Pyrukynd (mitapivat) / Agios Pharma, Avanzanite Bioscience, NewBridge Pharmaceuticals - LARVOL DELTA

High-throughput oxygen dissociation assay enables rapid screening of hemoglobin oxygen affinity modifying therapies (ASH 2025) - "The distinct and reproducible shifts in ODCs observed with mitapivat, voxelotor, and GBT021601 emphasize RHODA's potential as a powerful tool for evaluating therapeutic efficacy and optimizing dosage strategies for novel Hb-O₂ affinity-modifying drugs. By enabling routine ODC assessment in a microplate format, RHODA stands to accelerate drug development, facilitate genome-editing-based therapies, support blood bank quality control, and inform personalized management of hemoglobinopathies such as SCD."

Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Basal and stimulated intra-RBC and exported ATP and RBC adhesivity ex vivo in children with sickle cell disease (ASH 2025) - "RBC-specific PK (PKR) activators (PKRAs), such as etavopivat and mitapivat, are now approved in PK deficiency, and are being studied in SCD patients. In contrast, similar exposure to PKRA did not significantly increase intra-RBC ATP in SCD, and ATP export from SS RBCs rose in hypoxia but not after ex vivo PKRA treatment. Ongoing work addresses the determinants of cellular and exported ATP in HC and SCD RBCs (basal and treated) and the basis of the antiadhesive effect of this PKRA on SS RBCs."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Activation of pyruvate kinase by mitapivat potentially rescues ineffective erythropoiesis in models of diamond blackfan anemia. (ASH 2025) - "Using our novel mouse models of DBA, representing two of the most commonly affected ribosomal protein genes (i.e., RPS19 and RPL5), we evaluated how ribosomal haploinsufficiency affected metabolism in hematopoietic progenitor cells and maturing erythroblasts. We then assessed the effect of ex vivo treatment with the PK activator, mitapivat, both on murine cells derived from both the mouse models as well as on human cells derived from DBA patients."

Anemia • Genetic Disorders • Hematological Disorders • RPL5

Activation of pyruvate kinase by mitapivat potentially rescues ineffective erythropoiesis in models of diamond blackfan anemia. [WITHDRAWN] (ASH 2025) - "Cell culture with mitapivat (2 µM) improved the transition from EP1 to EP4 in RPL5, but not in RPS19 when compared to vehicle-treated cells. In summary, Rps19- and Rpl5-haploinsufficient mice exhibit different mechanisms of cell death and activation of PKs may improve erythropoiesis in Rpl5-haploinsufficient progenitors by supporting proliferation and differentiation, with a possible beneficial effect on ferroptosis."

Anemia • Aplastic Anemia • Beta-Thalassemia • Genetic Disorders • CD34 • PKM • RPL5

Understanding health literacy among patients with thalassemia: Results from a global patient survey by the Thalassemia Advocacy Advisory Council (ASH 2025) - P3 | "Here, wereport the results from the Thalassemia AAC global patient survey. A bespoke, 12–15-minute survey was self-administered to adults (≥18 years) with a self-reported physician diagnosis of alpha (α)- or beta (β)-thalassemia, excluding those diagnosed with α- or β-thalassemia trait or those currently enrolled in mitapivat clinical trials (e.g., ENERGIZE [NCT04770753] orENERGIZE-T [NCT04770779])... Despite participants reporting high confidence in disease understanding, several keyknowledge gaps were identified. Of particular importance, most patients were unaware of thehemoglobin level associated with increased rates of complications, and the need for regular monitoringof patients with non-transfusion-dependent thalassemia. The responses regarding hemoglobin mayreflect the lower treatment targets still used by many providers, and therefore a lack of awarenessamong HCPs."

Clinical • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders

Efficacy and safety of mitapivat in pediatric patients with pyruvate kinase deficiency who are not regularly transfused: Results from the Phase 3, global, randomized, double-blind, placebo-controlled ACTIVATE-Kids trial (ASH 2025) - P3 | "ACTIVATE-Kids is the first study to demonstrate improvements in Hb and markers ofhemolysis in children with PK deficiency who are not regularly transfused. Mitapivat, in tablets andpediatric granule formulation, was generally well tolerated and consistent with the safety profileobserved for adults and regularly transfused children with PK deficiency. The efficacy and safety resultsfrom ACTIVATE-Kids together with the previous ACTIVATE-KidsT (NCT05144256) study support thepotential for mitapivat to provide clinically substantial benefits in children with PK deficiency and mayprovide insight into the development of future clinical trials for pediatric pts with other hemolyticanemias."

