FDA Approves Luspatercept-aamt to Reduce Blood Transfusion Requirements in Patients with Beta Thalassemia

On 8 November 2019, the US Food and Drug Administration (FDA) approved luspatercept-aamt (Reblozyl) for treatment of anemia in adult patients with beta thalassemia requiring regular red blood cell transfusions (blood transfusions).

Luspatercept-aamt is the first drug to receive FDA approval for beta thalassemia treatment.

Luspatercept-aamt’s efficacywas assessed in 336 adults with beta thalassemia requiring regular red blood cell transfusions in BELIEVE, a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized in a 2:1 ratio to luspatercept-aamt (224) or placebo (112). Luspatercept-aamt was administered subcutaneously every 3 weeks as long as a reduction in transfusion requirements was observed or until unacceptable toxicity (side effects).

The primary efficacy outcome was the proportion of patients achieving, from week 13 through week 24, a reduction of at least 2 units in blood transfusion requirements, representing a 33% reduction in transfusion burden.

Among patients receiving luspatercept-aamt, 21.4% achieved this goal, compared with only 4,5% of placebo recipients. The most common side effects (>10%) in beta thalassemia patients receiving luspatercept-aamt were headache, bone pain, joint pain, fatigue, cough, abdominal pain, diarrhea and dizziness.

The recommended starting dose is given by subcutaneous injection every 3 weeks at 1 mg / kg.

How Does Luspatercept-aamt Work?

Luspatercept-aamt is a recombinant fusion protein that binds several endogenous TGF-a family ligands, thereby reducing Smad2 / 3 signaling. Luspatercept-aamt promotes erythrocyte maturation through differentiation of late-stage erythroid precursors (normoblasts).

What is beta thalassemia?

Beta thalassemia is a preventable blood disorder inherited from parents. It is an important public health problem in Mediterranean countries, including Turkey. Although it can be prevented through carrier identification, genetic counseling and prenatal diagnosis, at least 365.000 people with thalassemia are born worldwide each year and receive treatment. Turkey has approximately 1.300.000 thalassemia carriers and around 4.500 patients with thalassemia.

Beta thalassemia is a severe disease that substantially shortens life if treatment is not properly maintained and has a very negative impact on quality of life. Treatment is difficult and very expensive. The annual treatment cost for a patient with thalassemia is approximately 10.000 dollars. Preventing affected individuals from being born is therefore very important, and the government also supports taking the necessary preventive measures.

How does beta thalassemia develop?

Hemoglobin in our red blood cells carries oxygen needed by tissues. The hemoglobin molecule has two components: heme and globulin. In a healthy person, the globin protein consists of two pairs of polypeptide chains.

According to their polypeptide chains, adult erythrocytes contain 3 different types of hemoglobin:

1. Hemoglobin A: Its globin component consists of 2 alpha and 2 beta polypeptide chains. It accounts for 96-98% of total hemoglobin.
2. Hemoglobin F: Its globin component consists of 2 alpha and 2 gamma polypeptide chains; it accounts for less than 1% of total hemoglobin.
3. Hemoglobin A2: Its globin component consists of 2 alpha and 2 delta polypeptide chains; it accounts for less than 2-3% of total hemoglobin.

Hemoglobin production is controlled by genes. Thalassemia occurs if a genetic defect causes insufficient or faulty production of one of the globin chains forming hemoglobin. Thalassemia is named after whichever globin chain cannot be synthesized or has reduced synthesis. For example, altered beta globin synthesis causes beta thalassemia, while altered alpha globin synthesis causes alpha thalassemia. In beta thalassemia, abnormal hemoglobin structure causes red blood cells to break down rapidly, resulting in anemia.

What are carrier status and disease in beta thalassemia?

Humans have two copies of the genes for a trait, one inherited from the mother and the other from the father. For beta thalassemia, if the globin genes inherited from both parents are normal, the child is normal; if one is altered, the child is a carrier; if both are altered, the child has the disease.