Hereditary angioedema: examining the landscape of therapies and preclinical therapeutic targets

KEYWORDS:

• Hereditary angioedema
• kallikrein
• bradykinin
• recombinant
• monoclonal antibody
• Factor XII
• gene therapy
• C1-inhibitor
• prekallikrein

1. Introduction

The time since hereditary angioedema (HAE) – a rare or orphan disease – was first described in the nineteenth century has brought dramatic changes to its accurate understanding. The exploration of the roles of the complement, fibrinolytic, coagulation, and kinin-kallikrein systems underlying the pathophysiology of HAE, along with the expansion of the toolkit of molecular genetics, has opened new perspectives in the diagnosis and management of HAE. Currently, the following six types of the disease are known: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) was described first; it results from a mutation in the SERPING1 gene of the C1-inhibitor and has two types (I and II). The remaining four types are hereditary angioedema with normal functional C1-INH with mutation of Factor XII, plasminogen [1], or angiopoietin-1 genes [2], plus a form of unknown etiology [3]. The clinical manifestations of these HAE types are rather similar to one another. All are characterized by the acute onset of recurrent episodes of subcutaneous and/or submucosal angioedema. Generation of bradykinin as a vasoactive mediator plays an important role of the pathophysiology of C1-INH-HAE. Involvement of the contact-kinin system in HAE with normal C1-INH is likely to exist, but experimental evidence is still extremely weak.

The pathophysiology has been most completely elucidated in the case of C1-INH-HAE and can be summarized as follows: The deficiency of the complement regulatory protein C1-inhibitor reduces the control of the activation of the contact-kinin system. When activated, the zymogens Factor FXII (FXII) and plasma prekallikrein reciprocally cleave each other to generate the active proteases FXIIa and plasma kallikrein. Plasma kallikrein cleaves high-molecular-weight kininogen releasing bradykinin. Bradykinin binds to the B₂ receptor to release NO, prostacyclin, and endothelium-derived hyperpolarizing factor. These mediators cause vasodilation, increased vascular permeability, and smooth muscle contraction, which in turn lead to fluid extravasation and angioedema [4].

2. Body

2.1. Drug therapies for C1-INH-HAE

A number of treatment modalities have been developed, clinically tested, and licensed for the management of C1-INH-HAE in the first place. Some of the medicinal products available currently for this purpose (including attenuated androgens, antifibrinolytic agents, and progestogens) had been originally developed for other therapeutic uses, were introduced into the therapy of HAE empirically, and thus our knowledge about their modes of action is still incomplete [5]. By contrast, all recently developed medicinal products may be regarded as targeted therapies. These agents are used for acute therapy, which is intended to provide rapid, safe, and effective relief for HAE attacks regardless of the location and the severity of the swelling, or – when administered as prophylaxis – to reduce the frequency and severity of HAE attacks. These drugs are characterized by different modes of action including the inhibition of bradykinin release by replenishing the deficient C1-INH protein – this is accomplished by administering C1-INH concentrate derived from human plasma or purified from the breast milk of transgenic rabbits – or by inhibiting kallikrein with a kallikrein inhibitor, or by blocking the effect of the released bradykinin on its receptor with bradykinin B2-receptor antagonists. In addition to C1-INH replacement therapy, which could be administered previously by the intravenous route only, medicinal products for subcutaneous injection have become available in clinical practice. These agents are appropriate both for the acute treatment of HAE episodes (the kallikrein inhibitor ecallantide and the bradykinin B₂ receptor antagonist icatibant) and for prophylaxis (subcutaneous, plasma-derived C1-INH) [6]. CSL830, a low-volume, human plasma-derived, pasteurized, nanofiltered C1-inhibitor preparation is suitable for subcutaneous injection. Subcutaneous C1-inhibitor administered twice-weekly reduces the frequency of HAE attacks and helps to overcome many of disadvantages of long-term intravenous administration. Fully human, recombinant, monoclonal, IgG₁ type antibody against human plasma kallikrein–lanadelumab [7] has been developed for prophylaxis of HAE attacks. The introduction of lanadelumab represents a milestone in prophylaxis because this agent is intended for subcutaneous use, and its long duration of action allows dosing once or twice a month, which is rather comfortable for the patient. The pdC1-INH i.v. and s.c for acute treatment and prophylaxis, rhC1-INH and icatibant for acute treatment, and lanadelumab for prophylaxis are licensed for self-administration.

2.2. New therapies under development for HAE

The key considerations for the development of new medicinal products include easier administration and keeping the patient attack-free. Oral medicines have also come to the fore. Phase II and III studies are conducted with the oral kallikrein inhibitor BCX7353 administered both for the acute treatment and for the prophylaxis of HAE episodes [8]. However, the development of innovative drugs has not yet been concluded. The broad range of medicinal products administered for the treatment of HAE continues to expand and aids the prevention of HAE attacks predominantly. In particular, preclinical studies are being conducted with an additional two novel, potent and selective, orally administered kallikrein inhibitors [ATN-249 [9] and KVD900 [10]]. A series of macrocyclic analogs was designed and synthesized based on the cocrystal structure of the small-molecule plasma kallikrein (pKal) inhibitor 2, with the pKal protease domain. This led to the discovery of a potent, macrocyclic pKal inhibitor 29 [11], as well as a new program has been recently started to develop orally administered therapeutic agents for HAE [12]. Three new therapeutic targets have come into focus: prekallikrein, coagulation Factor XII, and the SERPING1 gene. IONIS-PKK_Rx, a single-stranded, antisense oligonucleotide (ASO) was developed against plasma prekallikrein (PKK) and tested in the mouse. PKK ASO selectively reduced liver mRNA expression and plasma protein levels. The plasma level of cleaved, high-molecular-weight kininogen also decreased in correlation with the observed reduction in permeability [13]. In a randomized, double-blind, placebo-controlled, dose-escalation Phase I study, healthy volunteers treated with IONIS-PKKRx achieved dose-dependent reductions of PKK level. As FXII is the principal initiator of the plasma contact system, it has been postulated that the inhibition of FXIIa by an anti-FXIIa antibody might prevent the onset of HAE attacks. Animal studies conducted with a fully human recombinant antibody (3F7) in mouse and rabbit models confirmed this antibody as a specific and potent inhibitor of FXIIa. A 3F7 affinity-matured form, CSL312 – a fully human, IgG4 type recombinant monoclonal antibody binds to the catalytic site of FXIIa, blocking its proteolytic activity – was found to be a potent inhibitor of FXIIa-mediated kallikrein activity. CSL312 exhibited a long plasma half-life in Cynomolgus monkeys and prolonged the inhibition of FXIIa activity following administration of a single dose in a 36-day study. Specific, antibody-mediated inhibition of FXII protease activity reduced edema-formation in animal models and prevented the formation of bradykinin following contact activation in plasma samples from patients with C1-INH-HAE type I/II, HAE with normal C1-INH, or acquired angioedema [14]. A Phase I, single-center, randomized, double-blind, placebo-controlled, single ascending dose study is underway. ALN-F12 – a siRNA (double-stranded small interfering RNA) conjugated to an N-acetylgalactosamine (GalNAc) ligand – suppresses the synthesis of the FXII protein [15]. Animal studies have demonstrated the significant decrease of FXII mRNA level and a dose-dependent reduction of vascular permeability during treatment with this agent. In mice, the subcutaneous administration of a single dose inhibited FXII and the effect persisted for over 2 months [16]. The therapies introduced so far or still in the development pipeline are all symptomatic treatments and each requires repeated administration. Recently, an innovative, adeno-associated virus-mediated (AAV) gene therapy has been developed. In a novel murine model of HAE, a single administration of an AAV gene transfer vector coding for human C1-INH (AAVrh.10hC1EI) provided sustained circulating C1-INH levels and markedly reduced vascular permeability, which was demonstrated by analysis of the extravasation of intravenously injected Evans blue dye in multiple organs. The early results are encouraging; however, further development, as well as formal drug safety and toxicology studies, is necessary [17].

3. Expert opinion

Perhaps, there is no other rare disorder for which such an abundance of different therapies would be available or under development. Among others, this might be explained by the underlying pathophysiology of HAE – that is, activation of the kinin-kallikrein system may be an important factor in the etiology of other disorders. Unraveling the genetic background of HAE might identify new therapeutic targets, such as plasminogen and angiopoietin 1. Moreover, further genes with yet uncharacterized roles have been implicated in the pathophysiology of HAE – these also might become possible targets. On the other hand, notwithstanding the remarkable progress achieved in drug development, a medicinal product capable of preventing the onset of angioedema attacks with absolute certainty is still not available. However, this would be the greatest expectation from a new agent, inasmuch it is impossible to predict in advance the occurrence of HAE attacks. Fortunate for the ongoing scientific effort, this subject has its scientific community and forum, the activity of which contributed significantly to the progress of drug research. The C1-INH Deficiency and Angioedema Workshop (http://www.2019.haenetworkshop.hu/) – an event held every 2 years in Budapest, Hungary since 1999 – has attracted a special mix of proactive participants, including academic researchers, laboratory professionals, clinicians, and the delegates of patient organizations – this creates an excellent opportunity for cooperation in research. Because HAE is an orphan disease, it is indispensable to ensure the availability of blood samples and patients in sufficient numbers for the purposes of basic research and of clinical studies. The International Patient Organization for C1-Inhibitor Deficiencies (https://haei.org/) and the HAE Global Registry (https://it.hae.cloud-r.eu/) provide much help in this respect. The expansion of the range of new therapeutic targets will open up new perspectives in the management of HAE. The ultimate goal is to introduce the interventions designed to influence these targets into clinical application and verify their usefulness in practice – because, as the saying goes, ‘the proof of the pudding is in the eating.’

Declaration of interest

H Farkas has served as a Consultant for, and has received honoraria, travel grants and lecture fees from CSL Behring, Shire, Biocryst, Pharming Group NV and Octapharma; she has also participated in clinical trials for CSL Behring, Shire, Biocryst and Pharming Group NV as a principal investigator. The author has 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has served as a consultant for Shire and CSL Behring. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.