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Agios Pharmaceuticals Announces Approval of Pyrukynd (Mitapivat) in European Union for Adults with Thalassemia
Agios Pharmaceuticals, Inc. announced that the European Commission (EC) has granted marketing authorization for PYRUKYND (mitapivat), an oral pyruvate kinase (PK) activator, in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassemia, with an orphan medicinal product designation. PYRUKYND becomes the only medicine approved in all European Union (EU) member states for this broad patient population. The EC’s decision is based on the results from the global, randomized, double-blind, placebo-controlled ENERGIZE and ENERGIZE-T Phase 3 trials in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia, respectively. The ENERGIZE trial randomized 194 non-transfusion-dependent alpha- or beta-thalassemia patients 2:1 to receive either mitapivat 100 mg twice daily or placebo. The primary endpoint was hemoglobin response, defined as an increase of =1.0 g/dL in average hemoglobin concentration from Week 12 through Week 24 compared with baseline. Key secondary endpoints included changes from baseline in average fatigue scores and in average hemoglobin concentration from Week 12 to Week 24. The trial also assessed safety and tolerability. The ENERGIZE-T trial randomized 258 transfusion-dependent alpha- or beta-thalassemia patients 2:1 to receive either mitapivat 100 mg twice daily or placebo. The primary endpoint was transfusion reduction response, defined as a =50% reduction in transfused red blood cell (RBC) units with a reduction of =2 units of RBCs transfused in any consecutive 12-week period through Week 48 compared with baseline. Several transfusion reduction measures were included as key secondary endpoints, and achievement of transfusion independence was a secondary endpoint. The trial also assessed safety and tolerability. For each trial, patients who completed the double-blind period had the option to transition into a corresponding open-label extension period, during which all patients receive mitapivat. Mitapivat is now approved for adults with thalassemia in the EU, Saudi Arabia, and United Arab Emirates under the brand name PYRUKYND, as well as in the U.S. under the brand name AQVESME (mitapivat). The medicine is also approved as PYRUKYND for adults with PK deficiency in both the U.S. and in Europe. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. 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. In patients with another condition treated with mitapivat at a higher dose than that recommended for patients with PK deficiency, liver injury has been observed. These events were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5x upper limit of normal (ULN) with or without jaundice. All patients discontinued treatment with mitapivat, and these events improved upon treatment discontinuation. Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5x ULN. Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected. 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. 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. Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. AQVESME is indicated for the treatment of anemia in adults with alpha- or beta-thalassemia. AQVESME can cause serious hepatocellular injury. Measure liver laboratory tests (ALT, AST, alkaline phosphatase and total bilirubin with fractionation) at baseline and every 4 weeks for 24 weeks and then as clinically indicated. Avoid use of AQVESME in patients with cirrhosis. Discontinue AQVESME if hepatic injury is suspected. Because of the risk of hepatocellular injury, AQVESME is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the AQVESME REMS. AQVESME can cause hepatocellular injury. Avoid use of AQVESME in patients with cirrhosis. In patients with thalassemia treated with AQVESME, liver injury with and without jaundice has been observed within the first 6 months of exposure. Obtain liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation) prior to the initiation of AQVESME, then every 4 weeks for the first 24 weeks, and as clinically indicated thereafter. Interrupt AQVESME if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Complete a comprehensive evaluation to rule out other causes of liver injury when drug-induced liver injury is suspected. Discontinue AQVESME if hepatocellular injury due to AQVESME is suspected. During the double-blind period, 2 of 301 patients (0.66%) with thalassemia treated with AQVESME experienced adverse reactions suggestive of hepatocellular injury. Three additional patients experienced adverse reactions suggestive of hepatocellular injury during the open-label extension periods after switching from placebo to AQVESME. Of these 5 patients, 2 had serious liver injury requiring hospitalization, including 1 patient who developed jaundice (peak bilirubin 32 mg/dL). Another patient developed jaundice (peak bilirubin 4 mg/dL) without requiring hospitalization.