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Topline results Phase 3 RISE UP in sickle cell disease November 19, 2025
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2 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 future meetings with, or submissions to, regulators, including the FDA; Agios’ plans for the development of mitapivat, tebapivat, AG-236 and AG-181; and the potential benefits of Agios’ strategic plans and focus. 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; competitive factors; 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 royalty payments related to the sale of its oncology business or any milestone or royalty payments related to its in-licensing of AG-236, 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; 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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3 Conference call agenda 1 Introduction Morgan Sanford, VP Investor Relations 2 CEO Opening Remarks Brian Goff, Chief Executive Officer 5 Clinical Implications Biree Andemariam, MD (External KOL) 6 CEO Closing Remarks and Q&A Brian Goff, Chief Executive Officer 4 Phase 3 RISE UP results Sarah Gheuens, MD, PhD, MMSc Chief Medical Officer and Head of R&D 3 Sickle Cell Disease Overview Biree Andemariam, MD (External KOL)
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4 Biree Andemariam, M.D. • Professor of Medicine and the American Red Cross Endowed Chair in Transfusion Medicine at the University of Connecticut School of Medicine • Founding Director of the New England Sickle Cell Institute (NESCI) • Director of the Connecticut Bleeding Disorders Center • Previously served as Chief Medical Officer and on the Board of Directors of the Sickle Cell Disease Association of America (SCDAA)
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5 CEO Opening Remarks Brian Goff, Chief Executive Officer
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6 Fueled by Connections to Transform Rare Diseases We build deep connections with rare disease communities, collaborating to develop and deliver innovative medicines that transform lives “The deficit is palpable in sickle cell disease. It’s glaringly apparent when I’m discussing treatment options with my provider, the limitations are clear. It’s discouraging when most days sickle cell monopolizes my life. Innovation isn’t just necessary, it’s urgent. Our community needs bold, life-changing solutions that reflect not just the complexities of this disease, but also the realities of our lives. ” - Cassandra, living with Sickle Cell Disease
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7 Sickle Cell Disease Overview KOL : Biree Andemariam, M.D.
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Sickle cell disease is a heterogenous and clinically complex disorder 8Kato et. al Nat Rev Dis Primers. 2018 Mar 15:4:18010. doi: 10.1038/nrdp.2018.10.Kavanagh et el. JAMA. 2022 Jul 5;328(1):57-68. doi: 10.1001/jama.2022.10233. Gbotosho et al. Front Immunol. 2021 Jan 27:11:561917. doi: 10.3389/fimmu.2020.561917. eCollection 2020. Sickle cell disease is a multi-system disorder affecting virtually every organ Core pathophysiology of chronic hemolytic anemia and vaso-occlusion leads to morbidity and mortality Hemolysis drives endothelial dysfunction, nitric oxide depletion and inflammatory activation – further amplifying the risk of vaso-occlusive events Patients face a lifetime of managing chronic organ damage and unpredictable acute crises
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Limited treatment options leads to complexity of care 9Dates presented in timeline reflect FDA regulatory appro val. 1. Appro ved under FDA’s accelerated appro val program. Hydroxyurea Approved 1998 L-glutamine Approved 2017 Crizanlizumab Approved 2019 Voxelotor Approved 20191 Gene therapies Approved 2023 2023 withdrawn from EU due to failed trial 2024 withdrawn globally due to safety
