Hereditary Angioedema (HAE)

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1		Vincenzo Montinaro	--	2298	2024-01-22 19:39:58	\|
2	format correct	Catherine Yang	-2 word(s)	2296	2024-01-23 01:43:03	\|

This entry is adapted from the peer-reviewed paper 10.3390/futurepharmacol4010005

Hereditary angioedema (HAE) is a rare disease caused by a genetic alteration of the SERPING1 gene and characterized by recurrent attacks of angioedema that involve the skin, and the mucosae of the gastrointestinal tract and upper airways, which significantly affect the quality of life of patients.

angioedema hereditary C1 inhibitor pharmacological treatment bradykinin

1. Introduction

Hereditary angioedema (HAE) is a clinical condition characterized by recurrent episodes of swelling that may affect the subcutaneous tissues of the extremities, trunk, face, or upper airways or the gastrointestinal mucosae or genitalia. It is a rare condition that affects 1:50,000 to 1:100,000 people in the general population and is determined by mutations of a specific gene called SERPING1, which codifies for a protein called C1 inhibitor, a regulatory component of the classical complement pathway that also shows anti-enzymatic activity that regulates the activation of several proteases included in the coagulation, fibrinolytic, and contact system pathways ^[1]. It is now clear that the specific pathogenesis of angioedema attacks resides in a lack of the regulatory activity of C1 inhibitor on the contact system enzymes pre-kallikrein and Factor XII, which normally undergo a mutual activation after modifications that occur on the endothelial surface ^[2]^[3]. Kallikrein acts on high molecular weight kininogen and generates a nonapeptide called bradykinin. This latter vasoactive peptide binds specifically to B2 receptors, G-protein coupled receptors that are constitutively expressed on endothelial cells. B2 receptors induce intracellular transduction mechanisms that, through steric rearrangement and destruction of VE-cadherin, produce an increased permeability of the endothelial layer to plasma fluids and the ultimate translocation of liquid from the intravascular space to the subcutaneous site of the derma. HAE patients do not show an increased risk of bleeding or thrombosis ^[4]^[5].

HAE is a genetic disease with an autosomal dominant pattern of transmission, and almost all patients show a heterozygous state, with one functioning allele. Homozygous HAE patients have been described but are very rare ^[6]. Typically, patients will have reduced circulating antigenic (type I) or functional (type II) levels of C1 inhibitor ^[7]. Due to the pattern of genetic transmission, probands have generally vertical or transversal familial transmission of the disease. However, frequent de novo mutations of the SERPING1 gene (up to 25% of all cases) must be kept in mind for those cases that do not show a familial pattern. Mutations of the SERPING1 gene, especially those that produce a type I phenotype (85% of cases), are diverse and include missense, non-sense, frameshift insertion or deletion or slicing defects which are spread all over the gene domains ^[8]; while mutations that produce a type II phenotype (15% of cases), are generally missense mutations localized in exon 8 ^[9]; overall, almost 750 different mutations have been reported ^[10].

2. State of the Art Treatment of Hereditary Angioedema

The objective of treatment of HAE is to reduce the number and severity of attacks and to restitute a normal quality of life to the patients. According to the last WAO/EAACI recommendations these objectives can be reached with approved therapies ^[11]. However, there are still some unmet needs for which several drugs are undergoing active testing and will probably enrich the therapeutic armamentarium towards the end of this decade.

