Most cases are caused by genetic mutations that lead to a deficiency (Type 1) or dysfunction (Type 2) of C1 esterase inhibitor, which regulates several pathways, including the kallikrein-kinin and contact activation system. There is a third, exceptionally rare type, whose cause is unknown.
Treatment relies on the prevention of attacks with drugs such as bradykinin inhibitors and, without such treatment, attacks typically occur every couple of weeks, lasting for a few days. Current prophylactic approaches are limited and tolerability is an issue.
An alternative treatment is being developed by Ionis. Donidalorsen is a ligand-conjugated antisense medicine that’s designed to reduce the production of prekallikrein (PKK).
This is a serine protease that is involved in the activation of an inflammatory mediator associated with acute HAE attacks. It has the potential to be given via monthly low-volume subcutaneous injections. In a compassionate use study, one patient with Type 1 HAE and another with Type 3 were first treated with donidalorsen for 12–16 weeks and then given 80 mg every 3–4 weeks for 7 or 8 months.1
Both patients had a meaningful reduction in HAE attack rates, with plasma prekallikrein activity levels being substantially decreased.
Results of a Phase II study have also been reported.2 In all, 20 patients with Type 1 or Type 2 HAE were randomised to receive 80 mg of donidalorsen or a placebo once a month for 17 weeks. There was a mean reduction of 90% in the number of monthly HAE attacks in weeks 1–17 and a mean reduction of 97% in weeks 5–17.
During this latter period, more than 90% of the treated patients were attack free, compared with none of those in the placebo group. Most of the adverse events were mild and their frequency was similar in both groups. The most common were headache and nausea, both of which were more common in the placebo group.
References
- D.M. Cohn, et al., N. Engl. J. Med. 383, 1242 (2020).
- D.M. Cohn, Am. Coll. of Asthma, Allergy & Immunology (ACAAI) Annual Scientific Meeting 2021 (4–8 November, New Orleans, LA, US).