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What are the challenges in the treatment of hemolytic anemia and vaso-occlusive crises in Sickle Cell Disease? 10 Xu et al. Blood. 2022 May 19;139(20):3030-3039. doi: 10.1182/bloo d.2021013873. Osunkwo et al Am J Hematol. 2021 Apr 1;96(4):404-417. doi: 10.1002/ajh.26063. Epub 2021 Feb 25. Shah et al J Health Econ Outcomes Res. 2019 May 3;6(3):106-117. doi: 10.36469/9667. eCollection 2019. VOC = vaso-occlusive crisis. There is a strong need for a physiologically anchored, well-tolerated, predictable therapy Hemolytic Anemia Vaso-occlusive crises • Persistent hemolytic burden leads to anemia, vaso-occlusive risk, endothelial dysfunction and drives end-organ damage • Limited options to meaningfully improve Hb levels or reduce hemolysis • Transfusions and hydroxyurea are inadequate for large proportion of patients • VOCs remain the leading cause of acute morbidity • Palliative approach to management of acute VOCs • Existing therapies have significant limitations
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11 Topline results RISE UP Phase 3 Sarah Gheuens, Chief Medical Officer and Head of R&D
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12Mo A = mechanism of action; ATP = adenosine triph osphate; ADP = adenosine diphosphate; DPG = diphosphoglycerate; PG = phosphoglycerate; RBC = red blood cell; FBP = fructose 1,6- bispho sphate; PEP = pho sphoenolpyruvate; PK = pyruvate kinase; Hb = hemoglobin. Mitapivat MoA – increases ATP, decreases 2,3-DPG Glucose FBP 1,3-DPG 3-PG PEP Pyruvate ADP ATP PK 2,3-DPG mitapivat Decreasing 2,3-DPG reduces HbS polymerization by increasing Hb oxygenation and may inhibit the sickling process Increasing ATP enhances RBC energy metabolism and may improve membrane integrity
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13 Hb response defined as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. SCPCs defined as: an acute episode o f pain that requires medical intervention, acute chest syndro me, priapism, hepatic or splenic sequestration. 1. Actual patients enrolled = 207. 2. Randomization stratified by the number of SCPCs in the prior year (<5, ≥5) and con comitant hydroxyurea use. 3. Patients who complete the double-blind period were eligible to receive mitapivat for an additional 216 weeks in an open-label extension period. 4. Change measured from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crisis; Hb = Hemoglobin; PROMIS = patient reported o utco me measurement information system. Phase 3 RISE UP trial design SCPC inclusion criteria For inclusion in the study, participants needed to have experienced at least 2 and no more than 10 SCPCs in the 12 months prior to enrollment Randomization2 2:1 N=1981 Mitapivat 100mg BID Matched placebo Mitapivat 100mg BID Double-blind period 52 weeks Open-label extension period3 216 weeks Safety follow-up (28 days after last dose) Key secondary endpoints • Average change in Hb concentration4 • Average change in indirect bilirubin4 • Average change in PROMIS-Fatigue 13a scores4 • Annualized frequency of hospitalizations for SCPC • Average change in percent reticulocyte4 Primary endpoints • Hb response • Annualized rate of SCPCs Stratification factors 1. No. of SCPCs in prior 12 months (<5, ≥5) 2. Hydroxyurea use (yes, no)
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14 Placebo N = 69 Mitapivat 100mg BID N = 138 Total N = 207 Age (yr) n 69 138 207 Mean (SD) 31.6 (12.94) 28.9 (11.32) 29.8 (11.92) Min, Max 17, 67 16, 68 16, 68 Age category 2 (yr), n (%) <35 46 (66.7) 105 (76.1) 151 (72.9) ≥35 23 (33.3) 33 (23.9) 56 (27.1) Sex, n (%) Male 26 (37.7) 62 (44.9) 88 (42.5) Female 43 (62.3) 76 (55.1) 119 (57.5) Ethnicity, n (%) Hispanic or Latino 10 (14.5) 21 (15.2) 31 (15.0) Not Hispanic or Latino 55 (79.7) 109 (79.0) 164 (79.2) Not reported 4 (5.8) 8 (5.8) 12 (5.8) Race, n (%) Black or African American 53 (76.8) 103 (74.6) 154 (75.4) White 8 (11.6) 20 (14.5) 28 (13.5) Asian 1 (1.4) 1 (0.7) 2 (1.0) Uknown 2 (2.9) 3 (2.2) 5 (2.4) Not reported 5 (7.2) 11 (8.0) 16 (7.7) Baseline characteristics balanced in both trial arms The den ominator used to calculate percentages is N, the number of subjects in the full an alysis set within each treatment group.
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15The denominator used to calculate percentages is N, the number of subjects randomized within each treatment group. 1. Includes transfusio ns within 12 months before IC and during screening. 2. Prior disease mo difying SCD-related therapies could include hydroxyurea, crizanlizumab, L-glutamine, and voxelotor. IC = informed con sent/assent; RBC = red blood cell; SCD = sickle cell disease; SCPC= sickle cell pain crisis. Placebo N = 69 Mitapivat 100mg BID N = 138 Total N = 207 Number of SCPCs in the Prior Year (randomization stratification factor), n (%) <5 57 (82.6) 113 (81.9) 170 (82.1) ≥5 12 (17.4) 25 (18.1) 37 (17.9) Hydroxyurea use (randomization stratification factor) No 18 (26.1) 35 (25.4) 53 (25.6) Yes 51 (73.9) 103 (74.6) 154 (74.4) SCD genotyping, n (%) HbSS 57 (82.6) 119 (86.2) 176 (85.0) HbSC 2 (2.9) 4 (2.9) 6 (2.9) HbS/b0-thalassemia 5 (7.2) 4 (2.9) 9 (4.3) HbS/b0+thalassemia 3 (4.3) 4 (2.9) 7 (3.4) Other sickle cell syndrome variants 1 (1.4) 3 (2.2) 4 (1.9) Missing 1 (1.4) 4 (2.9) 5 (2.4) Transfusion burden (number of RBC units) in the 52 weeks before IC, n (%)1 0 43 (62.3) 89 (64.5) 132 (63.8) 1-2 12 (17.4) 30 (21.7) 42 (20.3) 3-5 8 (11.6) 13 (9.4) 21 (10.1) >5 6 (8.7) 6 (4.3) 12 (5.8) Prior disease modifying SCD-related therapies, n (%)2 No 16 (23.2) 34 (24.6) 50 (24.2) Yes 53 (76.8) 104 (75.4) 157 (75.8) Disease characteristics balanced in both trial arms
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16Baseline is defined as the average of all assessments during the screening period up to the rando mization date. Assessments within 8 weeks after an RBC transfusion are excluded from the baseline derivation. Placebo N=69 Mitapivat 100 mg BID N=138 Total N=207 Baseline Hemoglobin (g/L) n 68 137 205 Mean (SD) 85.39 (12.045) 86.23 (11.046) 85.95 (11.364) Min, Max 58.0, 104.5 63.5, 109.5 58.0, 109.5 Baseline hemoglobin category, n (%) <80 g/L 20 (29.0) 41 (29.7) 61 (29.5) ≥80 g/L 48 (69.6) 96 (69.6) 144 (69.6) Missing 1 (1.4) 1 (0.7) 2 (1.0) Baseline indirect bilirubin (umol/L) n 68 137 205 Mean (SD) 30.09 (25.831) 32.94 (28.946) 31.99 (27.920) Min, Max 6.3, 148.7 3.9, 140.1 3.9, 148.7 Baseline lactate dehydrogenase (U/L) n 67 136 203 Mean (SD) 449.72 (199.884) 434.40 (178.238) 439.46 (185.305) Min, Max 189.5, 1162.0 176.5, 1237.0 176.5, 1237.0 Baseline reticulocytes/erythrocytes (fraction of 1) n 63 124 187 Mean (SD) 0.0940 (0.06102) 0.0998 (0.05138) 0.0978 (0.05472) Min, Max 0.020, 0.379 0.020, 0.287 0.020, 0.379 Baseline lab characteristics consistent with hemolytic anemia profile
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171.Defined as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change measured from baseline to average of Week 24 th rough Week 52. Hb = hemoglobin; SCPC = sickle cell pain crises; PROMIS = Patient Reported Outcomes Measurement Information System. Phase 3 RISE UP statistical testing strategy Primary endpoints Key secondary endpoints hierarchy Key secondary endpoints tested at the sum of the alpha for the primary endpoint(s) met Hb response 1 α1 = 0.02 Annualized rate of SCPCs α2 = 0.03 Average change in Hb concentration2 Average change in indirect bilirubin 2 Average change in PROMIS- Fatigue 13a scores2 Annualized frequency of hospitalizations for SCPC Average change in percent reticulocyte2
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18The den ominator used to calculate percentages is N, the number of subjects in the full an alysis set within each treatment group. OLE = open-label extension. Patient disposition – low discontinuation rate Double-blind treatment period Placebo N = 69 Mitapivat 100mg BID N = 138 Total N = 207 Discontinued, n (%) 13 (18.8) 18 (13.0) 31 (15.0) 85% of patients completed the 52-week double-blind treatment period 174/176 of patients who completed the double-blind treatment period opted onto the OLE portion
