Kallikrein inhibitors for angioedema: the progress of preclinical and early phase studies

ABSTRACT

Introduction

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent edema and predominantly caused by the dysregulation of the kinin-kallikrein system.

Areas covered

This manuscript presents the results of preclinical and early clinical trials of newer drugs targeting the dysregulated kinin-kallikrein system. ATN-249 is an oral drug that has shown promising results in preclinical and Phase I studies, and good tolerability in the prophylactic treatment of attacks. KVD900 is also an oral agent developed for the on-demand treatment of HAE attacks. It has shown positive results in Phase I/II studies, with rapid absorption. The third drug, IONIS-PKKRx, is an antisense oligonucleotide targeting plasma prekallikrein mRNA. It has shown a dose-dependent reduction of plasma prekallikrein levels and proenzyme activation in Phase I/II studies, and has shown promising results. STAR-0215 is a long acting anti-activated kallikrein monoclonal antibody. A Phase 1a single ascending dose trial evaluated its safety, pharmacokinetics, and pharmacodynamics. Lastly, NTLA-2002 is an investigational gene-editing therapy.

Expert opinion

The targeted treatment of the dysregulated kinin-kallikrein system with specific inhibitors is promising for the prevention of angioedema attacks. Ongoing phase III studies will provide further insight into the efficacy and long-term safety of these novel therapies, potentially expanding treatment options for HAE treatment.

KEYWORDS:

• Angioedema
• bradykinin
• clinical trial
• donidalorsen
• gene-editing therapy
• kallikrein
• prophylaxis
• sebetralstat

Article highlights

• Hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare, autosomal dominantly inherited disease, characterized by recurrent, unpredictable edematous episodes (HAE attacks).

• C1-INH-HAE is a bradykinin-mediated disorder and requires special therapy.

• Targeted therapies are aimed partly at replacing the missing C1-INH and partly at inhibiting the contact kallikrein-kinin system.

• Newly developed inhibitors of the kallikrein-kinin system target kallikrein or bradykinin B2 receptor using various techniques such as small inhibitory molecules, monoclonal antibodies, antisense oligonucleotides, CRISPR/Cas9.

• The kallikrein-kinin inhibitors are aimed partly at the resolution of HAE attack and partly at its development.

• This review summarizes the results of newly developed kallikrein-kinin system inhibitor drugs in preclinical and early clinical trials.

Declaration of interests

Z Balla has participated in clinical trials of CSL Behring, Pharvaris, and Takeda. H Farkas has received research grants from CSL Behring, Takeda, and Pharming and served as an advisor for the above companies and for Kalvista and Biocryst, Pharvaris, ONO Pharmaceuticals, Intellia, and has participated in clinical trials/registries for BioCryst, CSL Behring, Pharming, Kalvista, Pharvaris, and 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.