PKM2 x PKLR

CAMBRIDGE, Mass., Nov. 10, 2022 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in the field of cellular metabolism pioneering therapies for rare and genetically defined diseases, today announced that the European Commission (EC) has granted marketing authorization for PYRUKYND® for the treatment of PK deficiency in adult patients. PYRUKYND® is a first-in-class, oral PK activator and the first approved disease-modifying therapy for patients in the EU with this rare, debilitating, lifelong hemolytic anemia. “People with PK deficiency suffer from a lifetime of chronic anemia, associated complications and symptoms that can be detrimental to their work, family and social lives,” said Andreas Glenthøj, hematologist and head of the Danish Center for Hemoglobinopathies at Rigshospitalet, and associate professor at the University of Copenhagen. “PYRUKYND® offers new hope for this community, and I am honored to have contributed to the research efforts that enabled the approval of the first therapy for adults with PK deficiency in the EU.” “With today’s EU approval, we are proud to expand the positive impact of PYRUKYND® for more patients with PK deficiency around the globe,” said Brian Goff, chief executive officer at Agios. “We are dedicated to continued innovation on behalf of people with rare and genetically defined diseases, and are working to further expand the impact of PYRUKYND® through our ongoing investigational pivotal programs in pediatric PK deficiency, thalassemia and sickle cell disease.” Agios is providing access to PYRUKYND® for the treatment of PK deficiency in adults receiving care in the EU through a global managed access program. More details about this program can be found on Agios.com. PYRUKYND® was previously granted orphan drug designation by the EMA, which is maintained at the time of EU marketing authorization. Agios has also applied for a marketing authorization for PYRUKYND® as a treatment for PK deficiency in adult patients in Great Britain under the European Commission Decision Reliance Procedure (ECDRP) with the Medicines and Healthcare Products Regulatory Agency (MHRA). PYRUKYND® was approved by the U.S. Food and Drug Administration (FDA) in February 2022 for the treatment of hemolytic anemia in adults with PK deficiency. PYRUKYND® Safety and Efficacy Data The EU marketing authorization was based on results from two pivotal studies, ACTIVATE and ACTIVATE-T, conducted in not regularly transfused and regularly transfused adults with PK deficiency, respectively. The Phase 3 ACTIVATE trial of mitapivat achieved its primary endpoint. PYRUKYND® demonstrated a statistically significant increase in hemoglobin in patients with PK deficiency who are not regularly transfused. 40 percent (n=16) of patients randomized to PYRUKYND® achieved a hemoglobin response, compared to 0 patients randomized to placebo (2-sided p<0.0001). Statistically significant improvements compared to placebo were also demonstrated for all pre-specified secondary endpoints, including markers of hemolysis and ineffective erythropoiesis. The Phase 3 ACTIVATE-T trial of mitapivat achieved its primary endpoint. Mitapivat demonstrated a statistically significant and clinically meaningful reduction in transfusion burden for patients who are regularly transfused. 37 percent (n=10) of patients achieved a transfusion reduction response, defined as a ≥33% reduction in transfusion burden in the 24-week fixed dose period compared with individual historical transfusion burden standardized to 24 weeks. 22 percent (n=6) of patients were transfusion-free during the fixed-dose period. The most common adverse reaction across both studies was insomnia (19.4%), and the most common laboratory abnormalities observed were oestrone decreased (males) (43.5%) and oestradiol decreased (males) (8.7%). A full analysis of these data was presented at the 2021 European Hematology Association (EHA) Virtual Congress. Results from ACTIVATE were published in the New England Journal of Medicine, and results from ACTIVATE-T were published in The Lancet Haematology. An ongoing extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T is designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat; initial results from the extension study were presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition. The company is enrolling pediatric PK deficiency patients in two pivotal studies – ACTIVATE-kids and ACTIVATE-kidsT – in patients who are not regularly transfused and who are regularly transfused, respectively. Agios also continues to advance its Phase 3 ENERGIZE and ENERGIZE-T studies in non-transfusion-dependent and transfusion-dependent adults with thalassemia, respectively, as well as its Phase 2/3 RISE UP study in sickle cell disease. About PK Deficiency Pyruvate kinase (PK) deficiency is a rare, inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutation in the PKLR gene can cause a deficit in energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate (ATP) levels and a build-up of upstream metabolites, including 2,3-DPG (2,3-diphosphoglycerate). PK deficiency is associated with serious complications, including gallstones, pulmonary hypertension, extramedullary hematopoiesis, osteoporosis and iron overload and its sequelae, which can occur regardless of the degree of anemia or transfusion burden. PK deficiency can also cause quality of life problems, including challenges with work and school activities, social life and emotional health. Current management strategies for PK deficiency, including red blood cell transfusions and splenectomy, are associated with both short- and long-term risks. For more information, please visit www.knowpkdeficiency.com. About PYRUKYND® (mitapivat) PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, and for the treatment of PK deficiency in adult patients in the European Union. IMPORTANT SAFETY INFORMATION Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath. Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Drug Interactions: Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage. Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. Please see full Prescribing Information and Summary of Product Characteristics for PYRUKYND. About Agios Agios is a biopharmaceutical company that is fueled by connections. The Agios team cultivates strong bonds with patient communities, healthcare professionals, partners and colleagues to discover, develop and deliver therapies for rare and genetically defined diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's leadership in the field of cellular metabolism, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency and MDS-associated anemia. In addition to its clinical pipeline, Agios has multiple investigational therapies in preclinical development and an industry-leading research team with unmatched expertise in cellular metabolism and genetics. For more information, please visit the company’s website at www.agios.com.