The mainstay of the actual HAE therapies includes drugs for the treatment of single attacks with an on-demand basis and prophylactic treatments for both short-term pre-procedural prophylaxis (i.e., before surgery or dental procedures) or long-term prophylaxis aimed at preventing HAE attacks and potentially completely abrogating the occurrence of attacks. For on-demand treatment there are currently three drugs approved by the FDA and EMA and one more drug approved only by the FDA ^[12]. The first three are plasma-derived C1 inhibitor for IV injection (Berinert, CSL Behring, Marburg, Germany), recombinant human C1 inhibitor (Ruconest, Pharming, Leiden, The Netherlands), and icatibant (Firazyr, Takeda Pharmaceutical International AG, Dublin, Ireland), a specific antagonist of bradykinin binding to its receptor B2R, that can be administered by subcutaneous injection. Ecallantide (Kalbitor, Takeda) is the fourth drug approved only by the FDA; this is a polypeptide inhibitor of plasma kallikrein, administered subcutaneously. All these drugs have a different pharmacodynamic profile (Figure 1) and have been proved effective in halting the evolution of HAE attacks, including laryngeal attacks, in RCT studies, thus accelerating the resolution of an attack and providing relief shortly after administration and complete resolution of the attack in a few hours after injection. Moreover, post-registration registries have shown a consistent effect on the repetitive use and safety of these drugs over a long period of time ^[13].

Figure 1. Schematic representation of the principal mechanisms involved in the pathogenesis of hereditary angioedema attacks and pharmacodynamics of the actual available medications used for treating acute attacks. Abbreviations: PK: Prekallikrein; Kall: Kallikrein; F XII: Factor XII; HMWK: High Molecular Weight Kininogen; cHMWK: cleaved HMWK; BK: Bradykinin; BK2R: Bradykinin Receptor type 2.

For short-term prophylaxis, the only approved drug is plasma-derived C1 inhibitor (Bering, CSL Behring; Cinryze, Takeda), which is generally administered intravenously shortly (1 h) before the procedure. Due to the long half-life of plasma-derived C1 inhibitor—up to 32 h—a single injection of the proper dosage is sufficient to provide an adequate coverage even for long surgical procedures. Alternatively, an old approach for short term prophylaxis consisted of the administration of attenuated androgens, like danazol, at high dosage (i.e., 600 mg/day in three doses) for a period of 5 days before the procedure. The effect of danazol in preventing HAE attacks is not completely understood, but probably consists of a combination of a stimulation of C1 inhibitor synthesis and an increase in circulating metalloprotease that normally operate a catabolism of bradykinin. Attenuated androgens are no longer recommended as first line therapies, due to the high rate of adverse effects associated with the use of these drugs.

In the last 10–15 years there has been an increased use of long-term prophylaxis for HAE attacks, especially in patients that present with frequent attacks (>3–4/month) and severe attacks (laryngeal or abdominal). Owing to the availability of novel therapeutic options that include plasma-derived C1 inhibitor and a monoclonal antibody that targets activated plasma kallikrein, the last updated version of the WAO/EAACI guidelines on the management of HAE recommend that the goals of treatment are to achieve total control of the disease and to normalize patient’s lives ^[11]. The available therapeutic options then include plasma-derived C1 inhibitor for IV infusion (Cinryze, Takeda) or for subcutaneous administration at a higher dosage (Haegarda or Berinert sc, CSL Behring); both types of preparations need a twice-weekly infusion of each drug and can obtain a reduction in the attack rate of between 50% to a maximum of 88% for the subcutaneous C1 inhibitor preparation. Another more recent option for long-term prophylaxis is represented by lanadelumab, a humanized monoclonal antibody against activated plasma kallikrein, which is administered subcutaneously once every two weeks in the induction and once every 28 days after stabilization of the therapeutic response or after 6 months if the patient is attack-free. Lanadelumab can abate the attack rate by up to 73–87% ^[14]. Finally, an oral inhibitor of activated plasma kallikrein has recently been developed; berotralstat (Orladeyo, BioCryst Pharmaceutical, Dublin, Ireland) can be administered once a day for long-term prophylaxis. It can reduce attack frequency by 45–50% with a tendency toward increased efficacy for longer treatment periods. In Table 1 there is a synthesis of the main characteristics of actually available drugs for the treatment of HAE patients.

Table 1. Approved drugs for the treatment of HAE attacks or short-term or long-term prophylaxis.

Drug Name (Trademark)	Approved Indications	Dosage	Mechanism of Action
Plasma-derived C1 inhibitor (Berinert, CSL Behring)	Acute attacks STP All age groups	20 IU/kg iv	Inhibits factor XIIa and activated plasma kallikrein
Recombinant human C1 inhibitor (Ruconest, Pharming)	Acute attacks Adolescents and adults		Inhibits factor XIIa and activated plasma kallikrein
Icatibant (Firazyr, Takeda) *	Acute attacks Adults and age > 2 yr.	30 mg sc Reduced dosage	Bradykinin B2-receptor antagonist
Ecallantide (Kalbitor, Takeda)	Acute attacks Adults and adolescents	30 mg sc	Inhibits plasma kallikrein
Plasma-derived C1 inhibitor (Cinryze, Takeda)	Acute attacks, STP LTP All age groups	1000 IU 1000 IU iv every 3–4 days	Inhibits factor XIIa and activated plasma kallikrein
Plasma-derived C1 inhibitor (Haegarda, Berinert sc, CSL Behring)	LTP	60 IU/kg every 3–4 days	Inhibits factor XIIa and activated plasma kallikrein
Lanadelumab (Takhzyro, Takeda)	LTP Adults, adolescents	300 mg sc every 2 or 4 weeks	Inhibits activated plasma kallikrein
Berotralstat (Orladeyo, BioCryst)	LTP Adults, adolescents	150 mg daily orally	Inhibits activated plasma kallikrein

* Patent expired in 2019, generic icatibant is now available.

According to the efficacy of available treatments that allow the efficient management of attacks or reduce the frequency of attacks in long-term prophylaxis, but cannot offer complete disease control or normalize patients’ lives, there are some unmet needs that can be met with new drugs. For this reason, several pharmaceutical companies are actively developing new therapeutic options for HAE patients. In the next part, the researchers will review all the novel drugs that are undergoing active testing for efficacy and safety in HAE patients.

3. New Drugs for the Treatment of Hereditary Angioedema

Moving from the actual scenario of the treatment of hereditary angioedema, one can envision some possible unmet needs in the therapy for this specific condition: (1) the possibility to have an effective and rapid drug for treating on demand acute attacks that should allow the avoidance of any type of injective drug; (2) an effective oral drug for long-term prophylaxis with an efficiency of attack abatement comparable to the available injective molecules; (3) an injective drug for long-term prophylaxis with extended efficacy (2–3 months or more); (4) a definitive cure for the disease, possibly by genetic therapy.

Given these unmet needs, the pharmaceutical industry has undertaken a rush to try to fill all these needs. Therefore, several molecules have begun clinical experimentation and are actually under active testing in different phases (Table 2). In Figure 2, all the new tested drugs are shown according to their pharmacodynamic target. Several new molecules are undergoing experimentation and they have been developed with different pharmacologic technologies that include: (1) orally active, small inhibiting molecules, (2) monoclonal antibodies, (3) antisense oligonucleotide for RNA translation blockade, and (4) genetic technology for genome editing. According to the targets for which the different drugs have been engineered, it can indicate: (1) activated factor XII, (2) prekallikrein gene, (3) activated plasma kallikrein, (4) Bradykinin B2-receptor, (5) SERPING1 gene (genetic therapy), and (6) prekallikrein gene (genetic therapy) Figure 2.

Figure 2. Novel drugs for the treatment of acute attacks or long-term prophylaxis of hereditary angioedema which are undergoing clinical trials for testing efficacy and safety. mAb = monoclonal antibody; ASO = anti-sense oligonucleotide; siRNA = small interfering RNA.

Table 2. Active clinical trials that are testing the efficacy and safety of the novel drugs for the treatment of hereditary angioedema.

Medication	Producer	Trial Name/ Number	Therapy	Pharmacodynamics	Route	Phase	Estimated Completion
KVD900	KalVista Pharmaceuticals, Ltd.	KONFIDENT NCT05259917	ODT	Inhibitor of plasma Kallikrein	Oral	3	October 2023
Deucrictibant PHA-121	Pharvaris	RAPIDe-2 NCT05396105	ODT	Inhibitor of B2-bradykinin receptor	Oral	2/3	December 2024
Deucrictibant PHA-121	Pharvaris	HAE-CHAPTER-1 NCT05047185	LTP	Inhibitor of B2-bradykinin receptor	Oral	2	December 2026
Garadacimab	CSL Behring	NCT04739059	LTP	mAb, Inhibitor of activated Factor XII	Subcutaneous	3b	November 2025
STAR-0215	Astria Therapeutics Inc.	ALPHA-STAR NVT05695248	LTP	mAb, inhibitor plasma Kallikrein	Subcutaneous	1b/2	November 2024
STAR-0215	Astria Therapeutics Inc.	ALPHA-SOLAR NCT06007677	LTP	mAb, inhibitor plasma Kallikrein	Subcutaneous 1 dose every 3 or 6 months	2	October 2029
Donidalorsen IONIS-PKK-LRx	Ionis Pharmaceuticals, Inc.	OASIS-HAE NCT05139810	LTP	ASO, inhibitor plasma Kallikrein	Subcutaneous 1 dose every 4 or 8 weeks	3	April 2024
ADX-324	ADARx Pharmaceuticals	NCT05691361	LTP	siRNA, inhibitor of PKK synthesis	Subcutaneous	1	November 2024
NTLA-2002	Intellia Therapeutics	NCT05120830	Curation	CRISP-Cas9 gene editing, KLKB1 gene	Intravenous	1/2	December 2025
BMN 331	BioMarin Pharmaceutical	HAERMONY-1 NCT05121376	Curation	AAV5-vector SERPING1 gene therapy	Intravenous	1/2	November 2028

4. Genetic Therapies for the Curation of Hereditary Angioedema

The ultimate objective of any novel therapy for treating hereditary angioedema is curation of the disease. This can be obtained by manipulating the genome by inserting a new SERPING1 gene that will compensate for the mutated allele and, therefore, will restitute a condition similar to normality with two alleles producing a normal amount of the C1 inhibitor protein and, at the bottom, abrogating the predisposing condition for recurrence of angioedema attacks. The other modality of genetic therapy that is being explored for curation involves the manipulation of a different target gene, without the insertion of a new SERPING1 gene. A gene target is KLKB1, which codifies for plasma prekallikrein, the precursor of activated plasma kallikrein, a central enzyme in the generation of the ultimate mediator of angioedema attacks: bradykinin.

BioMarin pharmaceutical (San Raphael, CA, USA) is developing an adenovirus-based vector to carry the wild-type SERPING1 gene within the genome of HAE patients, which could determine a curation of the disease with one-time gene therapy. The specific product BMN 331 is under experimentation [HAErmony-1] with a phase 1–2 single arm, dose escalation, open label trial that is testing AAV5 hSERPING1 in patients with HAE type I or II [NCT05121376]; the gene sequence is under the control of a liver-specific promoter, so that the specific protein can be produced and released only by hepatocytes. Patients will receive a single IV injection of the BMN 331 at a dose that is selected from three doses and will be followed-up for 5 years thereafter, monitoring efficacy (levels of plasma C1 inhibitor) and safety. Completion of the study is estimated for November 2028, and at the moment no information has been released by the manufacturer.

The alternative approach is to use CRISP-Cas9 technology to perform gene editing of the KLKB1 gene, that codifies for prekallikrein. NTLA-2002 (Intellia Therapeutics, Inc., Cambridge, MA, USA) contains genetic material that, once included in the genome, will deactivate the KLKB1 gene, producing a significant reduction of circulating plasma levels of prekallikrein. Some interim data from the phase 1 and 2 trial [NCT05120830] were presented at the American College of Allergy, Asthma and Immunology in November 2022. They included data from 10 enrolled patients that had received 25, 50, or 75 mg IV injections of NTLA-2002. After 32 weeks, patients presented a reduction of plasma prekallikrein by 64–92% according to different dosages. Patients showed an attack-free period lasting up to almost 1 year, with a global reduction in the attack rate by 95%. Adverse effects were only mild, and the treatment showed a good safety profile ^[15].

References

Longhurst, H.; Cicardi, M. Hereditary angio-oedema. Lancet 2012, 379, 474–481.
Reshef, A.; Kidon, M.; Leibovich, I. The Story of Angioedema: From Quincke to Bradykinin. Clin. Rev. Allergy Immunol. 2016, 51, 121–139.
Zuraw, B.L.; Christiansen, S.C. HAE Pathophysiology and Underlying Mechanisms. Clin. Rev. Allergy Immunol. 2016, 51, 216–229.
Joseph, K.; Tholanikunnel, T.E.; Kaplan, A.P. Treatment of episodes of hereditary angioedema with C1 inhibitor: Serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis. Ann. Allergy Asthma Immunol. 2010, 104, 50–54.
Reshef, A.; Zanichelli, A.; Longhurst, H.; Relan, A.; Hack, C.E. Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. Allergy 2015, 70, 506–513.
Bafunno, V.; Divella, C.; Sessa, F.; Tiscia, G.L.; Castellano, G.; Gesualdo, L.; Margaglione, M.; Montinaro, V. De novo homozygous mutation of the C1 inhibitor gene in a patient with hereditary angioedema. J. Allergy Clin. Immunol. 2013, 132, 748–750.e3.
Germenis, A.E.; Speletas, M. Genetics of Hereditary Angioedema Revisited. Clin. Rev. Allergy Immunol. 2016, 51, 170–182.
Pappalardo, E.; Caccia, S.; Suffritti, C.; Tordai, A.; Zingale, L.C.; Cicardi, M. Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: Functional and structural correlates. Mol. Immunol. 2008, 45, 3536–3544.
Zahedi, R.; Aulak, K.S.; Eldering, E.; Davis, A.E., 3rd. Characterization of C1 inhibitor-Ta. A dysfunctional C1INH with deletion of lysine 251. J. Biol. Chem. 1996, 271, 24307–24312.
Santacroce, R.; D’Andrea, G.; Maffione, A.B.; Margaglione, M.; d’Apolito, M. The Genetics of Hereditary Angioedema: A Review. J. Clin. Med. 2021, 10, 2023.
Maurer, M.; Magerl, M.; Betschel, S.; Aberer, W.; Ansotegui, I.J.; Aygören-Pürsün, E.; Banerji, A.; Bara, N.A.; Boccon-Gibod, I.; Bork, K.; et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy 2022, 77, 1961–1990.
Christiansen, S.C.; Zuraw, B.L. Hereditary angioedema: On-demand treatment of angioedema attacks. Allergy Asthma Proc. 2020, 41, S26–S29.
Maurer, M.; Aberer, W.; Caballero, T.; Bouillet, L.; Grumach, A.S.; Botha, J.; Andresen, I.; Longhurst, H.J.; IOS Study Group. The Icatibant Outcome Survey: 10 years of experience with icatibant for patients with hereditary angioedema. Clin. Exp. Allergy 2022, 52, 1048–1058.
Zanichelli, A.; Montinaro, V.; Triggiani, M.; Arcoleo, F.; Visigalli, D.; Cancian, M. Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency. Expert. Opin. Emerg. Drugs 2022, 27, 103–110.
Longhurst, H.; Fijen, L.M.; Lindsay, K.; Butler, J.; Golden, A.; Maag, D.; Xu, Y.; Cohn, D.M. In vivo CRISP/Cas 9 editing of KLKB1 in patients with hereditary angioedema: A first in-human study. In Proceedings of the ACAAI Annual Scientific Meeting 2022, Louisville, KY, USA, 10–14 November 2022.

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