tebapivat (AG-946) / Agios Pharma - LARVOL DELTA

PKM AND PKLR MRNA EXPRESSION IN CD34+ CELLS DERIVED FROM PATIENTS WITH MYELODYSPLASTIC SYNDROMES (EHA 2025) - P2 | "PKM2 was the dominant mRNA transcript in CD34+ HSC, with lower expression in patients with MDS compared with HC. Gaining insight into the differential expression of PK isoforms during early hematopoiesis further enhances understanding of the potential for PK activation with tebapivat in LR-MDS."

Clinical • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34 • PKM

EX VIVO ACTIVATION OF PYRUVATE KINASE BY TEBAPIVAT REDUCES SICKLING AND RED BLOOD CELL ADHESION IN SICKLE CELL DISEASE (EHA 2025) - "A one-way ANOVA or Friedman test was performed to assess statistical significance.Six HbSS patients (median age 32 [range 18-46], n=3 female, n=3 on hydroxyurea) were included. Ex vivo treatment with tebapivat improved RBC metabolic and functional properties, including reduced sickling tendency in all RBC (sub)populations. Further, we demonstrated that both LD and HD RBCs responded to ex vivo treatment with tebapivat. More importantly, we observed a significant reduction in RBC adhesion to laminin indicating that PK activation improves SCD pathophysiology outside of RBC metabolism."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Dose-Finding Study of Tebapivat to Assess Efficacy, and Safety in Participants With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2 | N=56 | Recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Agios to Highlight Pyruvate Kinase Activation Portfolio with New Data in Rare Blood Disorders at 30th EHA Congress | AGIO Stock News (Gurufocus) - "Agios Pharmaceuticals (AGIO), a leader in developing pyruvate kinase (PK) activators, is set to present comprehensive data on its pioneering therapies at the 30th European Hematology Association (EHA) Congress in Milan. The focus will be on the results of the ACTIVATE-KidsT Phase 3 study involving mitapivat, which demonstrated a clinically meaningful reduction in transfusion burden among children with PK deficiency, though it did not meet the pre-specified statistical criterion essential for regulatory approval. More promising, the ESTIMATE Phase 2 trial delivered encouraging long-term data showcasing mitapivat's sustained efficacy and tolerability over a three-year period in patients with sickle cell disease....Additionally, preclinical findings for tebapivat revealed its potential in reducing red blood cell sickling and adhesion in sickle cell disease samples, underscoring its promise as a therapeutic candidate."

P2 data • P3 data • Preclinical • Metabolic Disorders • Sickle Cell Disease

Agios to Highlight Pyruvate Kinase Activation Portfolio with New Data in Rare Blood Disorders at 30th EHA Congress (Agios Pharma Press Release) - "Agios Pharmaceuticals, Inc...announced that new data on the company’s PK activators, mitapivat and tebapivat, will be featured in oral and poster presentations during the 30th European Hematology Association (EHA) Congress (EHA 2025) in Milan, Italy, June 12-15, 2025...'The presentations span serious conditions with limited or no treatment options, including sickle cell disease, thalassemia, PK deficiency, and myelodysplastic syndromes, offering meaningful results that highlight the therapeutic potential of mitapivat and tebapivat.'"

Clinical data • Preclinical • Beta-Thalassemia • Myelodysplastic Syndrome • Sickle Cell Disease

Industry Pipeline Session (Not Included in main event CME/CPD Credit) (MDS 2025) - P2 | "Agios is researching the potential of tebapivat, our potent, investigational, oral PK activator for both SCD and anemia due to LR-MDS...We are excited to deepen our connections with the MDS foundation and community. For more information, please visit www.agios.com or email medinfo@agios.com."

CME • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Polycythemia Vera

Key Upcoming Milestones & Priorities (GlobeNewswire) - "LR-MDS: Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025; Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, an siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025."

Enrollment status • IND • Myeloproliferative Neoplasm • Polycythemia Vera

A Dose-Finding Study of Tebapivat to Assess Efficacy, and Safety in Participants With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2 | N=56 | Not yet recruiting | Sponsor: Agios Pharmaceuticals, Inc.

New P2 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

AG946-C-004: A Study to Determine How Tebapivat is Absorbed, Broken Down, and Removed From the Body and the Extent to Which Tebapivat is Made Available in the Body in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Agios Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion

Agios Reports Fourth Quarter and Full Year 2024 Financial Results and Recent Business Highlights (GlobeNewswire) - "'Backed by a strong balance sheet and a highly experienced team, Agios is focused on maximizing the potential PYRUKYND launches in thalassemia and sickle cell disease in 2025 and 2026, respectively'...PYRUKYND Revenues: Generated $10.7 million in net revenue for the fourth quarter of 2024, a 20 percent increase from the third quarter of 2024, primarily driven by year-end stocking and adjustments to certain revenue reserves...Announce topline results from the Phase 3 RISE UP study of mitapivat in sickle cell disease in late 2025...Additionally, begin patient enrollment for the Phase 2 study of tebapivat in sickle cell disease in mid-2025. LR-MDS: Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025. Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, a siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025."

Commercial • Enrollment status • IND • Launch US • P3 data: top line • Anemia • Beta-Thalassemia • Hematological Disorders • Myelodysplastic Syndrome • Polycythemia Vera • Sickle Cell Disease

AG946-C-004: A Study to Determine How Tebapivat is Absorbed, Broken Down, and Removed From the Body and the Extent to Which Tebapivat is Made Available in the Body in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open

Agios Announces Key 2025 Milestones for Innovative Rare Disease Portfolio (GlobeNewswire) - "Sickle Cell Disease: Announce topline results from the Phase 3 RISE UP study of mitapivat in sickle cell disease in late 2025, with a potential U.S. commercial launch in 2026. Additionally, begin patient enrollment for the Phase 2 study of tebapivat in sickle cell disease in mid-2025."

Launch US • New P2 trial • P3 data • Sickle Cell Disease

Agios Announces Key 2025 Milestones for Innovative Rare Disease Portfolio (GlobeNewswire) - "Anticipated 2025 Milestones: Lower-Risk Myelodysplastic Syndromes (LR-MDS): Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025. Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, a siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025."

Enrollment status • IND • Myelodysplastic Syndrome • Polycythemia Vera

A Phase 2B, Open-Label Multicenter Study of Tebapivat (AG-946), a Potent Pyruvate Kinase Activator, in Patients with Anemia Due to Lower-Risk Myelodysplastic Syndromes (ASH 2024) - P2 | "Key exclusion criteria include : history of acute myeloid leukemia; secondary MDS; prior exposure to a PK activator, including tebapivat in the phase 2a portion of this trial; prior exposure to disease-modifying agents including imetelstat, lenalidomide, hypomethylating agents, and immunosuppressive therapies; treatment with ESAs ± granulocyte colony-stimulating factor <28 days prior to first dose; treatment with luspatercept <65 days prior to first dose.The primary endpoint is TI (transfusion-free for ≥8 consecutive weeks [TI8] during the Core Period). The phase 2b portion of the study will be initiated in the second half of 2024.Conclusions : This phase 2b study will evaluate the efficacy and safety of tebapivat at higher QD doses in patients with anemia due to LR-MDS. Further information is available at https : //clinicaltrials.gov/study/NCT05490446."

Clinical • P2b data • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • HK1 • PKM

A Study to Determine How Tebapivat is Absorbed, Broken Down, and Removed From the Body and the Extent to Which Tebapivat is Made Available in the Body in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Agios Pharmaceuticals, Inc.

New P1 trial

Results from a Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Tebapivat (AG-946) in Patients with Sickle Cell Disease (ASH 2024) - P1 | "Mitapivat, a pyruvate kinase activator, has demonstrated clinically meaningful improvement in hemoglobin (Hb) response and improvements in hemolysis and erythropoiesis in phase (Ph) 2 trials...Ten (62.5%) pts (4 [2 mg], 6 [5 mg]) were taking stable-dose hydroxyurea for ≥3 months prior to initiating tebapivat...Conclusions : Tebapivat was well tolerated in pts with SCD receiving either 2 mg or 5 mg QD for 28 days. This study provides further evidence that PK activation may have beneficial effects in pts with SCD."

