Biological therapy in hereditary angioedema: transformation of a rare disease

ABSTRACT

Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder.

Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated.

Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.

KEYWORDS:

• Hereditary angioedema
• bradykinin
• plasma derived C1 inhibitor
• recombinant human C1 inhibitor
• kallikrein inhibitor
• bradykinin B2 receptor antagonist
• FXII human monoclonal antibody
• acute treatment
• long-term prophylaxis

Article highlights

• Hereditary angioedema is a bradykinin-mediated angioedema caused in most cases by haploinsufficiency of C1 inhibitor function.

• Patient, physician, nurse, scientist, and pharmaceutical company collaboration has enabled development of life-changing therapies for this rare condition.

• Plasma-derived and recombinant C1 inhibitors are effective in terminating angioedema attacks and in prophylaxis.

• Synthetic peptides blocking kallikrein or bradykinin B2 receptor are effective in terminating angioedema attacks.

• Continuous inhibition of the contact pathway by a monoclonal antibody, which blocks kallikrein activity or with subcutaneous C1 inhibitor can result in complete freedom from angioedema attacks.

• Potential future therapies include oral acute and prophylactic treatments and gene therapy.

This box summarizes key points contained in the article.

Declaration of interest

H Longhurst has received honoraria, travel grants, and payment for lectures from Adverum, BioCryst, CSL Behring, Pfizer, Pharming and Shire/Takeda, and/or served as a consultant or participated in research with these companies. H Farkas has received honoraria, speaker fee, and travel grants from CSL Behring, Shire/Takeda, Swedish Orphan Biovitrum, Octapharma, Biocryst and Pharming and/or served as a consultant for these companies and has participated in clinical trials/registries for BioCryst, CSL Behring, Pharming and Shire/Takeda. 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.

Reviewer disclosures

One of the reviewers of this manuscript has served on the advisory board for Biocryst and served as expert witness in patent dispute regarding HAE medicine. Two additional Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.