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17th September 2021
Hereditary angioedema (HAE) is a rare, inherited disorder that presents with unpredictable, recurrent attacks of oedema, leading to a rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The condition affects around 1 in 50,000 of the population in the UK, which equates to around 1,500 people and the condition often first presents between the ages of 5 and 11 years.
The underlying cause of HAE is a mutation of the SERPING1 gene which codes for a protein, C1 esterase inhibitor (CI IHB), which regulates inflammatory pathways. This mutation can result in either low levels of C1 IHB, which is the most common presentation (type 1), accounting for around 85% of cases, or normal levels of C1 IHB, but with a reduced function (type 2). There is also a third, much rarer type characterised by normal C1 IHB levels but other mutations which also give rise to elevated levels of bradykinin. Irrespective of the underlying cause, reduced functioning of C1 IHB leads to an increased production of the vasoactive peptide, bradykinin which mediates vasodilation in subcutaneous or submucosal tissues.
The aim of treatment is to either reverse or prevent attacks with a view to improving patient’s quality of life. Treatments have been based on prophylactic use of C1 IHB concentrates, some of which have been developed as injectables for self-administration. In contrast, berotralstat, is an oral, once daily inhibitor of plasma kallikrein which is hydrolysed to release bradykinin.
The NICE approval was based on the findings of the randomised phase 3 trial, APex-2, a double-blind, parallel-group study in which patients were randomised 1:1:1, to receive once-daily berotralstat in a dose of 110 mg, 150 mg or placebo. In APex-2, the primary efficacy end point was defined as the rate of investigator-confirmed HAE attacks during the 24-week treatment period. The study found that use of berotralstat led to a significant reduction in attack rate at both 110 mg (1.65 attacks per month, p = .024) and 150 mg (1.31 attacks per month, p < .001) relative to placebo (2.35 attacks per month). An extension of APex-2 was published in June 2021 in which patients originally assigned to placebo were randomised to either 110 mg or 150 mg of berotralstat and followed for 48 weeks. At the study end, mean attack rates for the 150mg group declined from a baseline of 3.06 attacks/month to 1.06 at week 48. Similarly, for the 110mg group, attack rates reduced from a baseline of 2.97 to 1.35 at week 48.
NICE has declared berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema and recommended that the drug can be used under the following circumstances.
In people 12 years and older, only if:
• they have at least 2 attacks per month and
• it is stopped if the number of attacks per month does not reduce by at
least 50% after 3 months.
Source: NICE. Berotralstat for preventing recurrent attacks of
hereditary angioedema, September 2021.