Medically reviewed by Rachael Grace, MD
In the mid-1960s, David G. Nathan, MD, president emeritus of Dana-Farber and, at that time, a hematologist at Boston Children’s Hospital, published some of the first reports on a rare, inherited type of anemia caused by the breakdown of red blood cells because of a lack of a key enzyme.
Until now, there has been no disease-modifying treatment for the disorder, called pyruvate kinase deficiency. Symptoms vary among patients, but many receive supportive care with surgical removal of the spleen and/or repeated blood transfusions, which cause numerous complications in addition to those caused by the disease itself, such as gallstones, pulmonary hypertension, jaundice, low bone density, and iron overload.
Now, a physician-scientist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center has shown for the first time that a new drug can raise hemoglobin levels in about half of patients with pyruvate kinase deficiency, and the drug has been tolerated without major safety issues in studies to date.
The first disease-modifying treatment
Rachael Grace, MD, is lead author of a report in The New England Journal of Medicine on the safety and efficacy of mitapivat, an oral drug developed by Agios Pharmaceuticals, Inc., of Cambridge, Mass. Grace, who is the director of the hematology clinic at Boston Children’s Hospital, worked with Agios as they developed mitapavit. She also set up a registry for patients with this rare disease — estimated to affect about 3 in one million people — to gather information about the various complications of pyruvate kinase deficiency and how it is treated.
Grace says the New England Journal report is “very exciting for patients with pyruvate kinase deficiency and the providers who treat them.”
“It describes the first disease-modifying treatment for this disease,” she notes. “This study demonstrates that a molecular therapy can target an underlying enzyme defect of a hereditary enzymopathy.”
“This is the first report of a promising approach to drug-induced enhancement of a blood cell enzyme deficiency,” says Nathan. “It has huge significance because inherited deficiencies of enzyme activity are very common around the world. Until now, pyruvate kinase deficiency could only be treated with marrow stem cell transplant. Dr. Grace’s report represents a paradigm shift in therapeutics.”
What is pyruvate kinase deficiency?
Red blood cells, which contain the oxygen-carrying molecule hemoglobin, normally have a lifetime of about 120 days in the body’s circulation and are replaced by new ones spawned in the bone marrow. A lack of pyruvate kinase deprives red cells of energy they need to thrive, and the cells fall apart in just a few weeks, reducing red blood cell counts and hemoglobin levels.
Pyruvate kinase deficiency is inherited in an autosomal recessive pattern — both parents need to have a mutation in the gene for pyruvate kinase, called PKLR. At least 300 different mutations in the gene have been recognized.
In addition to the many medical complications that patients can develop, Grace says that the disorder in young children can cause them to lack energy, need frequent naps, and are often limited in activities outside school. In adults, the anemia can impair their ability to keep up with work and other responsibilities. In addition to these everyday symptoms, the complications may be life-threatening.
The study — and next steps
The experimental drug mitapivat is an oral agent that activates pyruvate kinase in red blood cells. It was first tested in the laboratory in red blood cells from patients, and then given to healthy volunteers.
The study in patients with pyruvate kinase deficiency was carried out at eight sites in North America and six sites in Europe. Fifty-two patients were randomized to receive a low dose or a high dose of mitapivat twice a day. Forty-three patients completed the 24-week core period; 36 patients entered an extension phase and 19 continue to participate in the extension phase.
The researchers reported that treatment with mitapivat led to a rapid, clinically significant increase in hemoglobin level in about half of the patients. This response was sustained for up to 35 months and was associated with improved results of tests for red blood cell breakdown. Side effects were generally mild and transient, and included headache, insomnia, and nausea.
Analysis of the results revealed that the patients who responded to the drug with a significant increase in hemoglobin were those whose PKLR gene contained at least one missense mutation — a single alteration in a letter of the genetic code that causes a change in an amino acid in a protein. The patients who did not respond to the drug had different types of mutations in the PKLR gene.
Grace says that further studies are needed to look at long-term safety and the safety of mitapivat in children. She adds that research toward a gene therapy treatment for pyruvate kinase deficiency is ongoing and might help patients who do not respond to a drug.