SWAlexander
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Pyruvate kinase deficiency of red cells Mutation in Gen PKLR
German interpretation of the article below (transl):
It is caused by (more than 100 known) mutations in the PKLR gene on chromosome 1.q22. They result in reduced activity of pyruvate kinase, a key enzyme in glycolysis. The erythrocytes are particularly affected, which, due to the lack of mitochondria, are dependent on glycolysis as the sole supplier of the energy carrier ATP.
The deficiency shortens the life span of the erythrocytes. They break down or are broken down prematurely in the spleen. Due to chronic hemolytic anemia, patients suffer from fatigue, jaundice, dyspnea, and tachycardia.
Serious complications include gallstones, pulmonary hypertension, thrombotic complications, osteoporosis, and iron overload. Treatment currently consists of splenectomy (intended to prolong the life of the red blood cells) and regular blood transfusions.
Mitapivat versus Placebo for Pyruvate Kinase Deficiency
Abstract
Background
Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency.
Methods
In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency–specific patient-reported outcome measures.
Results
Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo.
Conclusions
In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220. opens in new tab.)
https://www.nejm.org/doi/full/10.1056/NEJMoa2116634
German interpretation of the article below (transl):
It is caused by (more than 100 known) mutations in the PKLR gene on chromosome 1.q22. They result in reduced activity of pyruvate kinase, a key enzyme in glycolysis. The erythrocytes are particularly affected, which, due to the lack of mitochondria, are dependent on glycolysis as the sole supplier of the energy carrier ATP.
The deficiency shortens the life span of the erythrocytes. They break down or are broken down prematurely in the spleen. Due to chronic hemolytic anemia, patients suffer from fatigue, jaundice, dyspnea, and tachycardia.
Serious complications include gallstones, pulmonary hypertension, thrombotic complications, osteoporosis, and iron overload. Treatment currently consists of splenectomy (intended to prolong the life of the red blood cells) and regular blood transfusions.
Mitapivat versus Placebo for Pyruvate Kinase Deficiency
Abstract
Background
Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency.
Methods
In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency–specific patient-reported outcome measures.
Results
Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo.
Conclusions
In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220. opens in new tab.)
https://www.nejm.org/doi/full/10.1056/NEJMoa2116634