Garadacimab for hereditary angioedema aged 12 and over [D6394]

Hereditary angioedema (HAE) is a rare genetic disorder associated with the deficiency of the protein C1-esterase inhibitor which is a regulator of inflammatory pathways.

Normally C1-esterase inhibitor controls the enzyme cascade reactions sothat uncontrolled swelling of the subcutaneous and submucosal tissues do not occur.

In patients with HAE at times of physiological or psychological stress the function of the C1-esterase inhibitor is insufficient resulting in the accumulation of excessive fluid (oedema) and localised oedematous swellings.

The swellings often occur in the mouth the gut (affecting the submucosal tissues) and the airway causing difficulty with breathing (with potential asphyxia) and severe pain in the stomach.

The swellings can also occur in the deep tissues of the skin (affecting the dermis and subcutaneous tissues) causing significant impact for example if the hands feet or genitals are affected.

HAE attacks are associated with disfiguration severe pain inability to perform daily activities and feelings of fear and anxiety.

Many angioedema attacks are associated with trauma medical procedures emotional stress menstruation oral contraceptive use infections or the use of medications such as ACE inhibitors. But often a specific trigger cannot be identified.

Attacks are unpredictable; severity and frequency of previous attacks do not predict severity and frequency of future attacks. Attacks usually last approximately 2 to 5 days before resolving spontaneously.There are 3 types of HAE.

Types I (85%) and II (15%) are a result of a known genetic mutation and account for almost all cases of HAE (1):• type I is defined by low levels of a normal protein C1-esterase inhibitor in the plasma.• type II is defined by normal level of a dysfunctional protein C1-esterase inhibitor in the plasma.• HAE with normal C1 inhibitor (previously referred to as type III) is not a result of the deficiency of protein C1-esterase inhibitor.

However it is known that oestrogen has a role not yet fully understood.(2)It is estimated that type I and type II HAE affect at least 1 per 59000 of the UK population and can affect people of any ethnic group or gender.13 HAE usually presents in childhood with the mean age of onset being between 8 and 12-years.Attacks rarely occur before two years of age and are less frequent before adolescence. (1)There are 3 approaches to managing HAE: avoidance of factors that trigger HAE (e.g. minor trauma hormone replacement therapy) acute treatments and preventive (prophylactic) treatments of acute attacks.

Short-term preventive treatments aim to prevent an attack before known triggers for example dental work or surgery. Long-term preventative treatments are used routinely to reduce the need for treatment of acute attacks.

As a long term strategy attenuated androgens or C1-esterase inhibitors (C1-INH) such as Cinryze Ruconest or Berinert can be used.

Antifibrinolytics such as tranexamic acid can also be used.NICE Technology Appraisal 606 recommends lanadelumab for preventing recurrent attacks of hereditary angioedema in people aged 12 and older only if they are eligible for preventative C1-INH in line with NHS Englands commissioning policy andlowest dosing frequency of lanadelumab is used when the condition is in a stable attack-free phase.NICE Technology Appraisal 738 recommends berotralstat for preventing recurrent attacks of hereditary angioedema 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.References1.

NHS Clinical commissioning: plasma derived C1-esterase inhibitor for prophylactic treatment of HAE (2016). Accessed May 2024https://www.england.nhs.uk/commissioning/wpcontent/uploads/sites/12/2013/05/16045_FINAL.pdf2.

Amanda Rodrigues Miranda APFdU Dominique Vilarinho Sabbag Wellington de Jesus Furlani Patrícia Karla de Souza Osmar Rotta. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. An Bras Dermatol.2013;88(4):578–84.3. Yong PFK Coulter T El-Shanawany T et al.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom. Journal of Allergy and Clinical Immunology: In Practice. 2023.