Clinical • P3 data • CNS Disorders • Hematological Disorders • Hepatology • Infectious Disease • Insomnia • Pediatrics • Respiratory Diseases • Sleep Disorder • PKM

Efficacy of mitapivat in patients with transfusion-dependent alpha-thalassemia: Subgroup analysis from the ENERGIZE-T trial (ASH 2025) - P3 | "In this subgroup analysis, a higher proportion of pts with TD α-thalassemia in the mitapivatarm experienced reductions in transfusion burden, as determined by the primary and all key secondaryendpoints, and achieved protocol defined TI, whereas no pts with TD α-thalassemia in the placebo armachieved these endpoints. These data are consistent with the results of the overall population andsupport the beneficial effects of mitapivat in transfusion reduction in patients with α-thalassemia."

Clinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • PKM

Snh-119014, a novel pyruvate kinase activator, enhances ATP production and reduces oxidative stress in erythroid cells from patients with β-thalassemia major (ASH 2025) - "SNH-119014 activates PK, increases ATP production, and alleviates oxidative stress inerythroid cells from β-TM patients. Its comparable efficacy to AG-348 in ex vivo systems supports SNH-119014 as a promising candidate for therapeutic development in thalassemia."

Clinical • Oxidative stress • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • CD34

Long-term transfusion-free duration and impact on transfusion-related burdens: Results from the ongoing ENERGIZE-T open-label extension study of mitapivat in transfusion-dependent alpha- or beta-thalassemia (ASH 2025) - P3 | "This analysis demonstrates long-term duration of prolonged transfusion-free periods of upto 84.3 wks achieved with mitapivat and its potential impact on clinical and humanistic transfusion-related burdens, further supporting use of mitapivat as an effective oral disease-modifying therapy foradults with TD α- or β-thalassemia."

Clinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • PKM

Use of red cell deformability measurements to assess the impact of pyruvate kinase activators on combined drug and transfusion therapies (ASH 2025) - "Mitapivat-modified red cells had poorer deformability than HbAA RBC but were comparable to MIRCAmeasurements of deformability on two individuals who have undergone GT for SCD. Modification ofrecipient RBCs by mitapivat may be key to preventing SCD related complications while on CTT, and MIRCAis an effective tool to monitor the efficacy of combined CTT and mitapivat."

Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long-term mitapivat treatment improves inflammatory pro-fibrotic cardiomyopathy in a murine model of β-thalassemia. (ASH 2025) - "The mitapivat treated 12-months old Hbb3th+mice displayed decreased heart perivascular sclerosis, an early step of heartinterstitial fibrosis, and a reduction in degradation of the sarcoplasmic reticulum calcium ATPase cardiacisoform-2 (SERCA2A), a transport system important for myocardial performance, when compared tovehicle treated Hbb3th+mice. Taken together our data indicate that long-term mitapivat treatmentprotects against ß–thal related cardiomyopathy by synergistic effects on anemia and on heartmetabolomic profile, preventing the activation of pro-inflammatory and pro-fibrotic pathways."

Preclinical • Anemia • Atherosclerosis • Beta-Thalassemia • Cardiomyopathy • Cardiovascular • Fibrosis • Genetic Disorders • Hematological Disorders • Hypertrophic Cardiomyopathy • Immunology • Targeted Protein Degradation • EDN1 • NLRP3 • PKM • STAT3 • VCAM1

Ex vivo treatment by mitapivat, an allosteric pyruvate kinase activator, reduced oxidative stress to support terminal erythropoiesis of non-transfusion dependent thalassemia patients due to β-thalassemia/hb e disease (ASH 2025) - "This ex vivo study showed that the intracellular ROS decreased in the mitapivat-treatederythroid cells during the erythroid differentiation stages. The reduced oxidative stress and increasedATP production accompanied erythroid cell viability during the erythroid differentiation stages.Moreover, mitapivat-treated erythroid cells could differentiate to the late stages of erythropoiesiscompared to the vehicle. This study provides further mechanistic insight into clinical benefits that havebeen demonstrated for mitapivat in patients with thalassemia."

Oxidative stress • Preclinical • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders

Mitapivat improves red blood cell integrity by reducing membrane ubiquitination accumulation (ASH 2025) - P, P1 | "The function of p97 was impaired in HbSS RBCs, leading to the accumulation of p97 and K48-Ub on the cell membrane. Mitapivat as a PKR and PKM2 activator, significantly increased ATP production,restoring p97 function and reducing K48-Ub accumulation, further improving RBC membrane integrity."

Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Targeted Protein Degradation

Activation of pyruvate kinase by mitapivat potentially rescues ineffective erythropoiesis in models of diamond blackfan anemia. (ASH 2025) - "While proliferation was similar after 48 hours, differentiation wasmarginally enhanced in mitapivat-treated Rpl5 haploinsufficient cells.In CD34+-derived erythroid progenitors from RPL5 (n=4) and RPS19 (n=3) haploinsufficient DBA patients,we found similar levels of mRNA expression of PKLR and PKM2 when compared to controls (n=6). Cellculture with mitapivat (2 µM) improved the transition from EP1 to EP4 in RPL5, but not in RPS19 whencompared to vehicle-treated cells.In summary, Rps19- and Rpl5-haploinsufficient mice exhibit different mechanisms of cell death andactivation of PKs may improve erythropoiesis in Rpl5-haploinsufficient progenitors by supportingproliferation and differentiation, with a possible beneficial effect on ferroptosis."

Anemia • Aplastic Anemia • Beta-Thalassemia • Genetic Disorders • CD34 • PKM • RPL5

Activation Of Pyruvate Kinase by Mitapivat Potentially Rescues Ineffective Erythropoiesis in Models of Diamond Blackfan Anemia (ASH 2025) - "Using our novel mouse models of DBA, representing two of the most commonly affected ribosomal protein genes (i.e., RPS19 and RPL5), we evaluated how ribosomal haploinsufficiency affected metabolism in hematopoietic progenitor cells and maturing erythroblasts. We then assessed the effect of ex vivo treatment with the PK activator, mitapivat, both on murine cells derived from both the mouse models as well as on human cells derived from DBA patients."

Anemia • Genetic Disorders • Hematological Disorders • RPL5

S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission. (PubMed, Circulation) - "SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hematological Disorders • Immunology • Metabolic Disorders • GSN

Agios Provides Update on U.S. sNDA for Mitapivat in Thalassemia (GlobeNewswire) - "Agios Pharmaceuticals, Inc...announced that the U.S. Food and Drug Administration (FDA) has not yet issued a regulatory decision on the supplemental New Drug Application (sNDA) for mitapivat for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia and that the sNDA remains under active review. The Prescription Drug User Fee Act (PDUFA) goal date issued by the FDA was December 7, 2025."

FDA filing • PDUFA • Beta-Thalassemia

Agios Announces Topline Results from RISE UP Phase 3 Trial of Mitapivat in Sickle Cell Disease (GlobeNewswire) - "Trial met primary endpoint of hemoglobin response and key secondary endpoints of change from baseline in hemoglobin concentration and indirect bilirubin. Trial showed trend favoring mitapivat but did not meet statistical significance in primary endpoint of annualized rate of SCPCs (pain crises), and the key secondary endpoint of change from baseline in PROMIS Fatigue was not met. Patients in the mitapivat arm who achieved hemoglobin response had clinically meaningful benefits in SCPC-related endpoints and PROMIS Fatigue....Agios intends to submit a marketing application for mitapivat in the U.S. for sickle cell disease after having a pre-supplemental New Drug Application (sNDA) meeting with the U.S. Food and Drug Administration (FDA) in the first quarter of 2026. In addition, the company plans to submit detailed analyses from the RISE UP Phase 3 trial for presentation at future medical congresses."

