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Berotralstat Suppresses Hereditary Angioedema Attacks Without Safety Concerns

A recent study has discovered that once a day berotralstat – an oral inhibitor of plasma kallikrein, which suppresses hereditary angioedema or HAE attacks without posing strong safety concerns.

Berotralstat Suppresses Hereditary Angioedema Attacks Without Safety Concerns
Photo: Hereditary Angioedema | InStyleHealth

What Is Hereditary Angioedema?

Hereditary angioedema is a rare genetic or hereditary disorder which is characterized by recurring episodes of the accumulation of fluids outside the blood vessels, which is also blocking the normal flow of blood or lymphatic fluid and is causing a rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Hereditary angioedema is inherited as an autosomal dominant trait. These genetic diseases are determined by two genes, one received from the father and one from the mother.

The dominant genetic disorder occurs when only a single copy of an abnormal gene is necessary for the appearance of the disease. Abnormal gene can be inherited from either parent, or it can be a result of a spontaneous new mutation or genetic change in the affected person. The risk of passing the abnormal gene from affected parent to a child is 50% for each pregnancy regardless of the child’s gender.

Generally, the swelling is not accompanied by itching, for it might be with an allergic reaction. The swelling of gastrointestinal tract can lead to cramping. The swelling of the airway can lead to obstruction which is potentially a very serious complication.

Symptoms will develop as the result of deficiency or improper functioning of certain proteins that help in maintaining the normal flow of fluids through tiny blood vessels called capillaries. Although in other cases, fluids may accumulate in the other internal organs of the human body. The degree of severity of this illness greatly varies in every person with such condition.

Most common form of this disorder is hereditary angioedema type I – a result of abnormally low levels of certain complex proteins in our blood (C1 esterase inhibitors), which is also known as complements. The complements help regulate various body functions, such as flow of body fluids in and out of our cells. The hereditary angioedema type II – is a more uncommon form of the disorder, which occurs as a result the production of abnormal complement proteins.

What Are the Signs & Symptoms of Hereditary Angioedema?

A symptom of hereditary angioedema or HAE is the recurrent episodes of swelling of affected areas of the body due to the accumulation of excessive body fluid or edema. Areas of our body most commonly affected include our hands, feet, eyelids, lips, and even the genitals. An edema may also take place in the mucous membranes that line the respiratory and digestive tracts, which is prevalent or more common in people with hereditary angioedema than in those who have other forms of angioedema (e.g., acquired or traumatic). Individuals with this disorder generally have areas of swelling that are hard and painful, not red and itchy or pruritic. A skin rash or urticaria rarely is existent.

Symptoms of the hereditary angioedema or HAE can recur and be even become more severe in some cases. Injury, severe pain, surgery, dental procedures, viral illness, and stress can trigger or may worsen the recurring symptoms of hereditary angioedema.

The symptoms connected with swelling in the digestive system or gastrointestinal tract may include nausea, vomiting, acute abdominal pain, and other signs of obstruction. While edema of the throat or pharynx or in our voice-box (larynx) may result in painful and difficulty in swallowing or dysphagia, difficulty speaking or dysphonia, noisy respiration or stridor, and potentially asphyxiation which is life-threatening.

What Causes Hereditary Angioedema?

Hereditary angioedema is caused by a gene that is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present or existent in the nucleus of human cells, carry the genetic information for each person or individual. The pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of gender chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.

This genetic disorder, the hereditary angioedema, is caused by low levels or improper functioning of a protein called the C1 inhibitor. It is affecting the blood vessels – the capillaries. An HAE attack may result in rapid swelling of the hands, feet, limbs, face, intestinal tract, larynx (voice-box), or trachea (windpipe).

Berotralstat Treatment Suppresses Hereditary Angioedema Attacks

Experts conducted a double-blind, parallel-group study including 120 individuals who were randomized to receive 110- or 150-mg berotralstat or placebo. The participants were qualified if they had confirmed HAE due to C1 inhibitor deficiency and had at least two HAE attacks in a 56-day run-in period. Primary results was the rate of attacks in the 24-week treatment period.

The placebo group had an estimated, investigator-confirmed monthly HAE attack rate of 2.35 throughout the 24 weeks of observation. Comparatively, the 110-mg berotralstat dose generated a significantly lower attack rate of 1.65. The 150-mg dose similarly suppressed HAE attacks significantly vs placebo.

The treatment-emergent adverse events or TEAEs were recorded in 83% and 85% of the 110- and 150-mg berotralstat dose groups, accordingly. With the placebo arm, 77% experienced TEAEs. Most common TEAEs were abdominal pain, vomiting, diarrhea, and back pain.

Serious TEAEs were recorded in one patient in the 110-mg berotralstat arm and 3 patients in the placebo group, none of which were considered drug-related. Though, 3 drug-related grade 3 or 4 AEs were recorded, all in the 110-mg arm.

Researchers of this study said that the combination of efficacy, safety, and tolerability with convenient oral, once-daily dosing will make berotralstat an important addition to the HAE-C1 inhibitor therapeutic armamentarium.


Source: J Allerg Clin Immunol 2021;148:164-172.e9

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