The European Medicines Authority’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for a new drug to treat hereditary angioedema (HAE). Long-term treatment with Dawnzera (donidalorsen, Otsuka Pharmaceutical Netherlands B.V.) offers a potential 80% reduction in attack frequency. Prophylactic treatment is potentially lifesaving, as the condition carries a long-term mortality rate estimated between 32% and 56%.

HAE is a rare autosomal dominant disease involving episodic angioedema affecting various body parts, including hands, feet, face, and airways. Symptoms may also include bouts of excruciating abdominal pain, nausea, and vomiting due to swelling in the intestinal wall. Edema results from capillary leakage into tissues caused by inappropriately elevated bradykinin levels, which promote increased vascular permeability, vasodilatation, and smooth muscle contraction. Airway edema and asphyxiation may be fatal.

Approximately 75% of HAE cases are inherited and 25% believed to be due to de novo mutations. Prevalence figures are hard to come by as the disease is so rare, but it has been estimated to affect between 1 in 10,000 and 1 in 50,000 people. A national survey in the UK published in the Journal of Allergy and Clinical Immunology in 2023 estimated the minimum prevalence of HAE as 1 in 59,000 people. 

Patients Need On-Demand Treatment for Acute Attacks

International guidelines suggest that all HAE patients should be given an on-demand treatment for acute attacks and be taught to self-administer a C1 protease-inhibitor (C1-INH) or icatibant intravenously as early as possible when symptoms develop. Short-term prophylaxis may be given before angioedema attack precipitants, including medical, surgical, or dental procedures. 

In addition, long-term prophylactic treatment is recommended for all patients to attempt to achieve disease control and improve quality of life. Plasma-derived C1-INH is currently the preferred first line prophylactic agent, and donidalorsen now offers an alternative. The CHMP recommended that Dawnzera be given marketing authorization for the routine prevention of recurrent attacks of HEA in adults and adolescents aged 12 years and older. The drug is given as an 80 mg solution for injection in pre-filled pens. 

Drug Reduces Bradykinin Production

Donidalorsen is a targeted prekallikrein-directed antisense oligonucleotide conjugated to a triantennary N-acetylgalactosamine moiety that causes ribonuclease H1-mediated degradation of prekallikrein mRNA. This reduces production of the prekallikrein protein that regulates bradykinin, the potent vasodilator causing inflammation and swelling in HAE.

In a phase 3, double-blind, placebo-controlled study, donidalorsen given every 4 weeks yielded an 81% reduction in HAE attack rate compared with placebo from baseline to week 24. This sustained response was observed throughout the treatment period. The most common side effects included injection site reactions, increased hepatic enzymes, and hypersensitivity (including anaphylaxis).

Treatment with Dawnzera should be initiated under the supervision of a physician experienced in the diagnosis and management of patients with HAE.

Dawnzera was originally given orphan medicine status during its development. The EMA will now review the information available to date to determine if the orphan designation can be maintained.

Detailed recommendations for use of Dawnzera will be described in the summary of product characteristics, which will be published on the EMA website in all official European Union languages after the marketing authorization has been granted by the European Commission.