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191. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from Week 24 through Week 52 compared to baseline. SCPC = sickle cell pain crises; Hb = hemoglobin, PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. Primary endpoint – Hemoglobin response1 (≥1g/dL) Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 Placebo N = 69 Mitapivat 100mg BID N = 138 Hb responders, n (%) 2 (2.9) 56 (40.6) Adjusted difference in response rate (mitapivat vs placebo), % 37.7 95% CI (28.6, 46.8) 2-side p-value <0.0001 Primary endpoint was met – 40.6% response rate was observed in mitapivat arm No conclusions regarding statistical significance can be drawn on following endpoints
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20 Primary endpoint – Annualized rate of Sickle Cell Pain Crisis Placebo N = 69 Mitapivat 100mg BID N = 138 Annualized Rate of SCPC 3.05 2.62 95% CI (2.57, 3.64) (2.29, 3.01) Rate reduction (mitapivat vs placebo) (%) 14 95% CI (-4.1, 29.2) Rate ratio (mitapivat/placebo) 0.86 95% CI (0.71, 1.04) 2-sided p-value 0.1213 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System Trend favoring mitapivat with 14% reduction in annualized rate of SCPCs vs placebo Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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21 Key secondary endpoint – Average change from baseline in Hemoglobin concentration (g/L) Placebo N = 69 Mitapivat 100mg BID N = 138 Baseline n 68 137 Mean (SD) 30.09 (25.831) 32.94 (28.946) Average of week 24 through week 52 change from baseline LS mean (SE) 0.26 (1.177) 7.69 (0.862) 95% CI (-2.06, 2.58) (5.99, 9.39) Difference in LS Mean (SE) (mitapivat - placebo) 7.43 (1.309) 95% CI (4.85, 10.01) 2-sided p-value <0.0001 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. Statistically significant 0.7 g/dL difference between mitapivat and placebo for the average change from baseline in Hb concentration Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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22 Waterfall plot of average change from baseline in Hemoglobin concentration from Week 24 Through Week 52 Robust and sustained Hb response in the mitapivat arm
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23 Key secondary endpoint – Average change from baseline in indirect bilirubin (µmol/L) Placebo N = 69 Mitapivat 100mg BID N = 138 Baseline n 68 137 Mean (SD) 30.09 (25.831) 32.94 (28.946) Average of week 24 through week 52 change from baseline LS Mean (SE) 0.88 (1.864) -16.03 (1.381) 95% CI (-2.79, 4.55) (-18.75, -13.31) Difference in LS Mean (SE) (mitapivat - placebo) -16.91 (2.077) 95% CI (-21.01, -12.81) 2-sided p-value <0.0001 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. Average change from baseline in indirect bilirubin was significantly reduced in mitapivat arm vs placebo Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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24 Key secondary endpoint – Average change from baseline in PROMIS-Fatigue 13a scores Placebo N = 69 Mitapivat 100mg BID N = 138 Baseline n 53 102 Mean (SD) 52.72 (10.244) 53.49 (9.833) Average of week 24 through week 52 change from baseline LS Mean (SE) -2.55 (1.190) -2.72 (0.906) 95% CI (-4.60, 0.10) (-4.51, -0.93) Difference in LS Mean (SE) (mitapivat - placebo) -0.47 (1.268) 95% CI (-2.98, 2.04) 2-sided p-value 0.7112 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. No statistically significant difference in change from baseline for PROMIS-Fatigue 13a T-scores between mitapivat and placebo Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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25 Key secondary endpoint – Annualized rate of hospitalizations for SCPC Placebo N = 69 Mitapivat 100mg BID N = 138 Annualized frequency (rate) of hospitalizations for SCPC 