– Long-term Data for PYRUKYND® (mitapivat) in Adults with Pyruvate Kinase (PK) Deficiency and Adults with Thalassemia Demonstrate Sustained Improvement in Hemoglobin, Markers of Hemolysis and Other Disease Impacts – – New Data from Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Cohorts of Phase 1 Study of AG-946 in Healthy Volunteers Support Profile as Potent PK Activator and Initiation of Phase 2 Study in Myelodysplastic Syndromes (MDS)-associated Anemia – – Agios to Host Live and Webcast Investor Event on Dec. 12, 2022, at 7 a.m. ET – CAMBRIDGE, Mass., Nov. 03, 2022 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat rare and genetically defined diseases, today announced that a broad set of clinical and translational data from its programs in hemolytic anemias, including PK deficiency, thalassemia and sickle cell disease, will be presented at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition, to be held Dec. 10-13, 2022, in New Orleans. In total, 22 abstracts led by Agios and external collaborators will be presented. The accepted abstracts are listed below and are available online on the ASH conference website at https://www.hematology.org/meetings/annual-meeting/abstracts. PK DeficiencyData to be presented highlight that long-term treatment with PYRUKYND® in adults with PK deficiency is associated with sustained clinical benefits, including improvements in hemoglobin, iron overload, transfusion burden and patient-reported outcomes. In addition, Agios is presenting data supporting its pediatric PK deficiency program, including characterization of disease complications and co-morbidities in pediatric patients. Oral Presentation: Title: Long-term Improvements in Patient-reported Outcomes in Patients with Pyruvate Kinase Deficiency Treated with MitapivatPresentation Time: Sunday, Dec. 11, 2022, at 9:45 a.m. CT Oral Abstract Session: 904. Outcomes Research—Non-malignant Conditions: Classical Hematology: From Horses to ZebrasAbstract: 506Presenter: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada Poster Presentations: Title: Next Generation Sequencing for the Diagnosis of Hereditary Hemolytic Anemias Including Pyruvate Kinase Deficiency: Report from a No-cost Diagnostic ProgramPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 1010Lead Author: Jorune Balciuniene, PerkinElmer Genomics Title: Mitapivat Improves Iron Overload in Patients with Pyruvate Kinase DeficiencyPoster Session: 102. Iron Homeostasis and Biology: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 1021Lead Author: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada Title: Long-term Hemoglobin Response and Reduction in Transfusion Burden Are Maintained in Patients with Pyruvate Kinase Deficiency Treated with MitapivatPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2328Lead Author: Rachael F. Grace, M.D., MMSc, Dana-Farber/Boston Children's Cancer and Blood Disorders Center Title: Comorbidities and Complications in Pediatric Patients with Pyruvate Kinase Deficiency Enrolled in the Peak Registry / Peak Pediatric ComorbiditiesPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2329Lead Author: Rachael F. Grace, M.D., MMSc, Dana-Farber/Boston Children's Cancer and Blood Disorders Center Title: ACTIVATE-KidsT: Mitapivat in Children with Pyruvate Kinase Deficiency Who Are Regularly TransfusedPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2330Lead Author: Rachael F. Grace, M.D., MMSc, Dana-Farber/Boston Children's Cancer and Blood Disorders Center Title: Age of Onset of Complications in Patients with Pyruvate Kinase Deficiency: Analysis from the Peak RegistryPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2332Lead Author: Andreas Glenthøj, M.D., Ph.D., Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, DenmarkTitle: ACTIVATE-Kids: Mitapivat in Children with Pyruvate Kinase Deficiency Who Are Not Regularly TransfusedPoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2335Lead Author: Rachael F. Grace, M.D., MMSc, Dana-Farber/Boston Children's Cancer and Blood Disorders Center Title: Mitapivat Improves Markers of Hemolysis and Erythropoiesis in Patients with Pyruvate Kinase Deficiency Irrespective of Hemoglobin ResponsePoster Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster IIISession Date and Time: Monday, Dec. 12, 2022, 6-8 p.m. CTAbstract: 3644Lead Author: Hanny Al-Samkari, M.D., Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Publication Only: Title: The Launch of Two Sub-studies of the Peak Registry, A Global, Longitudinal Study of Pyruvate Kinase DeficiencyAbstract: 4960Lead Author: Carl Lander, Thrive with Pyruvate Kinase Deficiency Patient Organization ThalassemiaLong-term Phase 2 data for PYRUKYND® in adults with alpha- or beta-thalassemia treated for up to 72 weeks show sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis. Additional data underscore the significant disease burden across both alpha- and beta-thalassemia. Poster Presentations: Title: Mitapivat Improves Markers of Erythropoietic Activity in Long-term Study of Adults with Alpha- or Beta-non-transfusion-dependent ThalassemiaPoster Session: 112. Thalassemia and Globin Gene Regulation: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 