Medical Literature - 2023

Lochbaum R, Trainotti S, Hoffmann TK, Greve J, Hahn J. 12/2023 Journal of Dermatological Treatment.

>BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE.

METHODS: An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires.

RESULTS: Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy-efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime.

CONCLUSION: This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.

35(1):2290362

Available online at: dx.doi.org/10.1080/09546634.2023.2290362

Trainotti S, Johnson F, Hahn J, Hofauer B, Greve J, Wollenberg B, Hoffmann TK, Lochbaum R. 12/2023 The Journal of Allergy & Clinical Immunology in Practice.

BACKGROUND: Acquired angioedema with C1-inhibitor deficiency (AAE-C1-INH) is a rare condition resembling hereditary angioedema (HAE), but with late onset and low C1-inhibitor (C1-INH) due to consumption potentially caused by autoimmune diseases and mainly lymphatic malignancies. Being about 10-fold rarer than HAE, there is limited knowledge and no licensed therapy.

OBJECTIVE: To report clinical and biological data from a newly described population of 20 patients with AAE-C1-INH assessing diagnostic delay, AAE-C1-INH:HAE-ratio, underlying conditions, and therapeutic management in Germany.

METHODS: Retrospective data analysis of 20 patients from 2 angioedema centers in southern Germany.

RESULTS: Median age at symptoms' onset was 64 years (60% females), with predominant swellings of the face (85%) and low levels for C1-INH in almost all patients. The ratio AAE-C1-INH:HAE was 1:9.7. From symptoms' onset to diagnosis of AAE-C1-INH, the median delay was 7.5 months, and between AAE-C1-INH symptoms' onset and diagnosis of the underlying hematological condition (n = 9) it was 4 months (median). Four patients had a history of solid neoplasm, 1 had a papillary thyroid carcinoma as the only potential cause for AAE-C1-INH, with treatment of the malignancy resulting in resolution of AAE-C1-INH. All the symptomatic patients were treated with off-label on-demand icatibant subcutaneously or C1-INH concentrate intravenously, and 6 severely affected patients needed off-label long-term prophylaxis with good symptom control.

CONCLUSIONS: AAE-C1-INH is characterized by late-onset swellings mainly involving the face and low C1-INH levels. Diagnostic delay for AAE-C1-INH is further decreasing despite being about 10-fold rarer than HAE. Patients severely affected without underlying condition or no indication for treatment could benefit from off-label therapy. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

11(12):3772-3779

Available online at: dx.doi.org/10.1016/j.jaip.2023.09.003

Day C, Van der Walt J, Crombie K, Hendrikse C, Peter J. 08/2023 South African Medical Journal.

>BACKGROUND: Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm.

OBJECTIVE: To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA).

METHODS: We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1 June 2018 to 31 June 2020. Using ICD-10 coding, folders of adults >=18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event.

RESULTS: A total of 142 acute angioedema episodes were included, with a median (interquartile range) age of 42 (28 - 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20 (14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care.

CONCLUSION: Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

113(8):51-57

Available online at: samajournals.co.za/index.php/samj/article/view/717/562

Yong PFK, Coulter T, El-Shanawany T, Garcez T, Hackett S, Jain R, Kiani-Alikhan S, Manson A, Noorani S, Stroud C, Symons C, Sargur R, Steele C, Alachkar H, Anantharachagan A, Arkwright PD, Bernatoniene J, Bhole M, Brown L, Buckland M, Burns S, Chopra C, Darroch J, Drewe E, Edmonds J, Ekbote A, Elkhalifa S, Goddard S, Grosse-Kreul D, Gurugama P, Hague R, Herriot R, Herwadkar A, Hughes SM, Jones L, Lear S, McDermott E, Kham Murng SH, Price A, Redenbaugh V, Richter A, Riordan A, Shackley F, Stichbury J, Springett D, Tarzi MD, Thomas M, Vijayadurai P, Worth A. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

>BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care.

OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients.

METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data.

RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home.

CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

11(8):2476-2483

Available online at: dx.doi.org/10.1016/j.jaip.2023.04.035

Katelaris CH, Grumach AS, Bork K. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage. Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.

11(8):2309-2314

Available online at: dx.doi.org/10.1016/j.jaip.2023.06.022 (small fee)

Aygoren-Pursun E, Zanichelli A, Cohn DM, Cancian M, Hakl R, Kinaciyan T, Magerl M, Martinez-Saguer I, Stobiecki M, Farkas H, Kiani-Alikhan S, Grivcheva-Panovska V, Bernstein JA, Li HH, Longhurst HJ, Audhya PK, Smith MD, Yea CM, Maetzel A, Lee DK, Feener EP, Gower R, Lumry WR, Banerji A, Riedl MA, Maurer M. 02/2023 Lancet.

>BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks.

METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 x 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed.

FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38.3 years [SD 13.2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9.6 to >12] vs 8.0 h [3.8 to >12]; p=0.0010). There were no serious adverse events or adverse event-related discontinuations.

INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917).

FUNDING: KalVista Pharmaceuticals. Copyright © 2023 Elsevier Ltd. All rights reserved.

401(10375):458-469

Available online at: dx.doi.org/10.1016/S0140-6736(22)02406-0 (small fee)

Johnson F, Stenzl A, Hofauer B, Heppt H, Ebert EV, Wollenberg B, Lochbaum R, Hahn J, Greve J, Trainotti S. 12/2023 Clinical Reviews in Allergy & Immunology.