1.81 1.56 95% CI (1.44, 2.27) (1.31, 1.87) Rate reduction (mitapivat vs placebo) (%) 14 95% CI (-10.8, 32.7) Rate ratio (mitapivat vs placebo) (%) 0.86 95% CI (0.67, 1.11) 2-sided nominal p-value 0.2498 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. Trend in favor of mitapivat with 14% reduction in annualized rate of hospitalizations vs placebo Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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26 Key secondary endpoint – Average change from baseline in percent reticulocyte (fraction of 1) Placebo N = 69 Mitapivat 100mg BID N = 138 Baseline n 63 124 Mean (SD) 0.0940 (0.06102) 0.0998 (0.05138) Average of week 24 through week 52 change from baseline LS Mean (SE) -0.0013 (0.00499) -0.0236 (0.00367) 95% CI (-0.0112, 0.0085) (-0.0309, -0.0164) Difference in LS Mean (SE) (mitapivat - placebo) -0.0223 (0.00536) 95% CI (-0.0334, -0.0112) 2-sided nominal p-value 0.0001 1. Defin ed as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 co mpared to baseline. 2. Change from baseline to average of Week 24 through Week 52. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Repo rted Outcomes Measurement Info rmation System. Percent reticulocytes substantially decreased from baseline in the mitapivat arm vs placebo Primary endpoints Hb Response1 Annualized rate of SCPCs Key secondary endpoints Average change in Hb concentration2 Average change in indirect bilirubin2 Average change in PROMIS-Fatigue 13a scores2 Annualized rate of hospitalizations for SCPC Average change in percent reticulocyte2 No conclusions regarding statistical significance can be drawn on following endpoints
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27 Hemoglobin responders – Substantial clinical benefit observed in SCPC-related endpoints and PROMIS –Fatigue1 1. Post-hoc analyses. 2. Change from baseline to average of Week 24 through Week 52. 3. 40.6% of patients in mitapivat arm achieved Hb response, defined as ≥1.0 g/dL increase in average Hb fro m Week 24 through Week 52 compared to baseline. SCPC = sickle cell pain crises; Hb = hemoglobin; PROMIS = Patient Reported Outcomes Measurement Information System. 1.6 g/dL mean increase from baseline in Hb concentration 2 observed in Hb-responders3 in mitapivat arm Annualized rate of SCPC Annualized rate of hospitalizations for SCPC Average change from baseline in PROMIS-Fatigue 13a scores2 Hb-responder 2.20 (1.78, 2.71) 1.16 (0.87, 1.55) -5.19* (-7.92, -2.46) Hb Non-responder 2.98 (2.52, 3.53) 1.76 (1.41, 2.20) -2.55 (-4.94, -0.17) Rate ratio 0.74 (0.58, 0.94) Rate ratio 0.66 (0.48, 0.91) * ≥4.1 decrease clinically meaningful34% reduction26% reduction
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28The den ominator used to calculate percentages is N, the number of subjects in the safety analysis set within each treatment gro up. TEAE = treatment-emergent adverse event. Overall summary of safety Number (%) of Subjects with Placebo N=69 Mitapivat 100mg BID N=138 Any TEAEs 68 (98.6) 134 (97.1) Grade ≥ 3 TEAEs 28 (40.6) 46 (33.3) Treatment-related TEAEs 20 (29.0) 42 (30.4) Grade ≥ 3 treatment-related TEAEs 2 (2.9) 7 (5.1) Serious TEAEs 20 (29.0) 28 (20.3) Serious treatment-related TEAEs 0 1 (0.7) TEAEs leading to discontinuation of study drug 2 (2.9) 6 (4.3) TEAEs leading to dose reduction 0 7 (5.1) TEAEs leading to interruption of study drug 1 (1.4) 5 (3.6) TEAEs leading to death 1 (1.4) 2 (1.4) Treatment-related TEAEs leading to death 0 0 Favorable safety profile observed in RISE UP Phase 3 was consistent with that observed in prior mitapivat sickle cell disease trials Not all deaths are captured as adverse events per protocol. There was one additional death in the placebo group and one in the mitapivat arm, bringing the total fatal cases to 3 (2.2%) in mitapivat and 2 (2.9%) in placebo. There were also 2 deaths in the screening period.