Clinical • P1 data • PK/PD data • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Respiratory Diseases • Sickle Cell Disease

Dual Activation of PKR and PKM2 Reduced the Development of Fibrosis and Iron Deposition in a Sickle Cell Disease Nephropathy Mouse Model (ASH 2024) - P2, P2/3 | "Here, we investigate the efficacy of mitapivat (AG-348) and tebapivat (AG-946), activators of PKR and PKM2 under investigation for the treatment of SCD, in preserving renal function in two mouse models of renal injury : Berkeley sickle cell (BSC) model and anti-glomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis, which was used as a surrogate to model glomerular damage in SCN. These findings underscore the potential of PK activators in improving kidney health by reducing hemolysis and vaso-occlusion via PKR activation and slowing fibrosis development via PKM2 activation. Further studies to explore the potential role of PK activators in SCN are ongoing, including a phase 2 study to assess the efficacy and safety of mitapivat in pts with SCD and nephropathy (NCT06286046), and RISE UP, a phase 2/3 study to evaluate the safety and efficacy of mitapivat in pts with SCD (NCT05031780)."

Preclinical • Acute Kidney Injury • Anemia • Cardiovascular • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Inflammation • Lupus Nephritis • Nephrology • Renal Disease • Sickle Cell Disease • COL1A1 • COL1A2 • COL3A1 • COL5A2 • PKM

Agios to Present New Data on…Tebapivat in Rare Blood Disorders at 66th ASH Annual Meeting and Exposition (GlobeNewswire) - "A trial-in-progress publication that outlines the Phase 2b study evaluating the efficacy and safety of tebapivat in patients with anemia due to lower-risk myelodysplastic syndromes."

Trial status • Myelodysplastic Syndrome

A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS) (clinicaltrials.gov) - P2 | N=82 | Recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Agios Announces FDA Orphan Drug Designation Granted to Tebapivat (AG-946) for Treatment of Myelodysplastic Syndromes (MDS) (GlobeNewswire) - "Agios Pharmaceuticals, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to the company’s novel pyruvate kinase (PK) activator tebapivat (AG-946) for the treatment of myelodysplastic syndromes (MDS)....Agios completed a Phase 2a study of tebapivat in lower-risk MDS late last year and is currently initiating a Phase 2b study of tebapivat in lower-risk MDS."

Orphan drug • Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS) (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Agios Pharmaceuticals, Inc. | N=116 ➔ 80

Enrollment change • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Structure based design of AG-946, a pyruvate kinase activator (ACS-Fall 2024) - "It displayed a long on-target residence time and stabilized PKR R510Q, a prototypically unstable mutant PKR enzyme, preserving its activated catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PK, AG-946 is currently being evaluated in patients with lower-risk myelodysplastic syndrome and sickle cell disease."

Genetic Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease

EX VIVO PYRUVATE KINASE ACTIVATION IN HEREDITARY SPHEROCYTOSIS AND XEROCYTOSIS: IMPROVED ENZYME FUNCTION AND RED CELL PROPERTIES. (EHA 2024) - "Aims: To evaluate PK activity and stability in HS and HX, and to evaluate effects of ex vivo treatment with PKactivators mitapivat and AG-946 on RBC properties. PK activity is decreased in both HS and HX compared to HC. This is accompanied by decreased PKthermostability in HX specifically, suggesting distinct pathophysiology. Ex vivo treatment with allosteric PKactivators improved PK activity and thermostability in HS and HX."

Preclinical • Anemia • Genetic Disorders • Hematological Disorders

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients: A proof-of-concept study. (PubMed, Am J Hematol) - "Data showed decreased glycolytic activity in red blood cells of 2/3 of patients with lower-risk MDS. These results highlight a potential effect of the PK activator in this setting."

Journal • Preclinical • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers and in Participants With Sickle Cell Disease (clinicaltrials.gov) - P1 | N=122 | Completed | Sponsor: Agios Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease