Agios Announces Publication of Phase 2 Data in The Lancet Demonstrating Safety and Efficacy of PYRUKYND® (mitapivat) in Non-transfusion-dependent α- and β-Thalassemia
Orphan DrugFirst in ClassSmall molecular drugCollaborate
CAMBRIDGE, Mass., Aug. 11, 2022 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism pioneering therapies for genetically defined diseases, today announced that data from the core period of the open-label, Phase 2 study of PYRUKYND® (mitapivat) in adults with non-transfusion-dependent α- or β-thalassemia were published on August 11, 2022, in The Lancet. Data from this study were previously presented at the 2021 European Hematology Association (EHA) Annual Congress. PYRUKYND® is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase (PK) enzymes.
The publication can be accessed at the following link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01337-X/fulltext
“Consistent with previously reported findings, the data reported today underscore the potential of PK activation to improve hallmarks of α- and β-thalassemia, including hemolysis and ineffective erythropoiesis,” said Kevin Kuo, M.D., hematologist at University of Toronto, Toronto General Hospital, and an investigator in the study. “Thalassemia is a rare, debilitating lifelong blood disorder characterized by severe complications, with no treatment options for those with α-thalassemia and limited options for those with β-thalassemia. These data demonstrate the potential clinical benefits of mitapivat for a broad spectrum of thalassemia patients and support its continued investigation in pivotal trials.”
“We are encouraged by The Lancet’s publication of our Phase 2 thalassemia data for PYRUKYND®, which has the potential to serve as several important firsts for patients: the first oral therapy for thalassemia, and first treatment for all types of thalassemia – α and β, transfusion-dependent and non-transfusion-dependent,” said Sarah Gheuens, M.D., Ph.D., head of R&D and chief medical officer at Agios. “Enrollment is underway for the Phase 3 ENERGIZE and ENERGIZE-T studies of PYRUKYND® in adults with non-transfusion-dependent or transfusion-dependent α- or β-thalassemia, respectively, and we expect to enroll a substantial portion of patients in the trials by year-end.”
As reported in the publication, 16 of 20 patients (80%; p<0.0001), including five of five (100%) with α-thalassemia and 11 of 15 (73%) with β-thalassemia, achieved the primary endpoint of hemoglobin response, a ≥1.0 g/dL increase in hemoglobin concentration from baseline at one or more assessment between Weeks 4–12. The mean time to hemoglobin response was 4.5 weeks. Of the 16 patients who achieved the primary endpoint, 13 had a sustained response, defined as ≥1.0 g/dL increase in hemoglobin at two or more assessments between Week 12 and Week 24. A trend in decreasing concentrations of markers of hemolysis (total bilirubin and LDH concentrations) was observed in both α- and β-thalassemia patients, with decreases observed as early as Week 2. Decreases in erythropoietin concentrations were also observed in both α- and β-thalassemia patients. The greatest change in markers of hemolysis and erythropoiesis was observed in the first 8 weeks of treatment, and improvements were maintained over the duration of the core period.
The most common adverse events were initial insomnia (50%, including 1 patient [5%] with Grade 3), dizziness (30%, all Grade 1) and headache (25%, all Grade 2 or lower). Initial insomnia was the only Grade 3 or worse treatment-emergent adverse event considered to be treatment-related. One patient who had β-thalassemia discontinued after Week 4 due to a treatment-emergent adverse event deemed unrelated to the study drug.
PYRUKYND® was approved in February 2022 by the U.S. Food and Drug Administration (FDA) for the treatment of hemolytic anemia in adults with PK deficiency. PYRUKYND® is also under review by the European Medicines Agency (EMA) as a potential treatment for adults with PK deficiency, and Agios expects a regulatory decision in the EU by the end of 2022. Both the FDA and EMA have granted orphan drug designation to PYRUKYND® in PK deficiency. In addition, PYRUKYND® has been granted FDA orphan drug designation for the treatment of thalassemia and sickle cell disease, for which enrollment for ongoing pivotal studies is underway.
Mitapivat Phase 2 Study in Thalassemia
The open-label Phase 2 study evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of mitapivat treatment in adults with non-transfusion-dependent α- or β-thalassemia who have a baseline hemoglobin concentration of ≤10 g/dL. The trial enrolled 20 patients. All patients were treated with an initial dose of mitapivat 50 mg twice daily followed by a dose-level increase to 100 mg twice daily at the Week 6 visit based on safety evaluations and hemoglobin concentrations. Following the completion of the 24-week core period, patients had the opportunity to enroll in an optional 10-year extension period, which is evaluating long-term efficacy and safety of mitapivat in this population. Initial data from the extension period, which highlighted the long-term safety profile and durable improvement in hemoglobin and markers of hemolysis associated with mitapivat treatment in non-transfusion-dependent α- and β-thalassemia, were presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition.
About Thalassemia
Thalassemia is a rare, inherited blood disorder caused by mutations in either α- or β-globin genes, resulting in excessive destruction of red blood cells. Globin precipitates in thalassemia cause oxidative damage, leading to hemolytic anemia, ineffective erythropoiesis and iron overload.
Thalassemia is associated with serious complications, including fatigue, jaundice, facial bone deformities, delayed growth and development, abdominal swelling, dark urine and reduced life expectancy. Current management strategies for β-thalassemia can include red blood cell transfusions, splenectomy and stem cell transplant, which are associated with short- and long-term risks. There are currently no approved therapies for α-thalassemia.
PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.
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.
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 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 www.agios.com.
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