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

ABSTRACT

Introduction: 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.

KEYWORDS:

• Hereditary angioedema
• C1-inhibitor deficiency
• intravenous plasma-derived C1-inhibitor
• subcutaneous plasma-derived C1-inhibitor
• recombinant human C1-inhibitor
• kallikrein inhibitor
• Factor XII inhibitor
• prophylaxis
• acute treatment

Article highlights

• Hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare, life-threatening disease, characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks). It requires special therapy, as HAE attacks do not respond to conventional therapy.

• In addition to the conventional replacement therapy of C1-INH-HAE, which is based on the correction of C1-INH deficiency by supplying the protein from an external source, gene therapy is a promising alternative treatment in the future.

• The therapeutic alternative of inhibiting the targets of C1-INH is improving, as the range of licensed agents (icatibant and ecallantide), is expanded by novel medicinal products (such as small-molecule kallikrein inhibitors, monoclonal antibodies against Factor XII and kallikrein, and antisense oligonucleotide inhibitors against Factor XII and prekallikrein).

• The route of the administration of medicinal products is changing, as intravenous preparations are overshadowed by preparations to be administered by the oral or by the subcutaneous route. Furthermore, prophylaxis with long-acting agents comes to the fore.

• This review summarizes the status and the findings of the currently ongoing preclinical, Phase I and Phase II studies of C1-INH-HAE.

This box summarizes key points contained in the article.

Declaration of Interest

Henriette Farkas received honoraria, travel grants and payment for lectures from CSL Behring, Shire, Swedish Orphan Biovitrum, Biocryst, and Pharming, and/or served as a consultant for these companies. Kinga Viktória Kőhalmi has received travel grants from CSL Behring and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.