Agios Pharmaceuticals : ENERGIZE-T Phase 3 Topline Results Presentation

Topline Results:

Phase 3 ENERGIZE-T Study of

PYRUKYND ® (Mitapivat) in

Transfusion-Dependent Thalassemia

June 3, 2024

Agios conference call participants

TOPIC	PARTICIPANT
Opening Remarks	Brian Goff, Chief Executive Officer
Data Highlights from Phase 3 ENERGIZE-T Study	Jeremie Estepp, M.D., Medical Director
Regulatory Strategy in Thalassemia	Sarah Gheuens, M.D., Ph.D., Chief Medical Officer,
Head of Research and Development
Closing Remarks	Brian Goff, Chief Executive Officer
Q&A	Mr. Goff, Dr. Gheuens, 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

Data Highlights from Phase 3 ENERGIZE-T Study

Jeremie Estepp, M.D.

Medical Director

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

N = 171

2:1

randomization

100 mg BID		Placebo
	BID

24-week core period

Open-label extension (up to 5 years)

N = 240

2:1

randomization

100 mg BID		Placebo
	BID

48-week core period

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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Phase 3 ENERGIZE-T study: primary endpoint achieved

• Total of 258 patients were randomized 2:1 to 100 mg mitapivat (n=171) or placebo (n=87)
• 155 patients (90.6%) in the mitapivat arm and 83 patients (95.4%) in the placebo arm completed the 48-weekdouble-blind period of the study
• Transfusion reduction response (TRR) is defined as ≥50% reduction in transfused RBC units of ≥2 units of transfused
  RBCs in any consecutive 12-week period compared to baseline
• Treatment with mitapivat demonstrated a statistically significant transfusion reduction

response compared to placebo

Primary Endpoint	Placebo	Mitapivat 100 mg BID
N=87	N=171
TRR responders, n (%)	11 (12.6)	52 (30.4)
Adjusted difference TRR rate		17.6
(Mitapivat-Placebo), %
95% CI		(8.0, 27.2)
2-sidedp-value		0.0003

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Abbreviations: RBC = red blood cell; TRR = transfusion reduction response. Subjects withdrawn from the study before Week 12 (Day 85) are considered non-responders.

Baseline transfusion burden standardized to 12 weeks=total number of RBC units transfused during the 24-week period (168 days) before 'reference date' x12/24, where 'reference date' is the randomization data for subjects randomized and not dosed or the start of study treatment for subjects randomized and dosed.

The 95% CI and p-value are based on the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors.

ENERGIZE-T: additional results demonstrate mitapivat's durability of effect

Efficacy

Treatment with mitapivat demonstrated statistically significant improvements on all key secondary endpoints evaluating additional measures of reduction in transfusion burden:

• ≥50% reduction in transfused RBC units in any consecutive 24-week period through week 48 compared to baseline
• ≥33% reduction in transfused RBC units from week 13 through week 48 compared to baseline
• ≥50% reduction in transfused RBC units from week 13 through week 48 compared to baseline

Transfusion independence

• A higher proportion of patients in the mitapivat arm (9.9%) compared to the placebo arm (1.1%) achieved the secondary endpoint of transfusion independence (transfusion-free for ≥8 consecutive weeks through week 48)

Safety

• Overall, during the 48-weekdouble-blind period, incidence of adverse events (AEs) was similar across mitapivat and placebo arms
• In the mitapivat arm, 5.8% of the patients experienced an AE leading to discontinuation, compared to 1.2% of patients in the placebo arm

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Regulatory Strategy in Thalassemia

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

Chief Medical Officer, Head of Research and Development

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.

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