Researchers have published the results of a clinical trial that led to the U.S. Food and Drug Administration recently approving miatapivate to treat adults with pyruvate kinase deficiency — a rare genetic condition that causes the destruction of red blood cells. lead to, or hemolytic anemia. Primary results from a global, phase 3, randomized, placebo-controlled active trial conducted by an international team including investigators at Massachusetts General Hospital (MGH) have been published in . New England Journal of Medicine,
Lead author Hani al- says, “Lifelong anemia associated with pyruvate kinase deficiency results in chronic fatigue, reduced exercise tolerance, and decreased ability to concentrate on work or school, which makes it difficult to concentrate on a normal day.” I can challenge. Samkari, MD, is a hematologist and clinical investigator at MGH and assistant professor of medicine at Harvard Medical School. “In addition, most patients develop other potentially serious complications, such as iron in the liver and/or heart (which can lead to cancer or death), osteoporosis, gallbladder disease, blood clots and other issues. overload.”
Mutations in pyruvate kinase deficiency are characterized by pklr The gene that encodes the pyruvate kinase enzyme in red blood cells. This enzyme is important for maintaining the energy level of red blood cells and, therefore, their normal life span. Mitapivate can activate and stabilize the mutated pyruvate kinase that is expressed in the red blood cells of patients, thereby restoring the activity of the enzyme.
“It is a ‘disease modifying’ therapy because it targets the underlying problem to improve or eliminate anemia and potentially prevent or reverse many of the other complications associated with pyruvate kinase deficiency,” says Al-Samkari. ” “This is the first disease-modifying drug for pyruvate kinase deficiency, which has so far been treated only with adjuvant measures such as blood transfusion or removal of the patient’s spleen.”
In the active trial, designed and conducted by Al-Samkari and colleagues, 80 patients were randomized to receive either miatapivate (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. it was done. The primary end point was a hemoglobin response (an indicator of red blood cell levels) sustained at two or more scheduled assessments at weeks 16, 20 and 24.
Sixteen of the 40 patients (40%) receiving miatapivate had a hemoglobin response, compared with none of the patients receiving placebo. Patients receiving miatapivate also had a greater response than those receiving placebo with respect to secondary end points, including other markers of red blood cell health. There was also a significant improvement in quality of life for patients treated with Mitapivate compared to patients receiving placebo, as measured by disease-specific instruments.
The most common adverse events were nausea (in 18% of patients in the mitapivat group and 23% of patients in the placebo group) and headache (in 15% of patients in the mitapivet group and 33% of patients in the placebo group).
“The opportunity to develop a disease-modifying therapy for a disease such as pyruvate kinase deficiency not only helps patients with this disease, but also brings hope to patients with other similar disorders,” says Al-Sankari. “Since energy is everything for red blood cells, this drug could help patients with more common anemias like sickle cell disease and thalassemia. We’re looking at this in other clinical trials right now, and the preliminary studies are very promising. are.”
Additional study authors include Frédéric Galacteros, MD, PhD, Andreas Glenthoj, MD, Jennifer A. Rothman, MD, Oliver Andres, MD, Rachel F. Grace, MD, Marta Morado-Arias, MD, D. Mark Layton, MB, BS. , Koichi Onodera, MD, Madeleine Verhovsek, MD, Wilma Barcellini, MD, Satish Chonat, MD, Malia P. Judge, BS, Erin Zagadelov, FarmD, Rengi Xu, PhD, Peter Hawkins, PhD, Vanessa Bayen, MD, Sarah Ghuyens, MD, PhD, and Eduard J. Van Beers, MD.
This work was supported by Agios Pharmaceuticals.