Hereditary angioedema (HAE) and acquired C1-inhibitor deficiency (AAE-C1-INH) are orphan diseases. Berotralstat is a recently licensed long-term prophylaxis (LTP) and the first oral therapy for HAE patients. No approved therapies exist for AAE-C1-INH patients. This study is the first to report real-world clinical data of patients with AAE-C1-INH and HAE who received Berotralstat. All patients treated with Berotralstat were included in this retrospective, bi-centric study. Data was collected from patients' attack calendars and the angioedema quality of life (AE-QoL) and angioedema control test (AECT) questionnaires before treatment, and at 3, 6, and 12 months after treatment and was then analyzed. Twelve patients were included, 3 patients with AAE-C1-INH, 7 patients with HAE type I, and 2 patients with HAE-nC1-INH. One patient (HAE I) quit treatment. Berotralstat was associated with fewer attacks in all groups. After 6 months of treatment, a median decrease of attacks per month was noted for HAE type I patients (3.3 to 1.5) and AAE-C1-INH patients (2.3 to 1.0). No aerodigestive attacks were noted for AAE-C1-INH patients. For HAE-nC1-INH patients, a mean decrease from 3.8 to 1.0 was noted (3 months). For HAE I patients, the total AE-QoL lowered a mean of 24.1 points after 6 months, for HAE-nC1-HAE patients 8.0 points, and for AAE-C1-INH patients 13.7 points. AECT scores increased for HAE I patients (mean: 7.1), HAE-nC1-INH patients (9.0), and AAE-C1-INH patients (4.2) after 6 months. Patients with HAE, HAE-nC1-INH, and AAE-C1-INH treated with Berotralstat showed reduced angioedema attacks and improved AE-QoL and AECT scores. Copyright © 2023. The Author(s).

65(3):354-364

Available online at: dx.doi.org/10.1007/s12016-023-08972-2

Farkas H, Balla Z. 02/2023 Expert Review of Clinical Immunology.

>INTRODUCTION: Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) imposes a significant disease burden on patients and their families. Unpredictable episodes of angioedema, which can lead to life-threatening conditions, have a significant impact on the quality of life of the patient. The fundamental aim of the treatment of C1-INH-HAE is to ensure that patients can lead a normal life. The most effective way to do this is to prevent the onset of angioedema attacks.

AREAS COVERED: This review gives a brief overview of the safety and efficacy of the oral kallikrein inhibitor berotralstat in C1-INH-HAE disease. It provides a comprehensive synopsis of the results of the first clinical trials with a targeted oral kallikrein inhibitor (APeX-1 [NCT02870972]; ZENITH-1 [NCT03240133]; APeX-2 [NCT03485911]; APeX-S [NCT03472040]; APeX-J [NCT03873116]), reviewing evidence on the efficacy and safety of the drug, and placing berotralstat on the spectrum of long-term prophylactic therapeutic options.

EXPERT OPINION: The availability of the first targeted oral prophylactic drug, the kallikrein inhibitor berotralstat, in 2021, is a milestone in the treatment of patients with hereditary angioedema.

19(2):145-153

Available online at: dx.doi.org/10.1080/1744666X.2023.2150611 (small fee)

Longhurst HJ, Valerieva A. 03/2023 Journal of asthma and allergy.

Through its fluctuating disease activity and unpredictable attacks, hereditary angioedema (HAE) imposes a substantial patient burden. To minimize HAE burden and improve quality of life, treatment should involve individualized management strategies that address on-demand therapy and short-term/long-term prophylaxis. Goals of long-term prophylaxis include reducing the number, severity, and burden of HAE attacks. The best characterized forms of HAE arise from deficiency or dysfunction of C1-inhibitor (C1-INH; types I/II), and C1-INH replacement therapy is a first-line intervention for on-demand (acute) treatment of HAE attacks, short-term prophylaxis before high-risk procedures, and long-term prophylaxis. Randomized, double-blind, placebo-controlled crossover trials have shown dose-dependent efficacy with plasma-derived C1-INH (pdC1-INH) 40-60 IU/kg subcutaneously, pdC1-INH 1000 U intravenously, and recombinant human C1-INH (rhC1-INH) 50 IU/kg (maximum 4200 IU) intravenously, all administered twice weekly, as long-term prophylaxis in patients with a history of 2 to >=4 attacks/month. Overall, up to 83% (pdC1-INH 60 IU/kg) of patients experienced an HAE attack reduction threshold of >=70%, and up to 58% (pdC1-INH 60 IU/kg) achieved an attack reduction threshold of >=90%. Lower-dose intravenous pdC1-INH therapy (1000 U) was seemingly less effective, with 45% of 22 patients experiencing an HAE attack reduction threshold of >=70%, and up to 23% achieving an attack reduction threshold of >=90%. Higher-dose intravenous rhC1-INH 50 IU/kg (maximum, 4200 IU) twice weekly was of intermediate benefit. Despite a baseline mean attack frequency of 17.9 (during the 3 months prior to study treatment) and a mean attack frequency during a 4-week placebo period of 7.2, 52% of 23 patients experienced >=70% reduction in attack frequency and 26% of 23 patients experienced >=90% reduction in attack frequency. The increasing patient percentages treated with C1-INH replacement therapy as long-term prophylaxis meeting these high thresholds reinforces hopes and expectations that "attack freedom" is achievable, including for those with moderate or severe disease. Copyright © 2023 Longhurst and Valerieva.

16:269-277

Available online at: dx.doi.org/10.2147/JAA.S396338

Farkas H, Balla Z. 07/2023 Expert Opinion on Drug Safety.

>INTRODUCTION: Hereditary angioedema (HAE) is characterized by recurrent subcutaneously and/or submucosally localized edematous swellings. The first symptoms often appear in childhood, and they may become more frequent and severe in puberty. Since the appearance of HAE attacks is unpredictable regarding the localization and the frequency, the attacks put a significant burden on the patients and crucially impacts their quality of life.

AREAS COVERED: This review article analyzes the safety data acquired from the clinical trials conducted with the currently available medicinal products for the prophylactic treatment of hereditary angioedema due to C1 inhibitor deficiency and the safety data of observatory studies based on clinical practice. A review of the published literature was conducted using the PubMed database, clinical trials from ClinicalTrials.gov, and abstracts published at scientific conferences.

EXPERT OPINION: The currently available therapeutic products have a good safety and efficiency profile and the international guidelines recommend them as first-line treatments. The choice should be made based on the evaluation of the availability and the preference of the patient.

22(7):549-561

Available online at: dx.doi.org/10.1080/14740338.2023.2226861 (small fee)

Peter JG, Desai B, Tomita D, Collis P, Stobiecki M. 11/2023 World Allergy Organization Journal.