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29 1. (ALT or AST) >5xULN, ALT or AST >3x ULN + Total Bilirubin >2x ULN (or >2x Baseline if total bilirubin is >ULN at baseline) + direct bilirubin >50%. 2. Any liver test abnormality that led to study drug modification, in terruptio n, or discontinuation. SCD = sickle cell disease; HCI = hepatocellular injury. Summary of key observations related to liver events No similar cases of drug-induced HCI as were observed in thalassemia – no change to safety profile • Patients with SCD often have abnormal and fluctuating liver enzymes as part of their underlying disease • The protocol excluded patients with aspartate aminotransferase >2.5x the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5x the ULN (unless due to hepatic iron deposition) • Liver abnormalities were observed across both treatment arms • Any event that met pre-specified criteria 1 was reviewed for severity and causality for the likelihood of drug-induced liver injury, as was done for the thalassemia program • No imbalance between subjects taking mitapivat (7, 5.1%) and placebo (3, 4.3%) with values meeting the lab constellation of concurrent laboratory values with the highest sensitivity for drug -induced liver injury 2
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30SCPC = sickle cell pain crises; Hb = hemoglobin; HCI = hepatocellular injury; sNDA = supplemental new drug applicatio n; PROMIS = patient reported outcomes measurement system. Phase 3 RISE UP trial – summary and next steps Strong anti-hemolytic profile in total trial population with SCPC trend Clinically meaningful benefits in Hb-responders Favorable safety profile • 40.6% of patients achieved significant Hb response (≥1 g/dL) • Statistically significant improvement in other markers of hemolysis ― Hb concentration ― Indirect bilirubin • 1.6 g/dL mean increase from baseline in Hb concentration • Improvement in SCPC-related endpoints: ― 26% decrease in annualized rate of SCPC ― 34% reduction in annualized rate of hospitalizations for SCPC • Reduction in PROMIS-Fatigue T-score • No similar pattern of HCI as observed in thalassemia • Low discontinuation rate in the double-blind period • 174 out of 176 patients opted to rollover into open label extension Intend to submit a marketing application for mitapivat in the U.S. for sickle cell disease, after having a pre -sNDA meeting with the FDA in Q1 2026
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31 Clinical perspective KOL : Biree Andemariam, M.D.
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Phase 3 RISE UP data supportsmitapivatas meaningful potential treatment option for patients living with SCD 32SCD = Sickle Cell Disease; Hb = hemoglobin Patients living with sickle cell disease need therapies that – In Hb-responders, mitapivat showed benefit on measures related to these important factors Reduce anemia and hemolysis Reduce vaso-occlusion Lower healthcare utilization Improve fatigue Are well tolerated and safe
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33 CEO Closing Remarks Brian Goff, Chief Executive Officer
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34SCPC = sickle cell pain crises; Hb = hemoglobin; sNDA = supplemental new drug application. Phase 3 RISE UP trial – summary and next steps Intend to submit a marketing application for mitapivat in the U.S. for sickle cell disease, after having a pre-sNDA meeting with the FDA in Q1 2026 Strong anti-hemolytic profile in total population with SCPC trend Clinically meaningful benefits in Hb-responders Favorable safety profile
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35PDUFA = Prescription Drug User Fee Act ; sNDA = supplemental new drug application ; SCD = sickle cell disease; LR-MDS = lower-risk myelodysplastic syndromes; PV = polycythemia vera; PKU = phenylketonuria. Clear corporate priorities Remain committed to becoming sustainable rare disease company Maximize Mitapivat Advance pipeline Financial discipline Potential thalassemia FDA approval (PDUFA December 7 th) Preparation for potential sNDA filing in Sickle Cell Disease T ebapivat Phase 2 LR-MDS and SCD AG-236 Phase 1 PV AG-181 Phase 1 PKU Proactive steps to reduce operating expenses to extend cash runway; update to be provided early 2026 Remain committed to maximize shareholder value
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36 Q&A session
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37 Fueled by Connections to Transform Rare Diseases We build deep connections with rare disease communities, collaborating to develop and deliver innovative medicines that transform lives “Unfortunately, many people still don’t know what sickle cell disease is or how deeply it affects those living with it. It’s striking that for decades there have been so few treatment options for SCD. Surviving a stroke and multiple -organ failure in 2023 – and losing many friends to this illness – has driven me to advocate for better treatment options. ” Kyle, SCD patient and advocate