Agios Pharmaceuticals : EHA 2024 Investor Breakout Session Slides

Agios at EHA 2024

June 16, 2024

Agios conference call participants

TOPIC	PARTICIPANT
Introduction	Chris Taylor, VP Investor Relations and Corporate
Communications
Opening Remarks	Brian Goff, Chief Executive Officer
Mitapivat Phase 3 Development Program in Thalassemia	Sarah Gheuens, M.D., Ph.D., Chief Medical Officer, Head of
Research and Development
	Ali Taher, M.D., Ph.D., Professor of Medicine, Hematology &
ENERGIZE Data Overview	Oncology and Director - Naef K. Basile Cancer Institute,
	American University of Beirut Medical Center
ENERGIZE Quality of Life and Patient-Reported Outcome	Kevin Kuo, M.D., MSc, FRCPC; Division of Hematology,
Measures	University of Toronto
Closing Remarks	Brian Goff, Chief Executive Officer
Q&A	All speakers, Cecilia Jones (CFO), and Tsveta Milanova (CCO)

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Forward-looking statements

This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of mitapivat, Agios' plans for the future clinical development of mitapivat in alpha- and beta thalassemia; Agios' plans for future regulatory submissions; and Agios' strategic plans and prospects. The words

"anticipate," "expect," "goal," "hope," "milestone," "opportunity," "plan," "potential," "possible," "strategy," "will," "vision," and similar expressions are intended to

identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios' product candidates will successfully continue. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this presentation and various remarks we make during this presentation could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios' business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios' ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials;

unplanned cash requirements and expenditures; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product

candidates it is developing; Agios' ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of Agios' oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios' cash and cash equivalents; competitive factors; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios' public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this presentation and various remarks we make 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 otherwise, except as required by law.

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Opening Remarks

Brian Goff

Chief Executive Officer

Mitapivat Phase 3 Development Program in Thalassemia

Sarah Gheuens, M.D., Ph.D.

Chief Medical Officer, Head of Research and Development

PYRUKYUND® (mitapivat) is an oral, small molecule allosteric activator of pyruvate kinase with the potential to correct RBC metabolism

					Glycolysis
					Glucose
Hexokinase (HK) catalyzes the			HK
		Glucose-6-Phosphate
first step in glycolysis
					Frucose-6-Phosphate
					FBP
2,3-DPG is an important					1,3-DPG
regulator of the oxygen		2,3-DPG	3-PG
affinity of Hb3
					PEP

ADP

PK activation is expected to correct RBC metabolism by:

Normalizing the PK/HK ratio -

Decreased PK/HK ratio is observed in MDS

Reducing 2,3-DPG levels -

Elevated 2,3-DPG levels are associated with RBC sickling in

SCD

Increasing RBC energy production (ATP)

PK catalyzes the final step in glycolysis to generate ATP, which is essential for RBC function and stability1,2

PKR

ATP

Pyruvate

PK

Activator

- Reduced

ATP production and/or increased ATP demand is observed in PKD, thalassemia, SCD, and LR-MDS

ADP = adenosine diphosphate; ATP = adenosine triphosphate; DPG = diphosphoglycerate; FBP = fructose bisphosphate; m = mutant; PEP = phosphoenolpyruvate; PG = phosphoglycerate; PK = pyruvate

6 kinase; PKR = RBC-specific PK; RBC = red blood cell

1. Kung C et al. Blood 2017;130:1347; 2. Valentini G et al. J Biol Chem 2002;277:23807; 3. Rab MAE et al. Blood 2021;137:2997-3001

Two global, Phase 3, randomized controlled trials of PYRUKYND® in thalassemia encompass broad range of thalassemia patients

	N = 171					N = 240
	2:1				2:1
	randomization					randomization
100 mg BID			Placebo		100 mg BID				Placebo
		BID					BID
24-week core period			48-week core period

Open-label extension (up to 5 years)

Open-label extension (up to 5 years)

Primary endpoint

• Mean Hb ↑
  ≥ 1 g/dL from baseline

Secondary endpoints

• Fatigue, additional measures of Hb ↑, hemolysis, patient- reported outcomes, physical activity, iron metabolism, safety, PK/PD

Key inclusion criteria

• ≥ 18 years
• β-thalassemia± α-globin mutations, HbE β-thalassemia, or α-thalassemia (HbH disease)
• Non-transfusion-dependentdefined as ≤5 RBC units during the 24-week period before randomization and no RBC transfusions ≤8 weeks prior
• Hb ≤ 10.0 g/dL

Primary endpoint

• 50% reduction in transfusion burden in any 12-week rolling period

Secondary endpoints

• Additional measures of transfusion reduction, safety, PK/PD

Key inclusion criteria

• ≥ 18 years
• β-thalassemia± α-globin mutations, HbE β-thalassemia, or α-thalassemia (HbH disease)
• Transfusion-dependentdefined as 6 to 20 RBC units transfused and ≤6-weektransfusion-free period during the 24-week period before randomization

BID = twice daily; Hb = hemoglobin; HbE = hemoglobin E; HbH = hemoglobin H; PK = pharmacokinetics; PD = pharmacodynamics.

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Based on strength of two pivotal Phase 3 trials, Agios has potential to deliver the first therapy for all thalassemia subtypes

Mitapivat Thalassemia			Mitapivat Thalassemia
Phase 3 program			Phase 3 program
		~67%	~33%
		NON-TRANSFUSION	TRANSFUSION
•	Alpha- and Beta-	DEPENDENT (NTDT)	DEPENDENT (TDT)	•	Alpha- and Beta-
	thalassemia Non-	(~4K ADULTS)	(~2K ADULTS)		thalassemia
	transfusion dependent		U.S.		Transfusion dependent
	patients				patients
•	Primary endpoint			•	Primary endpoint
	achieved: Hemoglobin				achieved: Transfusion
	(Hb) response	~67%	NO APPROVED		Reduction Response
		THERAPIES
	Data announced		IN THE U.S. ~67%		Data announced
	January 3, 2024				June 3, 2024

Beta-THAL prevalence: HEOR Global THAL Epidemiology SLE (XCENDA, 2021); US: Paramore, et.al; DE: Borchert, et.al; Alpha-THAL prevalence: Agios internal estimates; LEK Analysis | Beta-THAL TD/NTD split: Thuret, et.al., Haematologica 2010; Magnolia TPP MR, April 2020 | Alpha-THAL TD/NTD split; Taher, et.al., Vox Sanguinis, 2015; Magnolia TPP MR, April 2020.

8 PYRUKYND® is under investigation for thalassemia and is not approved anywhere for that use.

ENERGIZE Data Overview

Ali Taher, M.D., Ph.D.

Professor of Medicine, Hematology & Oncology and Director - Naef K. Basile Cancer Institute, American University of Beirut Medical Center

Hb, hemoglobin; HbC, hemoglobin C; HbE, hemoglobin E; HbH, hemoglobin H; HbS, hemoglobin S; NTDT, non-transfusion-dependent thalassemia; RBC, red blood cell	10
Kuo KHM et al. Hemasphere 2022;6:23-4.