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.
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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