1030Lead Author: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada Title: Characterizing the Clinical, Health-related Quality of Life and Economic Burden of Alpha-thalassemia: A Systematic Literature Review and Evidence Gaps AssessmentPoster Session: 112. Thalassemia and Globin Gene Regulation: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 1036Lead Author: Khaled M. Musallam, M.D., Ph.D., Thalassemia Center, Burjeel Medical City, Abu Dhabi, United Arab Emirates Title: Clinical Burden of Alpha- and Beta-thalassemia Compared to Matched Controls in the Real-world SettingPoster Session: 112. Thalassemia and Globin Gene Regulation: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CTAbstract: 2351Lead Author: Arielle L. Langer, M.D., MPH, Division of Hematology, Brigham & Women’s Hospital Sickle Cell DiseaseData to be presented continue to highlight that PK activation may be a promising therapeutic approach for patients with sickle cell disease. Oral Presentations: Title: Effects of Pyruvate Kinase Activators on Red Blood Cell Rheology, Sickling and Senescence in Sickle Cell DiseasePresentation Time: Saturday, Dec. 10, 2022, at 9:45 a.m. CTOral Abstract Session: 114. Hemoglobinopathies, Excluding Thalassemia: Clinical and Epidemiological: Novel TherapiesAbstract: 8Presenter: Philippe Joly, Ph.D., Laboratory of Biochemistry and Molecular Biology, UF Biochemistry of Red Blood Cell Diseases, Est Center of Biology and Pathology, Hospices Civils de Lyon, Lyon France Title: Untargeted Metabolomics in Dried Blood Spots of Patients with Sickle Cell Disease Treated with the Pyruvate Kinase Activator MitapivatPresentation Time: Saturday, Dec. 10, 2022, at 10 a.m. CTOral Abstract Session: 114. Hemoglobinopathies, Excluding Thalassemia: Clinical and Epidemiological: Novel TherapiesAbstract: 9Presenter: Myrthe J. van Dijk, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands Title: AG-946 Normalizes Glycolysis and Improves Red Cell Indices in a Humanized Sickle Cell Mouse ModelPresentation Time: Sunday, Dec. 11, 2022, at 9:30 a.m. CTOral Abstract Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Targeting the Red Blood Cell: Novel Therapeutic Approaches in Sickle Cell DiseaseAbstract: 391Lead Author: Rohitash Jamwal, Ph.D., Agios Pharmaceuticals Title: PKLR Variants Associated with Acute Pain in Sickle Cell Disease Influence ATP Concentrations in Red Blood CellsPresentation Time: Sunday, Dec. 11, 2022, at 10 a.m. CTOral Abstract Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Targeting the Red Blood Cell: Novel Therapeutic Approaches in Sickle Cell DiseaseAbstract: 393Presenter: Xunde Wang, Ph.D., Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health Poster Presentations: Title: The Pyruvate Kinase Activator Mitapivat Improves Red Blood Cell Deformability and Sickling Kinetics in Adult Patients with Sickle Cell DiseasePoster Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CT Abstract: 1044Lead Author: Maureen Lundt, NHLBI / NIH, Bethesda, Maryland, United States Title: Feasibility of Near-infrared Spectroscopy for Monitoring Hemodynamic Changes in Sickle Cell Disease Patients Treated with MitapivatPoster Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CT Abstract: 1053 Lead Author: Timothy Quang, National Institute of Child Health and Human Development Title: Activating Pyruvate Kinase Improves Red Blood Cell Integrity by Reducing Band3 Tyrosine PhosphorylationPoster Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Poster IISession Date and Time: Sunday, Dec. 11, 2022, 6-8 p.m. CT Abstract: 2367Lead Author: Kang Le, Ph.D., National Institutes of Health AG-946New clinical data from the Phase 1 healthy volunteers study of Agios’ novel PK activator, AG-946, support the initiation of a Phase 2a/2b study in lower-risk myelodysplastic syndromes. Poster Presentations: Title: A Phase 2a/2b Multicenter Study of AG-946 in Patients with Anemia Due to Lower-risk Myelodysplastic SyndromesPoster Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster ISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 1773Lead Author: Hanny Al-Samkari, M.D., Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Title: Results from the Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy VolunteersPoster Session: 114. Hemoglobinopathies, Excluding Thalassemia: Clinical and Epidemiological: Poster IISession Date and Time: Saturday, Dec. 10, 2022, 5:30-7:30 p.m. CTAbstract: 2383Lead Author: Xiaoshu Dai, Ph.D., Agios Pharmaceuticals Conference Call InformationAgios will host a live investor event on Dec. 12, 2022, at 7:00 a.m. ET in New Orleans to review the key clinical oral and poster presentations from this year’s ASH meeting. The event will be webcast live and can be accessed under “Events & Presentations” in the Investors and Media section of the company's website at www.agios.com. The archived webcast will be available on the company's website beginning approximately two hours after the event. About AgiosAgios is a biopharmaceutical company that is fueled by connections. The Agios team cultivates strong bonds with patient communities, healthcare professionals, partners and colleagues to discover, develop and deliver therapies for rare and genetically defined diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's leadership in the field of cellular metabolism, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency and MDS-associated anemia. In addition to its clinical pipeline, Agios has multiple investigational therapies in preclinical development and an industry-leading research team with unmatched expertise in cellular metabolism and genetics. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking StatementsThis press release contains 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 and AG-946; Agios’ plans regarding future data presentations; and the potential benefit of its strategic plans and focus. The words “anticipate,” “expect,” “intend,” “potential,” “milestone,” “goal,” “will,” “on track,” “upcoming,” 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 or its collaborators 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. Moreover, there can be no guarantee that any medicines ultimately commercialized by Agios will receive commercial acceptance. 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 press release 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 the COVID-19 pandemic 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; the failure of Agios to receive milestone or royalty payments related to the sale of its oncology business, the uncertainty of the timing of any receipt of any such payments, and the uncertainty of the results and effectiveness of the use of proceeds from the transaction with Servier ;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 maintain key collaborations; 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 press release 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. Contacts Investors:Holly Manning, 617-844-6630Senior Director, Investor RelationsHolly.Manning@agios.com Media:Jessica Rennekamp, 857-209-3286Senior Director, Corporate CommunicationsJessica.Rennekamp@agios.com

Agios Expects a Decision on the Marketing Authorization Application by the European Commission within 67 Days of the Adoption of the Positive CHMP Opinion CAMBRIDGE, Mass., Sept. 16, 2022 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism pioneering therapies for rare and genetically defined diseases, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion on September 15, 2022, recommending the granting of a marketing authorization for PYRUKYND® (mitapivat) for the treatment of pyruvate kinase (PK) deficiency in adult patients. PK deficiency is a rare, debilitating, lifelong hemolytic anemia. PYRUKYND® is a first-in-class, oral PK activator that was recently approved by the U.S. Food and Drug Administration (FDA). If approved by the European Commission (EC), PYRUKYND® will be the first approved disease-modifying therapy for European patients with PK deficiency. “The positive CHMP opinion for PYRUKYND® is a landmark event for European patients with PK deficiency, who currently have no disease-modifying treatment options,” said Eduard J. van Beers, M.D., Ph.D., hematologist and associate professor at University Medical Center Utrecht. “PK deficiency is characterized by severe symptoms and complications, regardless of transfusion status, and has a significant impact on patients’ quality of life. If approved, I look forward to having an oral medication available that has demonstrated clinically meaningful impact for patients with a range of PK deficiency symptoms and presentations.” “Today’s positive CHMP opinion is an important step toward our goal of expanding PYRUKYND® access for adults with PK deficiency around the world,” said Sarah Gheuens, M.D., Ph.D., head of R&D and chief medical officer at Agios Pharmaceuticals. “In addition to this milestone, we remain focused on our global clinical development programs for PYRUKYND® in thalassemia, sickle cell disease and pediatric PK deficiency and look forward to expanding the impact of this medication to even more patients.” PYRUKYND® was previously granted orphan drug designation by the EMA. PYRUKYND® Safety and Efficacy Data The positive CHMP opinion was based on results from two pivotal studies, ACTIVATE and ACTIVATE-T, conducted in not regularly transfused and regularly transfused adults with PK deficiency, respectively. The Phase 3 ACTIVATE trial of mitapivat achieved its primary endpoint. PYRUKYND® demonstrated a statistically significant increase in hemoglobin in patients with PK deficiency who are not regularly transfused. 40 percent (n=16) of patients randomized to PYRUKYND® achieved a hemoglobin response, compared to 0 patients randomized to placebo (2-sided p<0.0001). Statistically significant improvements compared to placebo were also demonstrated for all pre-specified secondary endpoints, including markers of hemolysis and ineffective erythropoiesis. The Phase 3 ACTIVATE-T trial of mitapivat achieved its primary endpoint. Mitapivat demonstrated a statistically significant and clinically meaningful reduction in transfusion burden for patients who are regularly transfused. 37 percent (n=10) of patients achieved a transfusion reduction response, defined as a ≥33% reduction in transfusion burden in the 24-week fixed dose period compared with individual historical transfusion burden standardized to 24 weeks. 22 percent (n=6) of patients were transfusion-free during the fixed-dose period. The most common adverse reaction across both studies was insomnia (19.4%), and the most common laboratory abnormalities observed were oestrone decreased (males) (43.5%) and oestradiol decreased (males) (8.7%). A full analysis of these data was presented at the 2021 European Hematology Association (EHA) Virtual Congress, and results from ACTIVATE were published in the New England Journal of Medicine. An extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T is ongoing and designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat; initial results from the extension study were presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition. The company is enrolling pediatric PK deficiency patients in two pivotal studies – ACTIVATE-kids and ACTIVATE-kidsT – in patients who are not regularly transfused and who are regularly transfused, respectively. Agios also continues to advance its Phase 3 ENERGIZE and ENERGIZE-T studies in not regularly transfused and regularly transfused adults with thalassemia, as well as its Phase 2/3 RISE UP study in sickle cell disease. About PK Deficiency Pyruvate kinase (PK) deficiency is a rare, inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutation in the PKLR gene can cause a deficit in energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate (ATP) levels and a build-up of upstream metabolites, including 2,3-DPG (2,3-diphosphoglycerate). PK deficiency is associated with serious complications, including gallstones, pulmonary hypertension, extramedullary hematopoiesis, osteoporosis and iron overload and its sequelae, which can occur regardless of the degree of anemia or transfusion burden. PK deficiency can also cause quality of life problems, including challenges with work and school activities, social life and emotional health. Current management strategies for PK deficiency, including red blood cell transfusions and splenectomy, are associated with both short- and long-term risks. For more information, please visit . About PYRUKYND® (mitapivat) PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States. IMPORTANT SAFETY INFORMATION Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath. Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Drug Interactions: Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage. Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. Please see full Prescribing Information for PYRUKYND. About Agios Agios is a biopharmaceutical company that is fueled by connections. The Agios team cultivates strong bonds with patient communities, healthcare professionals, partners and colleagues to discover, develop and deliver therapies for rare and genetically defined diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's leadership in the field of cellular metabolism, Agios is advancing a robust clinical pipeline of investigational medicines with active and planned programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency and MDS-associated anemia. In addition to its clinical pipeline, Agios has multiple investigational therapies in preclinical development and an industry-leading research team with unmatched expertise in cellular metabolism and genetics. For more information, please visit the company’s website at . Cautionary Note Regarding Forward-Looking Statements This press release contains 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 Agios' products, including PYRUKYND® (mitapivat), and its strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “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. Management’s expectations and, therefore, any forward-looking statements in this press release 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 the COVID-19 pandemic on 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 future approved products, and launching, marketing and selling 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 and 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 collaborations; the failure of Agios to receive milestone or royalty payments related to the sale of its oncology business, the uncertainty of the timing of any receipt of any such payments, and the uncertainty of the results and effectiveness of the use of proceeds from the transaction with Servier; 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. While the list of factors presented here is considered representative, this list should not be considered to be a complete statement of all potential risks and uncertainties. Any forward-looking statements contained in this press release are made only as of the date hereof, and we undertake no obligation to update forward-looking statements to reflect developments or information obtained after the date hereof and disclaim any obligation to do so other than as may be required by law. Contacts Investors: Holly Manning, 617-844-6630 Senior Director, Investor Relations Holly.Manning@agios.com Media: Jessica Rennekamp, 857-209-3286 Senior Director, Corporate Communications Jessica.Rennekamp@agios.com