Investigational drugs in phase I and phase II clinical trials for hereditary angioedema

Abstract

Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required. Areas covered: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII. Expert opinion: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.

Hereditary Angio-Oedema for Dermatologists

“…Antifibrinolytics, especially tranexamic acid, have been used for many years and might be somewhat effective in up to one-third of patients [35, 56, 119, 120]. These drugs inhibit plasminogen activation and consequently reduce C1INH usage.…”

“…It should be used for LTP with an injection of 300 mg every 2 weeks in HAE patients 12 years of age and older [123, 124]. Progestins have also been used to reduce the number of HAE attacks [35, 125]. …”

“…An open-label multicentre study in 146 subjects for almost 3 years documented a 93.7% reduction in attack frequency in patients treated with Cinryze® 1,000 units every 3–7 days [111]. Low-volume plasma-derived C1INH concentrate (CSL830 with trade name Haegarda®) for subcutaneous administration has been licensed in the USA and is a patient-friendly approach [35]. The dose requirements (3,000–6,000 IU twice weekly) are higher than in intravenous administration.…”

“…Multiple new therapies are being investigated for the treatment of HAE: oral small molecule plasma kallikrein inhibitors (BCX7353, ATN-249, and KVD818), RNA-targeted antisense against prekallikrein (IONIS-PKKRx), RNA interference drugs against Factor XII (ALN-F12 and ARC-F12), and a Factor XIIa antagonist monoclonal antibody (CSL 312) are currently being investigated [35, 36, 134]. It is possible in the future that gene therapy with gene-editing techniques or viral vector-based gene transfer might also be an option with curative potential [135, 136].…”

“…Based on current insights into genetic and pathophysiological aspects of the disease, new therapies have been developed and introduced in clinical practice for HAE with C1INH deficiency within the last decade, and additional new drugs are on the horizon [35, 36]. Several investigational drugs, such as small synthetic molecules, oligonucleotides, or antibodies, which work by inhibiting Factor XII or kallikrein, are undergoing clinical trials.…”