7 December, 2023

FDA approves first disease-modifying therapy for a rare blood disorder

Pyruvate kinase deficiency is a rare genetic disease in which an enzyme used by red blood cells is present at abnormally low levels. This makes the red blood cells more susceptible to the destruction and can lead to hemolytic anemia.1,2,3

On February 17, 2022, the FDA approved a drug called mitapivat (marketed as Pyrukynd) to treat pyruvate kinase deficiency anemia in adults. This is the first drug specifically approved for treating pyruvate kinase deficiency.1

What is pyruvate kinase deficiency?

Pyruvate kinase deficiency is diagnosed in an estimated 3 to 9 out of one million people. However, the disorder is likely underdiagnosed and may affect around 1 in 20,000 Caucasians.1,2,3,4

This autosomal recessive condition is one of a group of rare blood disorders called hereditary nonspherocytic hemolytic anemias. These disorders involve red blood cells that do not form a spherical shape (as occurs in some hemolytic anemia conditions) but that do break down more rapidly than normal.2

Normal red blood cells remain in circulation for about 120 days. In pyruvate kinase deficiency, inherited mutations in the PKLR gene lead to reduced function of the enzyme pyruvate kinase, which is needed for energy generation in red blood cells. This leads to the destruction of abnormal red blood cells by the spleen just days or weeks after they form, followed by hemolytic anemia and enlarged spleen

: Visualization of the structure of the pyruvate kinase enzyme. (Creative Commons image by Thomas Spletstoesser) 

The severity of this disorder can span from mild to life-threatening. Depending on the severity of their condition, patients can experience shortness of breath, weakness, fatigue, fast heart rate, pale skin, jaundice, gallstones, and iron overload. Patients can also experience worsening of their condition during times of stress, such as when they have an infection or during pregnancy.4

Treatments for pyruvate kinase deficiency anemia

Mitapivat is considered the first specific, disease-modifying drug for pyruvate kinase deficiency, as most previous treatments are directed at controlling the symptoms and complications of this disorder. Blood transfusions may be necessary for children, adults, or even in the womb, and some individuals receive transfusions on a regular basis. Individuals with mild cases may never need a transfusion.2,3,4

Phototherapy for jaundice, chelation therapy for iron overload, and gallbladder removal may be performed if needed. Folic acid supplementation may be offered to support red blood cell production.4

Gallstones are one potential complication of pyruvate kinase deficiency, and gallbladder removal may be required

Splenectomy can lessen anemia in most patients; however, this surgery increases the risks of infections and of thrombosis. In children, splenectomy is delayed as long as possible to lessen the risk of serious infections.2,3,4

The new drug, mitapivat, binds to and increases the activity of the pyruvate kinase enzyme. Previous research has shown that it is able to bind to a variety of pyruvate kinase variants found in patients, although patients with certain mutations appear to have a poorer response or no response to mitapivat.5

Mitapivat clinical trials

Mitapivat received FDA approval on the basis of two clinical studies in adults with pyruvate kinase deficiency. In the first study, 80 patients who were not dependent on regular blood transfusions were randomized to receive either mitapivat or placebo over an average of 24 weeks. The primary outcome was hemoglobin response, defined as an increase in hemoglobin concentration of at least 1.5g/dL that is sustained over at least two assessments. In this double-blind study, forty percent of the participants taking mitapivat and no patients taking placebo showed a hemoglobin response.1,6

The second study was a single-arm trial in patients who did receive regular blood transfusions. These patients received the drug for an average of 40 weeks. Twenty-two percent of these treated patients did not require any transfusions during the last 24 weeks of the study. A total of thirty-three percent had at least a 33% reduction (compared to that patient’s baseline) in transfused blood units during the last 24 weeks of the study.1

The FDA cautions that mitapivat treatment should not be stopped suddenly and that it can produce side effects including increased urate, back pain, joint stiffness, and decreased estrone and estradiol (the latter was only assessed in men).1

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