-of-mechanism demonstrated in PK deficient patient red blood
cells
- Phase 1 safety, PK/PD data in healthy volunteers provide further support to
test AG-348 in individuals with PK deficiency
Clinical Development Goals
 Continue Natural History study to better understand the disease
 Initiate Phase 2 trial in PK deficient patients in first half 2015
50
Driven By Clear Corporate Vision and Values
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
51