"Drug (trade name, manufacturer)",Regulatory status,Self-administration,Dosage,Mechanism,Anticipated potential side effects
"Ecallantide (Kalbitor, Dyax)",Approved in the United States for patients ≥12 y of age,No,30 mg SC,Inhibits plasma kallikrein,"Uncommon: antidrug antibodies, risk of anaphylaxis"
"Icatibant (Firazyr, Takeda)",Approved in the United States for patients ≥18 y of age; approved in Europe for patients ≥2 y of age,Yes,"Pediatric (EU): 12-25 kg, 10 mg SC; 26-40 kg, 15 mg SC; 41-50 kg, 20 mg SC; 51-65 kg, 25 mg SC; >65 kg, 30 mg SC Adults: 30 mg SC",Bradykinin B2 receptor antagonist,Common: discomfort at injection site
"Plasma-derived nanofiltered C1INH (Berinert, CSL Behring)",Approved in the United States and Europe for children and adults,Yes,20 U/kg IV,"Inhibits plasma kallikrein, coagulation factors Xlla, XIIf and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin",Rare: risk of anaphylaxis Theoretical: transmission of infectious agent
"Recombinant human C1INH (Ruconest, Pharming)",Approved in the United States and Europe for adolescents and adults,Yes,50 U/kg up to 4200 U IV,"Inhibits plasma kallikrein, coagulation factors Xlla, XIIf and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin",Uncommon: risk of anaphylaxis in rabbit-sensitized individuals Theoretical: transmission of infectious agent

Problematic venous access (involving clotting and infection) led to the placement of indwelling ports for many patients. As in the case vignette, additional treatment did not always result in complete disease control. A major advance in prophylactic care for hereditary angioedema has been the approval of subcutaneous treatments, including plasma-derived C1 inhibitor and lanadelumab, a human monoclonal inhibitor of plasma kallikrein, in both cases circumventing the requirement for intravenous access and showing improved efficacy. As illuminated in the case vignette, the superior control achieved with these treatments approaches the goal of normalizing patients’ lives.

The principles guiding the management of hereditary angioedema are outlined in Table S2. Currently approved front-line therapies are discussed below and listed in Table 3. Their sites of action are shown in Figure 1.

Figure 1:
Caption: Contact, Complement, and Fibrinolytic Systems in Hereditary Angioedema (HAE) and Targets for Available Therapy.
Description: The plasma contact system consists of coagulation factor XII, plasma prekallikrein, and high-molecular-weight kininogen (HMWK). Also shown are mechanisms of action for drugs that are currently approved for the treatment of HAE with C1 inhibitor (C1-INH) deficiency; sites of inhibition by C1-INH, ecallantide, lanadelumab, and icatibant in the plasma contact system activation cascade are shown in red. Coagulation factor XII and the prekallikrein–HMWK complex have weak intrinsic enzymatic activity; an absence of C1-INH produces their active forms, factor XIIa and plasma kallikrein, respectively. Autoactivation, kallikrein, and plasmin produce additional factor XIIa. Factor XII fragment (factor XIIf) weakly stimulates the prekallikrein–HMWK complex to produce the kallikrein–HMWK complex (black dashed arrow). Without sufficient levels of functional C1-INH to inhibit plasma kallikrein, HMWK is cleaved, producing bradykinin. Cleaved HMWK may be a biomarker of disease activity. Heat shock protein 90 (HSP90), which is constitutively secreted by endothelial cells, also activates the prekallikrein–HMWK complex. C1-INH regulates the lectin pathway. Levels of mannose-binding lectin–associated serine protease 1 (MASP-1), MASP-1–C1-INH, and ficolin-3 may correlate with HAE activity; further validation is required. Factor XII–independent activation of HMWK cleavage occurs through HSP90 and potentially through MASP-1. Bradykinin, generated through the plasma contact system, binds to the bradykinin B2 receptor on endothelial cells. Bradykinin B2 receptor activation produces angioedema (fluid transfer) through several mechanisms, including increased endothelial-cell permeability, enhanced phosphorylation and inactivation of vascular endothelial cadherin, and expression of vascular permeability factors (vascular endothelial growth factor [VEGF]), all of which create vascular pores. Endothelial-cell activation promotes vasodilation and increased plasma osmolality. Induction and activation of bradykinin B1 receptor through inflammation and through engagement of bradykinin B2 receptor may be involved in angioedema. Bradykinin (BK) that is unbound and Lys-BK (not shown) are rapidly inactivated by angiotensin-converting enzyme and carboxypeptidases N and M to des-Arg-BK and des-Arg-Lys-BK (not shown), respectively. Des-Arg-BK is a weak ligand for bradykinin B1 receptor (indicated by the gray dashed arrow) and is of uncertain importance in HAE. Tissue kallikrein cleaves low-molecular-weight kininogen, releasing Lys-BK, which is acted on by carboxypeptidase, generating des-Arg-Lys-BK, a potent ligand for bradykinin B1 receptor (not shown). There is no evidence that the tissue kallikrein system is activated in HAE. Mutations in angiopoietin-1 prevent Tie2 from inhibiting vascular permeability. The classic complement pathway, rather than the alternative complement pathway, is shown. VEGFR denotes vascular endothelial growth factor receptor.

Table 3:
Caption: First-Line Treatments for Hereditary Angioedema with C1 Inhibitor Deficiency.*
Content:
"Drug (Trade Name, Manufacturer)",Approved Indications†,Dose,Mechanism of Action,Potential Side Effects
"Plasma-derived C1 inhibitor (Berinert, CSL Behring)","Acute attacks in all age groups, including women who are pregnant or breast-feeding",20 U/kg IV,"Inhibits plasma kallikrein, coagulation factors XIIa and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin",Rare: risk of anaphylaxisTheoretical: transmission of infectious agent
"Recombinant human C1 inhibitor (Ruconest, Pharming)","Acute attacks in adolescents and adults, including women who are pregnant or breast-feeding","50 U/kg IV (maximum dose, 4200 U)","Inhibits plasma kallikrein, coagulation factors XIIa and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin",Rare: risk of anaphylaxis (among rabbit-sensitized persons)Theoretical: transmission of infectious agent
"Ecallantide (Kalbitor, Takeda)",Acute attacks in patients ≥12 yr of age,30 mg SC,Inhibits plasma kallikrein,Common: prolonged PTT‡Rare: risk of anaphylaxis§Uncommon: antidrug antibodies
"Icatibant (Firazyr, Takeda)",Acute attacks in patients ≥18 yr of age¶,"Adults: 30 mg SCChildren:12–25 kg, 10 mg SC26–40 kg, 15 mg SC41–50 kg, 20 mg SC51–65 kg, 25 mg SC>65 kg, 30 mg SC",Bradykinin B2 receptor antagonist,Common: discomfort at injection site
"Plasma-derived C1 inhibitor (Cinryze, Takeda)",Prophylaxis in patients ≥6 yr of age‖,Children (6–11 yr): 500 U IV every 3–4 days; doses up to 1000 U IV every 3–4 days may be neededAdolescents >12 yr of age and adults: 1000 U IV every 3–4 days; doses up to 2500 U IV every 3–4 days may need to be considered on the basis of a patient’s response,"Inhibits plasma kallikrein, coagulation factors XIIa and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin",Rare: risk of anaphylaxisTheoretical: transmission of infectious agent
"Plasma-derived C1 inhibitor (HAEGARDA, CSL Behring)",Prophylaxis in patients ≥12 yr of age,60 U/kg SC twice weekly,"Inhibits plasma kallikrein, coagulation factors XIIa and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin",Common: mild injection-site reactionRare: risk of anaphylaxisTheoretical: transmission of infectious agent
"Lanadelumab (Takhzyro, Takeda)",Prophylaxis in patients ≥12 yr of age,300 mg SC every 2 wk; 300 mg every 4 wk may be considered if patient is attack-free for >6 mo,Inhibits plasma kallikrein,"Common: mild injection-site reaction, dizziness, prolonged PTT‡Rare: risk of anaphylaxis"

We report what we believe to be the first patient potentially cured of hereditary angioedema. Treatment of hereditary angioedema at present aims to provide on-demand treatment for attacks as well as long-term prophylaxis for patients with a high frequency of attacks. In recent years, substantial advances in therapy have become available to patients with hereditary angioedema, particularly with long-term prophylactic treatments. Berotralstat is an oral kallikrein inhibitor that has been shown to reduce the frequency of attacks by approximately 45% in a phase 3, double-blind, randomized, placebo-controlled trial and by 65% in real-world experience in the United Kingdom. Lanadelumab, a monoclonal antibody targeting kallikrein, has been shown to reduce attack frequency by up to 85%. Further treatments are undergoing assessment, such as garadacimab, a factor XIIa inhibitor that also appears to reduce attack frequency by approximately 85%. Although these advances are a vast improvement, they are not curative. Estimates from the United States show direct and indirect costs of $5000 to $12,000 per attack, and over half of patients have at least one attack per month, findings that highlight the need for longer-term treatment strategies.

Gene therapy approaches are also being pursued. Adeno-associated virus-based gene therapy and in vivo techniques based on clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) are being developed for a range of conditions, although current gene-editing technology may not be possible for patients with complex mutations. A recent study by Longhurst et al. showed a sizable reduction in hereditary angioedema attacks after a lipid nanoparticle CRISPR-Cas9 gene therapy with liver tropism targeting the gene encoding kallikrein B1, KLKB1, circumventing correction of SERPING1 mutations. This strategy led to a mean reduction of attacks of approximately 95% throughout the 48-week follow-up period.

Liver transplantation was previously considered to be a theoretical treatment option, with this report showing a proof of this principle.