>Background: Given the recent approval of oral berotralstat in several countries for hereditary angioedema (HAE) prophylaxis, transition from long-term androgens to berotralstat may occur in clinical practice. The open-label, Phase II APeX-S trial provided an opportunity to assess the safety and effectiveness of berotralstat in patients previously treated with differing durations of androgens and shorter transition periods. Therefore, we examined the safety, effectiveness, and impact on quality of life of berotralstat after prior androgen use in patients from the APeX-S trial. Alanine aminotransferase (ALT) elevations were also examined because of the association with androgen exposure and hepatic function impairment.

Methods: We conducted an analysis of a subset of 39 patients from the APeX-S trial aged >=12 years with HAE due to C1 inhibitor deficiency (HAE-C1-INH) with prior androgen use who discontinued androgen therapy within <60 days of receiving berotralstat. Patients received daily berotralstat (150 mg) and were divided into subgroups for this analysis based on time between androgen discontinuation and berotralstat commencement (<14 days versus 14 to <60 days).

Results: Berotralstat was generally well tolerated, with nasopharyngitis (21%), upper respiratory tract infection (15%), nausea (15%), diarrhea (15%), and abdominal pain (10%) being the most common adverse events occurring in >=10% of the total subset. Only 7/145 (5%) of all APeX-S study patients with a prior history of androgen therapy experienced ALT elevations, 6 of which were grade 3 or 4 toxicities. All 7 patients recovered without sequelae and belonged to the subgroup of patients who transitioned <14 days after discontinuing androgens (n = 18). A reduction in monthly attack rate versus Month 1 was observed over 12 months for all patients who transitioned from prior androgen therapy to berotralstat prophylaxis in under 60 days, irrespective of duration of prior androgen therapy or timing of transition (N = 39). Similarly, meaningful patient-reported improvements from both Angioedema Quality of Life Questionnaire and Treatment Satisfaction Questionnaire for Medication scores were achieved, with a sustained benefit shown over the berotralstat treatment period.

Conclusions: Berotralstat treatment led to sustained HAE symptom control irrespective of duration of prior androgen therapy or timing of transition. Most patients safely transitioned from long-term androgens to berotralstat. Although occurring in a small group of patients, liver-related adverse events following berotralstat treatment may be associated with a shorter androgen washout period, but further research is required to confirm this.

Clinical trial registration: NCT03472040. Retrospectively registered March 21, 2018. Copyright © 2023 The Authors.

16(11):100841

Available online at: dx.doi.org/10.1016/j.waojou.2023.100841

Anonymous. 03/2023 Canadian Agency for Drugs and Technologies in Health.

WHAT IS THE CADTH REIMBURSEMENT RECOMMENDATION FOR ORLADEYO?: CADTH recommends that Orladeyo be reimbursed by public drug plans for routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older, if certain conditions are met.

WHICH PATIENTS ARE ELIGIBLE FOR COVERAGE? Orladeyo should only be reimbursed for adults and adolescents with HAE according to the criteria used by public drug plans for lanadelumab for the prevention of HAE attacks.

WHAT ARE THE CONDITIONS FOR REIMBURSEMENT? In addition to following pre-existing criteria for lanadelumab, Orladeyo should not be used in combination with other medications for long-term prevention of angioedema. Orladeyo should only be reimbursed if its cost is reduced.

WHY DID CADTH MAKE THIS RECOMMENDATION? Two clinical trials demonstrated that Orladeyo reduced the frequency of HAE attacks compared with placebo. Orladeyo may meet some needs that are important to patients, such as administration by mouth rather than injection, and fewer HAE attacks. Based on CADTH's assessment of the health economic evidence, Orladeyo does not represent good value to the health care system at the public list price. A price reduction is therefore required. Based on public list prices, Orladeyo is estimated to cost the public drug plans approximately $93 million over the next 3 years. However, the actual budget impact is uncertain given large differences between the sponsor's and CADTH's reported budget impact, and because it includes products provided through both Canadian Blood Services and public drug plans.

ADDITIONAL INFORMATION: WHAT IS HAE? HAE is a rare hereditary disorder, with which patients experience recurring episodes of painful and potentially life-threatening swelling of the skin, abdomen, or throat. It is estimated that 1 in 93,000 to 1 in 50,000 people have HAE.

UNMET NEEDS IN HAE: Current treatments reimbursed to prevent HAE attacks require injection, and some are made from blood products. Other treatment options are needed that reduce HAE attacks but are easier to administer.

HOW MUCH DOES ORLADEYO COST? Treatment with Orladeyo is expected to cost approximately $310,463 per patient annually.

Available online at: cadth.ca/berotralstat

Meadows JA, Anderson J, Gower RG. 06/2023 Annals of Allergy, Asthma, & Immunology.

>BACKGROUND: Caring for patients with hereditary angioedema (HAE), especially rural patients, has challenges.

OBJECTIVE: To confirm experiences of allergy and immunology health professionals in diagnosing and treating patients with HAE, including those living in rural settings.

METHODS: An online survey of 2996 members of the American College of Allergy, Asthma, and Immunology was conducted in April 13 to May 3, 2022. Eligible participants were association members (physician, fellow, or allied health professional members) currently practicing allergy or immunology, in the United States, seeing or treating at least 1 patient with HAE yearly.

RESULTS: A total of 138 responders saw an average of 9 patients with HAE yearly; 12% of the patients resided in a rural area. They reported that 66% of their patients with HAE had type I, 15% type II, and 19% HAE C1nl-INH. Misdiagnosis was the top diagnostic challenge reported (82%). Inability to afford treatment was the top treatment challenge (76%). Other observations include the sentiment that patients with HAE with government insurance are at a disadvantage because it is not accepted by many specialists who treat HAE (64%) and that better payments for drugs from Medicaid and Medicare (57%) and better payments to providers from Medicaid and Medicare (49%) could better support the treatment of patients in rural settings. Responders expressed a preference for therapies administered at home (72%). Since the coronavirus disease 2019 pandemic, 86% of the respondents used telehealth for appointments occasionally.

CONCLUSION: Our findings illustrate the challenge of diagnosing HAE, especially HAE C1nl-INH, and the economic challenges of treatment, which can be compounded for those living in rural areas. We provide a call to action for addressing several of these real challenges. Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

130(6):760-767.e3

Available online at: dx.doi.org/10.1016/j.anai.2023.03.005 (small fee)

Lochbaum R, Hoffmann TK, Greve J, Hahn J. 11/2023 Journal der Deutschen Dermatologischen Gesellschaft.

Bradykinin-mediated angioedema is a rare, non-allergic, potentially life-threatening disease. ACE inhibitor-induced angioedema and hereditary angioedema (HAE) are the two most common presentations. Therapeutic options, pathophysiology and diagnosis continue to be investigated, with considerable progress in HAE over the last few decades. For all patients with bradykinin-mediated angioedema, there are several medications that should be avoided or administered with caution. Some of the triggering medications are well known, while others are suspected or of unknown significance. A common denominator is that there is no approved therapy for bradykinin-mediated angioedema as a drug side effect. Some medications, such as tissue plasminogen activator, have a higher incidence of angioedema with potential airway compromise than ACE inhibitors, although this fact is widely underappreciated. In this review, we aim to summarize what is currently known and recommended about concomitant medication in HAE patients and the interaction of other bradykinin-influencing drugs. Copyright © 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.

21(11):1283-1289

Available online at: dx.doi.org/10.1111/ddg.15154

Craig TJ, Reshef A, Li HH, Jacobs JS, Bernstein JA, Farkas H, Yang WH, Stroes ESG, Ohsawa I, Tachdjian R, Manning ME, Lumry WR, Saguer IM, Aygoren-Pursun E, Ritchie B, Sussman GL, Anderson J, Kawahata K, Suzuki Y, Staubach P, Treudler R, Feuersenger H, Glassman F, Jacobs I, Magerl M. 04/2023 Lancet.

>BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema.

METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged >=12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (<=17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs >=3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418.

FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0.27, 95% CI 0.05 to 0.49) than in the placebo group (2.01, 1.44 to 2.57; p<0.0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0.0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0.00-0.31) for garadacimab and 1.35 (1.00-3.20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events.

INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults.

FUNDING: CSL Behring. Copyright © 2023 Elsevier Ltd. All rights reserved.

401(10382):1079-1090

Available online at: dx.doi.org/10.1016/S0140-6736(23)00350-1 (small fee)

Papi A, Stapleton RD, Shore PM, Bica MA, Chen Y, Larbig M, Welte T. 04/2023 Lung.

>BACKGROUND: Garadacimab, a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, activated coagulation factor XII (FXIIa), and may play a protective role in preventing the progression of COVID-19. This phase 2 study evaluated the efficacy and safety of garadacimab plus standard of care (SOC) versus placebo plus SOC in patients with severe COVID-19.

METHODS: Patients hospitalised with COVID-19 were randomised (1:1) to a single intravenous dose of garadacimab (700 mg) plus SOC or placebo plus SOC. Co-primary endpoint was incidence of endotracheal intubation or death between randomisation and Day 28. All-cause mortality, safety and pharmacokinetic/pharmacodynamic parameters were assessed.

RESULTS: No difference in incidence of tracheal intubation or death (p = 0.274) or all-cause mortality was observed (p = 0.382). Garadacimab was associated with a lower incidence of treatment-emergent adverse events (60.3% vs 67.8%) and fewer serious adverse events (34 vs 45 events) versus placebo. No garadacimab-related deaths or bleeding events were reported, including in the 45.9% (n = 28/61) of patients who received concomitant heparin. Prolonged activated partial thromboplastin time (aPTT), and increased coagulation factor XII (FXII) levels were observed with garadacimab versus placebo to Day 14, whilst FXIIa-mediated kallikrein activity (FXIIa-mKA) was suppressed to Day 28.

CONCLUSION: In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema.

CLINICALTRIALS.GOV IDENTIFIER: NCT04409509. Date of registration: 28 May, 2020. Copyright © 2023. The Author(s).

201(2):159-170

Available online at: dx.doi.org/10.1007/s00408-023-00615-9

Hide M, Ohsawa I, Nurse C, Yu M. 11/2023 Journal of Dermatology.

The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open-label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged >=12 years with >=1 investigator-confirmed HAE attack during the 4-week run-in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26-week treatment period if patients had well-controlled symptoms (e.g., attack-free) for 6 months. The primary efficacy endpoint was no investigator-confirmed HAE attacks (attack-free status) during days 0-182. Other outcomes included the rate of investigator-confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean +/- SD age 41.9 +/- 12.4 years) were enrolled. During the first 26 weeks (days 0-182), five (41.7%) patients were attack-free. The mean +/- SD HAE attack rate per month decreased by 74.0%, from 3.8 +/- 2.4 during baseline to 1.2 +/- 2.6 during the overall 52-week treatment period. There were no deaths or discontinuations due to treatment-emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti-drug antibody results. The most frequent TEAEs were injection-site reactions (37 events in six patients). Most of the injection-site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE. Copyright © 2023 Takeda Pharmaceuticals and The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

50(11):1381-1391

Available online at: dx.doi.org/10.1111/1346-8138.16909

Strassen U, Bas M, Wirth M, Wirth M, Groger M, Stelter K, Volkenstein S, Kehl V, Kojda G, Hoffmann TK, Hahn J, Trainotti S, Greve J. 02/2023 American Journal of Emergency Medicine.

>BACKGROUND: ACE inhibitor (ACEi) induced angioedema predominantly affects the upper aerodigestive tract. As ACEi induced angioedema is mediated by bradykinin, therapeutic response to antihistamines and glucocorticoids remains unsatisfactory. In bradykinin mediated hereditary angioedema, C1-esterase inhibitor (C1INH) is an effective and approved treatment since many years. Our aim was to evaluate the therapeutic effect of C1INH in ACEi induced angioedema.

METHODS: We performed a double-blind, parallel-group, multicentre randomised placebo-controlled trial between December 2013 and September 2018. Eligible were adults with ACEi induced angioedema with airway obstruction. Participants were randomised 1:1 to single doses of either C1INH (20 IU/kg) or placebo (0.9% NaCl) i.v in addition to standard care (i.v. 500 mg prednisolone and 2.68 mg clemastine) i.v. Composite symptom scores were assessed at baseline and up to 48 h, at discharge and 1 week after discharge. Physician assessed time to complete oedema resolution (TCER) and time to onset of relief (TOR).

RESULTS: 30 patients (16 C1INH, 14 placebo) were randomised and dosed. 25 (9 C1INH, 12 placebo) completed the study. TCER was 29.63 h +/- 15.56 h in the C1INH and 17.29 h +/- 10.40 h in the placebo arm (p = 0.0457). TORs were 4.13 h +/- 3.38 h and 2.86 h +/- 1.29 h for C1INH and placebo, respectively (p = 0.4443). There were no adverse events related to study medication.

CONCLUSIONS: In the context of baseline application of steroids and antihistamines C1INH was inferior in the treatment of ACEi induced angioedema when compared to placebo with respect to time to complete resolution of symptoms. Eudra-CT Number: 2012-001670-28. Copyright © 2022 Elsevier Inc. All rights reserved.

64:121-128

Available online at: dx.doi.org/10.1016/j.ajem.2022.12.001 (small fee)

Suffritti C, Sartorio S, Berra S, Janu VP, Caccia S, Zanichelli A. 03/2023 The Journal of Allergy & Clinical Immunology in Practice.

Lanadelumab, a monoclonal plasma kallikrein inhibitor, is approved for C1-INH-HAE long-term prophylaxis. Similarly to C1-INH-HAE, angioedema in C1-INH-AAE is mediated by bradykinin released from kininogen by kallikrein. Thus, lanadelumab could be effective in preventing attacks in this form of angioedema.

11(3):963-965.e1

Available online at: dx.doi.org/10.1016/j.jaip.2022.10.041 (small fee)

Fukuda T, Yamagami K, Kawahata K, Suzuki Y, Sasaki Y, Miyagi T, Jacobs I, Lawo JP, Glassman F, Akama H, Hide M, Ohsawa I. 07/2023 Allergology International.

>BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE.

METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16.

RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h*%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation.

CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273. Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.

72(3):451-457

Available online at: dx.doi.org/10.1016/j.alit.2023.02.002

Cohn DM, Aygoren-Pursun E, Bernstein JA, Farkas H, Lumry WR, Maurer M, Zanichelli A, Iverson M, Hao J, Smith MD, Yea CM, Audhya PK, Riedl MA. 09/2023 Clinical and Translational Allergy.

>BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged >=12 years with HAE-C1-INH.

>METHODS: To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation-based approach using phase 2 data.

RESULTS: Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI-C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI-C rating of at least "A Little Better" for two time points in a row.

CONCLUSIONS: Patient feedback and phase 2 data support PGI-C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on-demand treatment for HAE-C1-INH attacks. Copyright © 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.

13(9):e12288

Available online at: dx.doi.org/10.1002/clt2.12288

Caballero T, Lleonart-Bellfill R, Pedrosa M, Ferrer L, Guilarte M. 07/2023 Journal of Investigational Allergology & Clinical Immunology.

>BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is a rare disease characterized by swelling episodes. It affects quality of life (QOL) and can be fatal when the upper airways are involved. Treatment is individualized, with therapeutic options including on-demand treatment (ODT) and short- and long-term prophylaxis (STP, LTP). However, available guidelines are not always clear about the selection of treatment, the goals of treatment, or how achievement of these goals is assessed.

OBJECTIVE: To review available evidence for the management of HAE-C1INH and build a Spanish expert consensus to steer management towards a treat-to-target approach, while addressing some of the less clear aspects of the Spanish guidelines.

METHODS: We reviewed the literature on the treat-to-target management of HAE-C1INH, focusing on treatment selection and goals and the tools available to assess whether the goals have been achieved. We discussed the literature based on clinical experience and drew up 45 statements on undefined management aspects. A panel of 53 HAE experts validated the statements through a 2-round Delphi process.

RESULTS: The goals for ODT and STP are to minimize the morbidity and mortality of attacks and to prevent attacks caused by known triggers, respectively, while the main goal of LTP is to decrease the rate, severity, and duration of attacks. Furthermore, when prescribing, clinicians should consider the reduction in adverse effects, while increasing patient QOL and satisfaction. Appropriate instruments for assessing achievement of treatment goals are also indicated.

CONCLUSIONS: We provide recommendations on previously unclear aspects of HAE-C1INH management with ODT, STP, and LTP, focusing on clinical and patient-oriented goals.

33(4):238-249

Available online at: dx.doi.org/10.18176/jiaci.0875

Riedl MA, Hinds DR, Prince PM, Alvord TM, Dosenovic S, Abdelhadi JF, Brownrigg JR, Camp CL, Machnig T, Banerji A. 07/2023 Allergy & Asthma Proceedings.

BACKGROUND: New hereditary angioedema (HAE) treatments have become available in recent years for the treatment of HAE due to C1-inhibitor (C1-INH) deficiency, including two subcutaneous (SC) options: a monoclonal antibody (lanadelumab) and a plasma-derived C1-INH concentrate (SC-C1-INH). Limited real-world data on these therapies have been reported.

OBJECTIVE: The objective was to describe new users of lanadelumab and SC-C1-INH, including demographics, healthcare resource utilization (HCRU), costs, and treatment patterns before and after beginning treatment.

METHODS: This was a retrospective cohort study that used an administrative claims data base. Two mutually exclusive cohorts of adult (ages >=18 years) new users of lanadelumab or SC-C1-INH with >=180 days of continuous use were identified. HCRU, costs, and treatment patterns were assessed in the 180-day period before the index date (new treatment use) and up to 365 days after the index date. HCRU and costs were calculated as annualized rates.

RESULTS: Forty-seven patients who used lanadelumab and 38 patients who used SC-C1-INH were identified. The most frequently used on-demand HAE treatments at baseline were the same for both cohorts: bradykinin B2 antagonists (48.9% of the patients on lanadelumab, 52.6% of the patients on SC-C1-INH) and C1-INHs (40.4% of the patients on lanadelumab, 57.9% of the patients on SC-C1-INH). More than 33% of the patients continued to fill on-demand medications after treatment initiation. Annualized angioedema-associated emergency department visits and hospitalizations decreased after initiation of treatment, from 1.8 to 0.6 for the patients on lanadelumab and from 1.3 to 0.5 for the patients on SC-C1-INH. Annualized total healthcare costs after treatment initiation in the database were $866,639 and $734,460 for the lanadelumab and SC-C1-INH cohorts, respectively. Pharmacy costs accounted for >95% of these total costs.

CONCLUSION: Although HCRU decreased after the initiation of treatment, angioedema-associated emergency department visits and hospitalizations and on-demand treatment fills were not completely eliminated. This indicates ongoing disease and treatment burden despite use of modern HAE medicines.

44(4):275-282

Available online at: dx.doi.org/10.2500/aap.2023.44.230026

Betschel SD, Banerji A, Busse PJ, Cohn DM, Magerl M. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

Hereditary angioedema (HAE) is a rare disease characterized by sudden and often unprovoked episodes of swelling that can be potentially life-threatening when it involves the upper airway. The treatment options for both acute episodes of HAE and LTP, used to minimize the frequency and severity of angioedema attacks, were limited historically to very few options, had considerable side effects, and/or had considerable burden of treatment. Fortunately, through the elucidation of the pathophysiology of HAE, the development of newer targeted therapies has been possible both for acute therapy and long-term prophylaxis and even more are on the horizon. Because of the rapid development of these therapies, it can be challenging for clinicians to keep abreast of newer and developing treatments for HAE. This review article will outline the current and potential future treatments for HAE. It will also highlight important considerations when treating special HAE patient populations including women and pediatric patients. Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

11(8):2315-2325

Available online at: dx.doi.org/10.1016/j.jaip.2023.04.017 (small fee)

Riedl MA. 02/2023 Immunology & Allergy Clinics of North America.

In recent years, hereditary angioedema (HAE) management has substantially advanced but also become more complex with additional therapeutic options. Pregnancy significantly influences the clinical symptoms of HAE in many women because of estrogen effects or other physiologic factors, and also introduces important safety concerns related to HAE medications. Management of HAE during pregnancy requires clinicians to be familiar with the potential clinical course, triggers, and recommended treatment strategies to provide guidance and optimal medical management to women and families affected by the condition. This review provides an overview of data, considerations, and recommendations related to HAE and pregnancy. Copyright © 2022 Elsevier Inc. All rights reserved.

43(1):145-157

Available online at: dx.doi.org/10.1016/j.iac.2022.05.011 (small fee)

Riedl MA, Danese M, Danese S, Ulloa J, Maetzel A, Audhya PK. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

>BACKGROUND: Hereditary angioedema (HAE) with normal C1-INH (HAE-nl-C1INH) is phenotypically similar to HAE resulting from C1-INH deficiency (HAE-C1INH). Confirmatory diagnostic tests for HAE-nl-C1INH are limited and few clinical study data exist regarding management of the condition. Therefore, survey studies may provide initial estimates of prevalence, diagnosis, and management patterns of this condition.

OBJECTIVE: To estimate the prevalence and describe current management patterns for HAE-nl-C1INH in the United States (US).

METHODS: We conducted an Internet-based survey of US physicians to estimate the prevalence of the HAE-nl-C1INH population in the United States. Potential participating physicians were identified from the US Hereditary Angioedema Association database and IQVIA Xponent prescription database. Eligible physicians were invited to complete an online survey between June and September 2021.

RESULTS: A total of 113 physicians provided data for the estimation of HAE-nl-C1INH prevalence and 81 physicians treating HAE-nl-C1INH patients provided data about treatment patterns. In bias-corrected analysis, we estimated 1,230 to 1,331 HAE-nl-C1INH patients within the United States between May 2019 and April 2020. Mean time to diagnosis for HAE-nl-C1INH was approximately 6 years (range, 2.4-13.5 years). Response to medication was commonly used to inform diagnosis (antihistamine response or nonresponse used by 73% of physician respondents, corticosteroids by 57%, or HAE-specific medications by 74%), and Factor XII genetic testing was used by 43%.

CONCLUSIONS: These survey data provide estimates of HAE-nl-C1INH prevalence in the United States as well as current diagnosis and management strategies. Results may be useful for developing studies to assess treatment efficacy and safety, and potentially improve the diagnosis for and management of this patient population. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

11(8):2450-2456.e6

Available online at: dx.doi.org/10.1016/j.jaip.2023.01.023

Rocour S, Cochard B, Daniel V, Martin L, Corvaisier M. 01/2023 Journal of Clinical Pharmacology.

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n = 66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas. Copyright © 2022, The American College of Clinical Pharmacology.

63(1):29-39

Available online at: dx.doi.org/10.1002/jcph.2125 (small fee)

Katelaris CH, Boicos K, Button PH, McCloud PI, Burton PK, Perram FA, Youssef S, Tognarini D. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

>BACKGROUND: To understand the impact and burden of disease experienced by patients with hereditary angioedema (HAE).

OBJECTIVE: To determine whether the use of short message service (SMS) to communicate with patients with HAE facilitates the collection of attack rate, medication use, and quality of life measurements.

METHODS: Patients aged 12 years and older with doctor-confirmed HAE C1-inhibitor deficiency types I and II were invited to participate. We devised a novel method for monitoring attacks by using questions weekly via SMS to gain a more accurate picture of the burden of HAE in Australian patients in real time.

RESULTS: A total of 2,648 weekly SMS messages were sent to 47 participants; 1,892 responses were received (71%). Participants reported 463 attacks across all treatment groups. Sixty percent of attacks were treated. Icatibant and C1-inhibitor concentrate were administered IV for 210 and 67 attacks, respectively. Of the 463 recorded attacks, 23 necessitated presentation to the hospital (5%), predominantly for facial and/or throat swelling. Several participants reported attacks (n = 186), which they chose not to treat. Most of those attacks were rated mildly severe. Twenty-one participants reported lost days owing to HAE attacks (44.7%). Fifty-eight attacks (17%) resulted in time away from work or school, equating to a total of 85.5 days lost.

CONCLUSIONS: This study was a first of its kind, real-world, prospective, observational study of Australian patients living with HAE. Despite the availability of effective on-demand therapies, HAE remains burdensome. Wider access to safe and effective prophylactic therapies is needed for patients living with HAE. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

11(8):2457-2467.e1

Available online at: dx.doi.org/10.1016/j.jaip.2023.02.037

Lumry WR, Maurer M, Weller K, Riedl MA, Watt M, Yu M, Devercelli G, Meunier J, Banerji A. 07/2023 Annals of Allergy, Asthma, & Immunology.

>BACKGROUND: Hereditary angioedema (HAE) is associated with a substantial disease burden. Lanadelumab reduced the HAE attack rate during 132 weeks of follow-up in the HELP open-label extension (OLE) Study (NCT02741596).

OBJECTIVE: To measure the impact of long-term lanadelumab treatment on patient-reported outcomes (PROs).

METHODS: Rollover patients (completed the 26-week HELP study [NCT02586805]) and nonrollovers (newly enrolled) received lanadelumab 300 mg every 2 weeks. PROs (Angioedema Quality of Life Questionnaire [AE-QoL], Short Form Health Survey 12-item version 2, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment-General Health Questionnaire, and EQ-5D-5L questionnaire) were assessed at baseline (day 0 of HELP OLE) and various time points until the end-of-study visit. The Angioedema Control Test, Treatment Satisfaction Questionnaire for Medication, and Global Impression of Treatment Response were administered starting at week 52.

RESULTS: The mean (SD) change in AE-QoL total score from baseline to end-of-study for rollovers (n = 90) was -10.2 (17.9), exhibiting further improvement from HELP in health-related quality of life (HRQoL); 48.9% of rollovers achieved the previously defined 6-point minimal clinically important difference. Nonrollovers (n = 81) reported a change of -19.5 (21.3). Controlled disease (Angioedema Control Test total score >=10) was reported by 90.2% of rollovers and 95.9% of nonrollovers at the end of the study. Excellent treatment response was reported by 78.7% of patients and 82.4% of investigators. Results from other PROs indicated a slight improvement in anxiety, a high level of satisfaction with treatment, and increased work productivityor activity.

CONCLUSION: Clinically meaningful improvement in HRQoL was exhibited with long-term lanadelumab treatment, supporting the benefit of lanadelumab therapy associated with attack prevention.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02586805 (HELP Study) and NCT02741596 (HELP open-label extension). Copyright © 2023. Published by Elsevier Inc.

131(1):101-108.e3

Available online at: dx.doi.org/10.1016/j.anai.2023.03.028

Watt M, Malmenas M, Romanus D, Haeussler K. 06/2023 Journal of Comparative Effectiveness Research.

AIM: With no head-to-head studies comparing the effectiveness of lanadelumab and berotralstat for prevention of hereditary angioedema (HAE) attacks, this network meta-analysis (NMA) aimed to indirectly compare the effectiveness of these treatments.

MATERIALS & METHODS: The NMA, using the published data from Phase III trials, was performed using a frequentist weighted regression-based approach following Rucker et al. Efficacy outcomes of interest were HAE attack rate per 28 days and >=90% reduction in monthly HAE attacks.

RESULTS & CONCLUSION: In this NMA, lanadelumab 300 mg administered every 2 weeks or every 4 weeks was associated with statistically significantly higher effectiveness versus berotralstat 150 mg once daily (q.d.) or 110 mg q.d. for both efficacy outcomes assessed.

12(6):e220188

Available online at: dx.doi.org/10.57264/cer-2022-0188

Shah CH, Princic N, Evans KA, Schultz BG. 01/2023 Journal of Medical Economics.

>AIMS: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period.

METHODS: Patients were identified in the Merative MarketScan Databases who had >=1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a <= 60-d gap in days of supply over 18 months, and were enrolled for >=6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a >= 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t-tests and McNemar's test.

RESULTS: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively (p < .01).

LIMITATIONS: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance.

CONCLUSIONS: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

26(1):871-877

Available online at: dx.doi.org/10.1080/13696998.2023.2232260

Barnes GD, Ageno W, Castellucci LA, Chiasakul T, Eslick R, Ferreiro JL, Gailani D, Gorog DA, Lip GYH, Raffini L, Rezende SM, Weitz JI, Cuker A. 05/2023 Journal of Thrombosis & Haemostasis.

Oral anticoagulation therapy has evolved beyond vitamin K antagonists to include oral direct thrombin inhibitors and factor Xa inhibitors. Collectively known as "direct oral anticoagulants," this class of medications represents the current standard of care for the prevention and treatment of common thrombotic disorders, including atrial fibrillation and venous thromboembolism. Medications that target factors XI/XIa and XII/XIIa are currently under investigation for several thrombotic and nonthrombotic conditions. Given that these emerging medications will likely have distinct risk-benefit profiles to the current direct oral anticoagulants, may have different routes of administration, and could be used for unique clinical conditions (e.g., hereditary angioedema), the International Society on Thrombosis and Haemostasis Subcommittee on Control of Anticoagulation assembled a writing group to make recommendations on the nomenclature of anticoagulant medications. With input from the broader thrombosis community, the writing group recommends that anticoagulant medications be described by the route of administration and specific targets (e.g., oral factor XIa inhibitor). Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.

21(5):1381-1384

Available online at: dx.doi.org/10.1016/j.jtha.2023.02.008

Hide M, Wang Y, Dote N, Miyakawa K, Sugiura K, Ishida K. 11/2023 Journal of Dermatology.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients. Copyright © 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

50(11):1473-1477

Available online at: dx.doi.org/10.1111/1346-8138.16883

Yeich A, Elhatw A, Ashoor Z, Park K, Craig T. 01/2023 Expert Opinion on Drug Safety.

>INTRODUCTION: Hereditary Angioedema (HAE) attacks show an increased frequency and severity for pregnant and lactating females secondary to the hormonal changes. The diagnosis and management of HAE in pregnant and lactating females pose a challenge for physicians due to the rarity of the disease and the paucity of the data for specific management.

AREAS COVERED: In this manuscript, we discuss the diagnosis and special presentation of HAE types 1 and 2 in pregnant and lactating females, including acute management, short-term prophylaxis, long-term prophylaxis, and drugs that should be avoided. Relevant publications were found through key word search of papers indexed in both Google Scholar and PubMed on 1 July 2022.

EXPERT OPINION: Treatment of HAE in the past has been mainly provided by experts; however, with more medications and an increasing number of patients, knowledge of how to care for HAE patients during pregnancy and lactation is important to review. Despite approval of additional medications in many countries, plasma-derived C1-inhibitor remains the drug of first choice for treatment in this unique population. Additional research is needed to increase safe access to other therapy options. We hope that future clinical studies, registries, and databases will shed additional light on this subject.

22(1):17-24

Available online at: researchgate.net/publication/333586185_Safety_of_Recombinant_Human_C1_Esterase_Inhibitor_for_Hereditary_Angioedema_Attacks_During_Pregnancy

Herraez L, Alvarez Sala P, Mielgo R. 08/2023 The Journal of Allergy & Clinical Immunology in Practice.

Subcutaneous plasma-derived C1 esterase inhibitor was safe and effective in the patient reported. Consequently, it could be a valuable option for the long-term prophylaxis of pregnant and breast-feeding patients who present with hereditary angioedema attacks and normal levels of C1 esterase inhibitor and mutated factor XII.

11(8):2587-2588

Available online at: dx.doi.org/10.1016/j.jaip.2023.04.025 (small fee)

Szilagyi D, Horvath HR, Andrasi N, Kempler MS, Balla Z, Farkas H. 11/2023 Scientific Reports.

Due to the similarity between the pathomechanism of SARS-CoV-2 infections and hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE), a possibility emerged that C1-INH-HAE may worsen the course of the infection, or that the infection may influence the severity of angioedema (HAE) attacks in C1-INH-HAE patients. Our study aimed to evaluate the effects of the COVID-19 pandemic on the quality of life (QoL) of Hungarian C1-INH-HAE patients, and to survey the acute course of the infection, post COVID symptoms (PCS), vaccination coverage and the side effects of vaccines in this patient population. 93 patients completed our questionnaire between 1st July 2021 and 31st October 2021. In this same period and between March 2019 and March 2020, 63 patients completed the angioedema quality of life questionnaire (AE-QoL). Out of those patients infected with SARS-CoV-2 in the examined period (18/93 patients; 19%), 5% required hospitalization, 28% experienced HAE attacks in the acute phase of the infection, and 44% experienced PCS. A total number of 142 doses of vaccines were administered to the patients. Serious vaccine reactions did not occur in any case, 4 (5%) out of the 73 vaccinated patients experienced HAE attacks. No significant difference (p = 0.59) was found in the median of the AE-QoL total score, or in the number of HAE attacks prior and during the pandemic. Based on our study, HAE patients did not experience more serious SARS-CoV-2 infection, and it did not aggravate the course of HAE either. Changes in the QoL were not significant, and vaccines were safe in HAE patients. Copyright © 2023. The Author(s).

13(1):20446

Available online at: dx.doi.org/10.1038/s41598-023-47307-1

Zuraw BL, Maurer M, Sexton DJ, Cicardi M. 01/2023 Allergology International.

Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE. Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.

72(1):54-62

Available online at: dx.doi.org/10.1016/j.alit.2022.06.001

Sundler Bjorkman L, Thulin M, Ekstrom M, Nordenfelt P, Egesten A. 02/2023 The Journal of Allergy & Clinical Immunology in Practice.

>BACKGROUND: Hereditary angioedema (HAE) is caused by low levels of or defects in C1 inhibitor. Although disease activity may be modified by prophylaxis, emergency treatment, treatment for comorbidities, and oral contraceptives, the extent of their use is unclear.

OBJECTIVE: To investigate trends in the use of disease-specific and interfering drugs in patients with HAE compared with the general population in Sweden.

METHODS: In a nationwide, longitudinal study, 239 patients with HAE and 2 383 controls were compared with the Prescribed Drug Register (2005-2019). These data reflect rates of dispensed prescriptions from pharmacies in Sweden.

RESULTS: Attenuated androgens were used by approximately 10% of patients with HAE. The number of individuals treated with prophylactic plasma-derived C1 inhibitor increased during this period to reach almost 25% in men and 35% in women in 2019. Tranexamic acid was prescribed to 5% to 15% of patients, primarily children and young adults. Rates of prescriptions for icatibant, an emergency medication, showed a steady increase since its introduction in 2010, in particular among middle-aged women, suggesting poorly controlled disease. The use of diuretics, calcium channel blockers, and gestagens was more common in patients with HAE than in controls, whereas angiotensin-converting enzyme inhibitors were rarely collected.

CONCLUSIONS: Despite concerns regarding side effects, approximately 10% of patients with HAE received attenuated androgens for long-term prophylaxis. The common use of emergency medication also suggests poorly controlled disease in many patients, highlighting the need for increased focus on prophylactic treatment. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

11(2):621-628

Available online at: dx.doi.org/10.1016/j.jaip.2022.11.034

Konstantinou GN, Riedl MA, Valent P, Podder I, Maurer M. 01/2023 The Journal of Allergy & Clinical Immunology in Practice.

Chronic spontaneous urticaria (CSU) is primarily a T2-dominant disease with a complex genetic background. Skin mast cell activation can be induced not only via the IgE-FcepsilonRI axis but also from several other distinct mechanisms, molecules, and receptors involved in CSU onset, persistence, and exacerbation. These include autoallergy, autoimmunity, central or peripheral neuroimmune dysregulation, activation of both extrinsic and intrinsic coagulation pathways, and microbial infections. Besides mast cells, recent reports suggest the active and direct involvement of basophils and eosinophils. Several biological characteristics or biomarkers have been linked with CSU's known endotypes and may help forecast therapeutic responses. The introduction of biologic therapy for CSU has been a major advance in the last 10 years. The cornerstone of angioedema (AE) pathogenesis is increased vascular permeability and plasma leakage into the deeper dermis and subcutis, either mediated by histamine or bradykinin (BK). C1-inhibitor deficiency, hereditary or acquired, is the primary cause of BK-mediated AE due to increased plasma BK concentration. Other complex conditions have been identified, with some likely involving contact system dysregulation and other putative mechanisms related to vascular endothelial dysfunction. The approval of multiple hereditary-AE-specific therapies for both prevention and acute attacks has revolutionized treatment of this disease. Any new knowledge of the pathogenesis of CSU and AE offers the opportunity to improve patient information, physician-patient communication, prediction of therapeutic responses, selection of precise tailor-made treatment for each patient, and exploration of novel treatment options for those who do not achieve disease control with current medications. Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

11(1):94-106

Available online at: dx.doi.org/10.1016/j.jaip.2022.11.006 (small fee)