What is thalassaemia and are better treatments on the way?

The condition is caused by the body struggling to make haemoglobin, the iron-containing protein in the blood that carries oxygen

New clinical trials are a step forward in efforts to treat thalassaemia. Photo: The National

The news this week that Abu Dhabi is to begin clinical trials of a drug called Mitapivat could herald a step forward in the treatment of thalassaemia in the UAE.

As reported in The National, Burjeel Medical City is taking part in phase 3 trials to test the drug’s safety and to see how effective it is at treating adults with the inherited blood disorder.

Here we look at thalassaemia and consider how significant Mitapivat may prove to be.

What is thalassaemia?

Thalassaemia is a group of blood disorders that mean people do not produce enough haemoglobin, the iron-containing protein that carries oxygen in the blood. Lower haemoglobin levels make patients anaemic and cause fatigue and shortness of breath.

Other symptoms may include weakness, slow growth and changes to the bones of the face, the result of bone marrow overexpansion, which alters appearance. Also, the skin may be pale or yellowish and the urine dark. People with thalassaemia may additionally be more at risk of infections.

There are two main forms of thalassaemia, alpha and beta, depending on which of the two parts of the haemoglobin molecule, the alpha or the beta chain, the body is less able to produce.

What causes thalassaemia?

Thalassaemia develops when a person inherits particular gene mutations. Alpha thalassaemia results from a person inheriting mutations in the haemoglobin alpha gene, HBA, which codes for the alpha chain.

There are two copies of this gene, HBA1 and HBA2, on chromosome number 16. Most people have 23 pairs of chromosomes, a copy from each parent, so each of us has four copies of HBA genes in total.

A person with a single mutated HBA gene copy will not have any symptoms, while someone with two will have mild symptoms. A person with three has moderate-to-severe thalassaemia, while babies with four are usually stillborn, according to the Mayo Clinic in the US.

Beta thalassaemia is caused by mutations in the haemoglobin beta gene, HBB, of which there is a single copy on chromosome number 11. A person inherits two HBB gene copies, one from each parent.

With one mutated copy, symptoms are mild (beta thalassaemia minor), while two mutated copies usually causes moderate-to-severe symptoms (beta thalassaemia major), with abnormalities typically beginning before the second birthday.

Sometimes a person with two mutated HBB copies has a milder form, beta thalassaemia intermedia, depending on which part of the beta chain the mutation affects.

Two parents, each of whom is a carrier, with mutated genes but no symptoms, may have a child with severe thalassaemia.

Thalassaemia was described in a 2020 review in the Orphanet Journal of Rare Diseases as "one of the most common genetic abnormalities", with the carrier rate globally estimated at between 1 per cent and 5 per cent.

Can the condition be prevented?

Thalassaemia tends to be more common in people of Middle Eastern, African, Mediterranean and South, South-East or East Asian descent.

Consanguineous marriages often contribute to higher rates of thalassaemia in parts of the Middle East, because with these marriages, the husband and wife are more likely to have similar genes to one another. This increases the likelihood of two carriers having children together.

The UAE has an extensive pre-marital screening programme to highlight whether prospective couples are at risk of having a child with thalassaemia.

However, a 2017 study in the journal Plos One by two researchers at UAE University in Al Ain noted that, despite efforts to reduce the number of children born with thalassaemia, "there is still a large carrier population in the UAE".

"As soon as the government stops its emphasis on thalassaemia control at [the] present level, the thalassaemia major population will experience a resurgence," the researchers wrote.

"Therefore, we suggest that the UAE government continues its current level of thalassaemia management and develops various additional ways to reduce carrier-carrier marriages."

Can it be treated?

According to the UK’s National Health Service, monthly blood transfusions may be required by people with beta thalassaemia major, the most severe form of the disease. Patients with milder forms may require blood transfusions, but less frequently.

These blood transfusions, and the disease itself, may lead to excessive levels of iron building up in the blood, sometimes damaging the heart, lungs and the endocrine system of glands throughout the body.

To combat this, patients may require chelation therapy, in which they are given drugs intravenously that contain substances that bind to the iron, which the body is then able to excrete.

According to the University of Pennsylvania Health System in the US, while less severe forms of thalassaemia may not shorten life expectancy, people with beta thalassaemia major often die in their 20s because the build-up of iron in the blood causes heart failure.

Mitapivat, the drug being evaluated in the UAE, increases activity of an enzyme called pyruvate kinase, a deficiency of which can cause red blood cells to be destroyed prematurely.

One part of the Abu Dhabi trials, Energise, will evaluate Mitapivat’s effectiveness at improving haemoglobin levels in patients not requiring regular transfusions.

The study’s other programme, Energise-T, will consider whether transfusion requirements can be reduced in individuals with more severe disease.

A study last year reported in The Lancet medical journal found that all patients with alpha thalassaemia and 73 per cent of those with beta thalassaemia had improved levels of haemoglobin after taking Mitapivat. The research indicated that the drug helped red blood cells to mature or increased their survival.

"This study establishes proof of concept that activation of pyruvate kinase by the oral agent Mitapivat improves anaemia in patients with non-transfusion-dependent alpha thalassaemia and beta thalassaemia," wrote the researchers, who were from Canada, the US and the UK.

So thalassaemia patients may have improved prospects if further trials prove successful and the drug is made available more widely.