FDA event • P3 data: top line • Sickle Cell Disease

Improvements in Markers of Hemolysis and Liver Iron Concentration in Mitapivat-Treated Adult Patients with a Delayed Hemoglobin Response (ASH 2023) - P3 | "Adult pts with PK deficiency who do not show early Hb improvements (≥1. 5 g/dL) with mitapivat may still experience a delayed Hb response, generally preceded by improvements in hemolysis. In addition, pts with BL iron overload may experience decreases in LIC that correspond to increases in Hb."

Clinical • Anemia • Genetic Disorders • Hematological Disorders

Mitapivat Treatment Increases β-Thalassemic Erythroblasts Energy Production and Responsiveness to Oxidative Stress (ASH 2023) - P2 | "In conclusion, our data show that both pklr and pkm isoforms are expressed in the late phase of β-thal erythropoiesis. The ability of mitapivat to activate both PKLR and PKM2 might represent an added value to limit oxidation during b-thal erythropoiesis, ensuring an improved β-thal erythroblasts maturation and survival."

Oxidative stress • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • CD34 • HMOX1 • PKM • PRDX2 • PRRX2

In Pursuit of Healthier Red Blood Cells: The RISE UP Phase 2/3 Clinical Trial of Mitapivat in Sickle Cell Disease (ASH 2023) - "Sponsored by Agios Pharmaceuticals, Inc. This session will include a patient perspective provided by Golie Lorenzo Green."

Clinical • P2/3 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (ASH 2023) - "A subset of samples were examined for RBC reactive oxygen species (ROS) content and adhesivity to laminin with and without stimulation by epinephrine...Interestingly, we also found that RBC [ATP] was lower in the RBCs of patients with higher total Hb, while it was higher in individuals with higher retic counts, suggesting that more long-lived RBCs have diminished [ATP], despite the fact that both [ATP] and total Hb have been reported to rise substantially after treatment with pyruvate kinase activators etavopivat and mitapivat...Similarly, senicapoc, which also reduces hemolysis, although by a different mechanism, failed to lessen VOE frequency...Anti-adhesive agents (crizanlizumab, rivipansel, sevuparin) have thus far failed to yield marked improvements in VOE frequency, but our results suggest that, in order to decrease the frequency of VOEs, it is not sufficient to reduce sickling and hemolysis. On the other hand, higher HbF levels were associated with lower admission..."

Cardiovascular • Genetic Disorders • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sickle Cell Disease • MMP9

One-Year Safety and Efficacy of Mitapivat in Sickle Cell Disease: Follow-up Results of a Phase 2, Open-Label Study (ASH 2023) - P2, P2/3 | "In addition, the annualized rate of vaso-occlusive events reduced significantly from 1.33 ± 1.32 to 0.64 ± 0.87 (p=0.0489) when combining the DFP and FDEP (Table 1 and Figure 1). Conclusion Overall, this study demonstrated long-term safety and efficacy of treatment with mitapivat in SCD, warranting further evaluation in the ongoing phase 2/3 RISE UP study (ClinicalTrials.gov NCT05031780)."

Clinical • P2 data • Anemia • Cardiovascular • Genetic Disorders • Hematological Disorders • Infectious Disease • Nephrology • Novel Coronavirus Disease • Pulmonary Embolism • Respiratory Diseases • Sickle Cell Disease

Longitudinal Characterization of Hemodynamic Changes with Multimodal Optical Techniques in Patients with Sickle Cell Disease Treated with Mitapivat (ASH 2023) - P1/2 | "Hemodynamic changes appear to be more easily observed in the brain rather than the skeletal muscle. Our data suggest that NIRS could be an adjunct for non-invasive hemodynamic monitoring in patients with SCD undergoing treatment."

Clinical • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease

Functional and Multi-Omics Signatures of Mitapivat Efficacy upon Activation of Pyruvate Kinase in Red Blood Cells from Patients with Sickle Cell Disease (ASH 2023) - P1, P1/2 | "Unsupervised analyses of omics data confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of oxygen affinity (p50) and sickling kinetics (t50) during mitapivat treatment. Multi-omics analysis of RBCs from HbSS patients treated with mitapivat identified benefits for glycolysis, DPG consumption and ATP generation, as well as activation of the Lands cycle."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease