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

Tebapivat: Pharmacokinetic Properties in Preclinical Species and Pharmacodynamic Responses Associated With Pyruvate Kinase Activation in Wild-Type Mice. (PubMed, Biopharm Drug Dispos) - "Lastly, we observed long-lived blood pharmacodynamics (up to 14 d), non-linear red blood cell partitioning, and the convergence of terminal blood drug concentrations from different doses in mice. We hypothesize these findings are most consistent with target-mediated drug disposition and are a result of the long residence time of tebapivat on its pharmacological target pyruvate kinase in red blood cells, and thus represents a subtle saturable property related to the high potency of tebapivat."

Journal • PK/PD data • Preclinical • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease

Agios Provides Update on Phase 2 Trial of Tebapivat in Sickle Cell Disease (Agios Pharma Press Release) - "The trial included a 12-week, double-blind, placebo-controlled period in which 59 participants were randomized....The trial’s primary endpoint of hemoglobin response (≥1.0 g/dL increase in average hemoglobin concentration from Weeks 10 through 12 compared with baseline) was achieved by 43.8% (n=7/16), 47.1% (n=8/17), and 29.4% (n=5/17) in the 2.5 mg QD, 5.0 mg QD, and 7.5 mg QD tebapivat arms, respectively, and 33.3% (n=3/9) in the placebo arm. The safety and tolerability of tebapivat in the Phase 2 trial were consistent with that observed in prior sickle cell disease trials....Agios has decided not to advance tebapivat in sickle cell disease."

Discontinued • P2 data • Sickle Cell Disease

Earlier this month, Agios announced that the U.S. Food and Drug Administration (FDA) accepted its supplemental New Drug Application (sNDA) for the accelerated approval of mitapivat, an oral PK activator, in sickle cell disease with a Priority Review (Agios Pharma Press Release) - "The Prescription Drug User Fee Act (PDUFA) goal date for this sNDA is November 1, 2026."

FDA filing • PDUFA • Priority review • Sickle Cell Disease

Agios Pharmaceuticals, Inc…announced that it will not advance tebapivat, a next-generation oral pyruvate kinase (PK) activator, in lower-risk myelodysplastic syndromes (LR-MDS). (GlobeNewswire) - "This decision follows results from its Phase 2b trial that did not meet the company’s predefined threshold to support further development in this indication...While tebapivat demonstrated evidence of biological activity, clinical benefit was not observed in a sufficient proportion of patients or subgroup of patients to meet the company’s predefined threshold for advancement in LR-MDS. Tebapivat was well tolerated across all dose levels, with no new safety signals identified."

Discontinued • P2 data • Myelodysplastic Syndrome

Pyruvate Kinase Activation in the Management of Thalassemia and Sickle Cell Disease. (PubMed, Hemoglobin) - "Although hydroxyurea, luspatercept, and curative approaches such as allogeneic transplantation and gene therapy have expanded the therapeutic landscape, major unmet needs persist because of limited access, variable response, toxicity, cost, and incomplete control of anemia, ineffective erythropoiesis, hemolysis, and/or vaso-occlusion...Mitapivat, a first-in-class oral PK activator, has shown encouraging activity across thalassemia and SCD...Tebapivat and etavopivat, two additional PK activators in earlier stages of development, have also shown promising metabolic, hematologic, and rheologic effects. Overall, PK activation represents a promising disease-modifying strategy in thalassemia and SCD, although optimal patient selection, affordability, and equitable global access will need to be addressed."

Journal • Review • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease • Transplantation

A Dose-Finding Study of Tebapivat to Assess Efficacy, and Safety in Participants With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2 | N=59 | Active, not recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

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

AG946-C-003: A Dose-Finding Study of Tebapivat to Assess Efficacy, and Safety in Participants With Sickle Cell Disease (clinicaltrialsregister.eu) - P1/2 | N=20 | Active, not recruiting | Sponsor: Agios Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

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

Completed patient enrollment in the Phase 2b trial of tebapivat in LR-MDS. (The Manila Times) - "Following findings from the Phase 2a trial, the Phase 2b trial is evaluating three higher daily doses (10 mg, 15 mg, and 20 mg) versus placebo over 24 weeks. Topline results from this trial are expected in early 2026."

Enrollment closed • P2 data • Myelodysplastic Syndrome

Anticipated 2026 Milestones (The Manila Times) - "Enrollment in the Phase 2b LR-MDS trial of tebapivat was completed in 2025. Agios expects to report topline results from this trial in the first half of 2026....Agios expects to report topline results from a Phase 1 healthy volunteer trial of AG-236, a small interfering RNA (siRNA) targeting TMPRSS6 as a potential treatment for PV, in the first half of 2026."

P1 data • P2b data • Myelodysplastic Syndrome • Polycythemia Vera

A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS) (clinicaltrials.gov) - P2 | N=87 | Active, not recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2028 ➔ Mar 2029 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Biochemical and Metabolomic Analysis of Glycolytic Activity in Red Blood Cells from Low-Risk Myelodysplastic Syndromes (LR-MDS) Patients and in-Vitro Effect of the Pyruvate Kinase Activator AG-946 (ASH 2023) - "Our data demonstrates decreased glycolytic activity in a large cohort of anemic pts with LR-MDS versus HC, with reduced PK activity in 1/3 of cases, decreased PK/HK ratio in nearly all subjects, and reduced ATP in 2/3 of pts. Furthermore, in vitro incubation with AG946 led to an increase in PK activity and PK/HK ratio and stable ATP levels in RBCs of LR-MDS pts across all WHO classifications. Metabolomic analysis confirmed an altered RBC-metabolic status of MDS versus HC at baseline with possible modulation of glycolysis by AG946, further supporting a potential therapeutic role of PK Activation with AG946 in LR-MDS."

Omic analysis • Preclinical • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

The Pyruvate Kinase (PK) Activator AG-946 Improves PK Properties and Red Blood Cell (RBC) Characteristics upon Ex Vivo treatment of RBCs from Patients with Myelodysplastic Syndromes (ASH 2023) - P2 | "Our findings show that RBCs from MDS patients have decreased PK activity and thermostability. We demonstrate that ex vivo treatment with AG-946 increases PK activity and ATP levels and restores PK thermostability. Moreover, ex vivo treatment with AG-946 improves RBC hydration, suggesting that improved energy status directly improves RBC functional properties."

Preclinical • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Pyruvate Kinase Thermostability Is Associated with Red Blood Cell Adhesion, Deformability and Oxygen Affinity in Patients with Sickle Cell Disease (ASH 2023) - P1, P2, P2/3, P3 | "Currently there are several clinical trials ongoing investigating the efficacy of PK activation by small molecules such as mitapivat (NL8517, NCT04000165, NCT05031780), AG-946 (NCT04536792) and etavopivat (NCT04624659, NCT04987489). This study shows for the first time a significant correlation between PK thermostability in sickle RBCs and RBC functions, such as adhesion, deformability and oxygen affinity. Our results suggest that enhancing the activity and stability of PK, with PK activators, is an attractive target in SCD that might improve other pathophysiological targets outside RBC metabolism. Future studies are needed to explore how activation of PK will affect these altered sickle RBC properties in vivo."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

AG-946, an Activator of Pyruvate Kinase, Improves Ineffective Erythropoiesis in the Bone Marrow of Mouse Models of Myelodysplastic Syndromes (ASH 2023) - "Our data suggest AG-946 treatment improves erythroblast maturation in two MDS mouse models as demonstrated by a reduction in early-stage erythroblasts (BasoE, PolyE) coupled with an increase in late-stage erythroblast populations (OrthoE + Retic). These data are the first to suggest that PK activation by AG-946 could improve ineffective erythropoiesis in MDS."

Preclinical • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NUP98

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

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 • 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

Tebapivat Improves Red Cell Deformability and Decreases Sickling in Patients With Sickle Cell Disease: A Phase 1 Trial Substudy. (PubMed, Eur J Haematol) - No abstract available

Journal • P1 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

PKM and PKLR mRNA Expression in CD34+ Cells Derived From Patients With Myelodysplastic Syndromes (SOHO 2025) - P2 | "PKM2 was the dominant mRNA transcript in CD34+ HSC, demonstrating lower expression in patients with MDS compared with HC. This insight into the differential expression of PK isoforms during early hematopoiesis further enhances understanding of the potential for PK activation with tebapivat to address ineffective erythropoiesis in patients with anemia due to low-risk MDS (NCT05490446). The original abstract was accepted as a publication at EHA2025."

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

Second Quarter 2025 and Recent Corporate Highlights (The Manila Times) - "Tebapivat Sickle Cell Disease - Dosed the first patient in the Phase 2 trial investigating tebapivat in sickle cell disease. The trial is enrolling across three dose cohorts (2.5mg, 5mg, 7.5mg) and placebo and the primary endpoint will measure hemoglobin response, defined as a ≥1g/dL increase in hemoglobin concentration from week 10 to week 12, compared to baseline. Lower-risk Myelodysplastic Syndromes (LR-MDS) - Continue to progress patient enrollment in the Phase 2b trial for tebapivat in LR-MDS with target enrollment completion by the end of 2025."

Enrollment status • Myelodysplastic Syndrome • Sickle Cell Disease

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