Hereditary Angioedema Attacks Research Articles

The complexities of decision-making associated with on-demand treatment of hereditary angioedema (HAE) attacks

BackgroundHereditary angioedema (HAE) is characterized by debilitating attacks of tissue swelling in various locations. While guidelines recommend the importance of early on-demand treatment, recent data indicate that many patients delay or do not treat their attacks.ObjectiveThis survey aimed to investigate patient behavior and evaluate the key factors that drive on-demand treatment decision-making, as reported by those living with HAE.MethodsPeople living with HAE were recruited by the US Hereditary Angioedema Association (HAEA) to complete a 20-minute online survey between September 6, and October 19, 2022.ResultsRespondents included 107 people with HAE, 80% female, 98% adults (≥ 18 years). Attack management included on-demand therapy only (50%, n = 53) or prophylaxis with on-demand therapy (50%, n = 54). Most patients (63.6%) reported that they did not carry on-demand treatment at all times when away from home. The most common reason for not carrying on-demand treatment when away from home was ‘prefer to treat at home’ (72.1%). Overall, 86% of respondents reported delaying on-demand treatment, despite recognizing the initial onset of an HAE attack and despite 97% of patients agreeing that it is important to recover quickly from an HAE attack. Reasons for non-treatment or treatment delay included ‘the attack is not severe enough to treat’ (91.9% and 88.0%, respectively), ‘cost of treatment’ (31.1% and 40.2%, respectively), anxiety about refilling the prescription for on-demand treatment quickly (31.1% and 37.0%, respectively), the pain (injection or burning) associated with their on-demand treatment (18.9% and 28.3%, respectively), the lack of a suitable/private area to administer on-demand treatment (17.6% and 27.2%, respectively), lack of time to prepare on-demand treatment (16.2% and 16.3%, respectively), and a ‘fear of needles’ (13% and 12.2%, respectively). Survey findings from the patient perspective revealed that when on-demand treatment was delayed, 75% experienced HAE attacks that progressed in severity, and 80% reported longer attack recovery.ConclusionsSurvey results highlight that decision-making regarding on-demand treatment in HAE is more complicated than expected. The burden associated with current parenteral on-demand therapies is often the cause of treatment delay, despite acknowledgment that delays may result in progression of HAE attacks and longer time to recovery.

The Burden of Hereditary Angioedema in a Large Family in Brazil

Introduction: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. Methods: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. Results: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients’ current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. Conclusions: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema.

Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks. Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured. Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema. The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.

Experience of lanadelumab usage for long-term prophylaxis of attacks in hereditary angioedema in patients of the Moscow region

BACKGROUND: Hereditary angioedema is a rare disease with high frequency for orphan diseases. The autosomal dominant type of inheritance leads to a significant number of affected patients in families. Angioedema attacks significantly impair the quality of life. hereditary angioedema causes life-threatening conditions which depend on edema’s localization. AIM: To evaluate the efficacy and safety of lanadelumab for long-term prophylaxis in hereditary angioedema in routine practice. MATERIALS AND METHODS: 16 patients with hereditary angioedema were enrolled in the observational single-center study. The data were researched: sex, patients age, age of symptoms onset, efficacy of previous methods of therapy, type of hereditary angioedema, genetics of the disease, contraindications for other prophylaxis methods. The efficacy of therapy was evaluated according to the duration of the course, the frequency of administration, the number of attacks of edema during the period of observation, and the improvement of the quality of life according to the AAS28 scale. Safety of use was evaluated by the presence of adverse events during the investigation. RESULTS: The long-term prophylaxis with lanadelumab was effectively and safety for all of 16 patients. Single attacks during of therapy were provoked by the influence of significant triggers. Life-threatening attacks were not registered. The frequency of lanadelumab injections was reduced after 12 months of usage for 50% of patients. The improvement of the quality of life (from 6 to 38 according to AAS28 scale) was confirmed for all patients. Adverse events weren’t registered during the period of treatment. CONCLUSION: The long-term prophylaxis of edema in hereditary angioedema with lanadelumab usage was approved as efficiently and safety.

PCR267 Real-World Impact of Treated Hereditary Angioedema Attacks on Patients’ Quality of Life

PCR267 Real-World Impact of Treated Hereditary Angioedema Attacks on Patients’ Quality of Life

P24 Real-World Impact of Treated Hereditary Angioedema Attacks on Patients’ Employment and Work Productivity

P24 Real-World Impact of Treated Hereditary Angioedema Attacks on Patients’ Employment and Work Productivity

Efficacy and Safety of Donidalorsen for Hereditary Angioedema

BackgroundHereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein–kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression.MethodsIn this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25.ResultsA total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P=0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity.ConclusionsDonidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.)

Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks

BackgroundApproved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy.MethodsIn this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of “a little better” on the Patient Global Impression of Change scale (ratings range from “much worse” to “much better”) at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from “none” to “very severe”) at two or more consecutive time points within 12 hours and complete attack resolution (a rating of “none” on the PGI-S scale) within 24 hours.ResultsA total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P=0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P=0.004 and P=0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P=0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported.ConclusionsOral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.)

A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300mg every 2weeks (Q2W) to every 4weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.

Garadacimab for hereditary angioedema attack prevention: long-term efficacy, quality of life, and safety data from a phase 2, randomised, open-label extension study

Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. CSL Behring.

Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema

Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (&gt;1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p &lt; 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema

BackgroundClinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. ObjectiveTo achieve consensus on a Core Outcome Set comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. MethodsA Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. ResultsFifty-eight worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of ≥90% was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. ConclusionThis international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

The Disease Burden of Hereditary Angioedema: Insights from a Survey in French-Canadians from Quebec.

Limited data are available on the clinical profile and disease burden of hereditary angioedema (HAE) in Canadians. This study aimed to assess HAE disease characteristics and the burden of disease in Canadians with HAE types I, II, and normal levels of C1 inhibitor (nC1-INH). A 46-item patient survey evaluating clinical characteristics and burden of disease was developed and disseminated by the HAE patient organization Angio-oédeme héréditaire du Québec in Quebec, Canada, from May 2019 to February 2020. The survey received Research Review Board ethics approval. In the 35 respondents, HAE type I was the most common (46%), followed by nC1-INH (43%). Female participants were significantly younger at first symptom presentation than males (p=0.04). Prior to diagnosis, 69% of participants underwent unnecessary treatments and procedures, with a 10-year delay between first symptoms and diagnosis. Before starting the current treatment, 42% of participants experienced weekly HAE attacks. Most participants identified experiencing attacks in the abdomen (89%), followed by the larynx (66%), feet (66%), hands (63%), and face (63%). Most attacks were severe or moderate, yet almost half of patients waited >1 hr before getting medical attention at their last emergency department (ED) visit. HAE was associated with decreased health-related quality of life, leading to significant functional impairment in personal and professional life. As compared to HAE type I/II, patients with HAE nC1-INH were treated more often with tranexamic acid for long-term prophylaxis, and their condition was less controlled, resulting in more attacks and ED visits. HAE manifests in this patient population as frequent moderate-to-severe attacks and a high disease burden; the HAE subtype may differentially affect care requirements. There is an urgent need for increased awareness and education on HAE among treating physicians.

Management of Hereditary Angioedema in Pediatric, Pregnant, and Breast-Feeding Patients: An Expert Opinion – A Secondary Publication

Hereditary angioedema (HAE) is a rare inherited condition marked by recurrent skin and submucosal edema. HAE is caused by a C1 inhibitor deficiency or decreased C1 inhibitor function. The initial attack may occur during childhood or pregnancy, with symptoms ranging from classic angioedema to nonspecific stomach cramps. In this review, we discuss strategies for children and pregnant women to manage HAE attacks effectively and safely in light of the recent increase in HAE diagnosis. To begin, an aggressive work-up is necessary to confirm HAE-1/2 and to determine the most effective countermeasures. Secondly, in the event of an acute attack, plasma-derived C1-inhibitor is the first line of defense for children and pregnant women. Icatibant is also appropriate for use, except in pregnant women. Fresh frozen plasma (FFP) may be suggested as an alternative. Thirdly, proactive measures to prevent HAE attacks should be considered whenever a procedure is performed that may result in an exacerbation. Finally, FFP, attenuated androgen, and antifibrinolytic agents are recommended for long-term prophylaxis in South Korea where the C1 inhibitor is scarce. However, when making a decision, it is necessary to consider both the efficacy and the risk of adverse effects. For proper management, written action plans and first-aid kits are required. The action plans should be customized to the patient’s unique circumstances.

Anxiety Associated with On-Demand Treatment for Hereditary Angioedema (HAE) Attacks

Anxiety Associated with On-Demand Treatment for Hereditary Angioedema (HAE) Attacks

Real-world reporting rates of administration-site reactions with on-demand treatment of hereditary angioedema attacks.

Background: Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/or submucosal swelling. Objective: To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzed administration-site adverse drug reactions (ADR) associated with approved on-demand HAE therapies reported in the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). Methods: We searched the FAERS database from October 1, 2009, to March 31, 2022, for reports of all FDA-approved on-demand therapies for HAE: plasma-derived C1-inhibitor (pdC1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (rhC1-INH). ADRs in which the drug was listed as the "primary suspect" were recorded for each drug. ADR preferred terms were grouped into 18 ADR domains based on semantic and/or clinical similarity, and the number of reports for each drug was calculated per year from the time of approval through March 2022, and descriptive results were presented. Preferred terms associated with administration-site ADRs identified from clinical trials and denoted on approved HAE drug U.S. package inserts were examined in a complementary analysis. Results: The highest reported rates of administration-site ADRs per year were site pain (17.9 reports per year), site erythema (7.4 per year), and site swelling (6.7 per year). RhC1-INH was the only drug for which access-site complications and/or malfunctions were reported (9.5 per year). PdC1-INH had the highest rate of incorrect route of product administration (3.7 per year). PdC1-INH showed statistically significant elevated reporting rate of injection-site reactions (reporting odds ratio [ROR] 3.59 [2.36-5.46]; empirical Bayesian geometric mean [EBGM] 1.97 [1.39]). Icatibant and rhC1-INH showed a statistical trend toward an increased reporting rate of administration-site reactions. Conclusion: Real-world data from FAERS were generally consistent with adverse events reported in clinical trials and suggest that patients experience substantial treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks. It should be noted that ADR rates are not exposure adjusted and are based on spontaneous reporting.

An expert panel's review on patients with hereditary angioedema switching from attenuated androgens to oral prophylactic therapy.

Background: Hereditary angioedema (HAE) is a rare condition marked by swelling episodes in various body parts, including the extremities, upper airway, face, intestinal tract, and genitals. Long-term prophylaxis (LTP), prescribed to control recurring HAE attacks, is integral to its management. Previously, attenuated androgens (AAs) were the only oral LTP options. However, in 2020, berotralstat, an oral plasma kallikrein inhibitor, was approved in the United States. A 2018 survey of adults with HAE type I or type II showed that almost all the patients who used prophylactic HAE medication preferred oral treatment (98%) and felt that it fit their lifestyle better than injectable treatment (96%). Still, guidelines lack consensus on transitioning patients from AAs to alternative oral prophylactic therapy. Objective: This paper aims to share expert insights and patient feedback on transitioning from AAs to berotralstat, an alternative oral prophylactic therapy, from the perspective of clinicians with extensive experience in treating patients with HAE. Methods: A panel of five HAE specialists convened for a virtual half-day roundtable discussion in April 2023. Results: Discussions about transitioning from AAs to berotralstat were prompted by routine consultations, patient inquiries based on independent research, ineffective current treatment, or worsening AA-related adverse effects. For patients who switched from AAs, the physicians reported that the decision was influenced by the alternative therapy's ability to prevent HAE attacks, its safety, and the once-daily administration schedule. All expert panel members identified fewer AA-related adverse effects; better quality of life; and less severe, shorter, and less frequent HAE attacks as clinical or patient goals they hoped to achieve through the treatment switch. Conclusion: The emergence of new, highly specific LTP drugs for HAE calls for the development of comprehensive recommendations and guidelines for transitioning from AAs to alternative oral prophylactic therapy. The expert panel highlighted key factors to consider during the development of such guidelines.

COVID-19 infection and vaccination in patients with hereditary angioedema: a multicentric study.

Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE.Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

Lanadelumab demonstrates high efficacy in reducing the frequency of angioedema attacks in patients with severe HAE in real-life settings

Introduction and objective: Evaluation of lanadelumab efficacy in preventing angioedema attacks in patients with severe hereditary angioedema due to C1-inhibitor deficiency in Poland and descriptive analysis of this group of patients. Materials and methods: Retrospective analysis of patients treated with lanadelumab in Poland. Data were acquired from the electronic database of the National Health Fund, compiled from 15 hereditary angioedema centres. Only patients with severe hereditary angioedema course (at least 12 severe – abdominal, pharyngeal or laryngeal – hereditary angioedema attacks per six months, requiring on-demand medications) initiated treatment. The patients received lanadelumab 300 mg every two weeks. The efficacy of the therapy was assessed after six months. Results: Lanadelumab was initiated in a total of 43 patients (group B). Twenty of them achieved the follow-up point after six months (group A). The mean age of the patients was 44 years. The majority (76.7%) were female and 79% had a family history of hereditary angioedema. Most patients (95.3%) had HAE-1 (absolute deficiency of C1-inhibitor). On average, within six months before treatment, group A patients experienced 19.7 (95% confidence interval, CI: 16.06–23.33) severe hereditary angioedema attacks. In the six months following treatment initiation, the number of attacks decreased to an average of 0.5 (95% CI: 0–1.0), with significant reductions in all types of hereditary angioedema attacks – abdominal (p &lt; 0.0001), pharyngeal (p &lt; 0.005), and laryngeal (p &lt; 0.05). Utilisation of on-demand medications dropped from an average of 23.5 (95% CI: 16.7–30.3) to 0.5 standard therapeutic dose (95% CI: 0–1.1). Conclusions: The study highlights the therapeutic potential of lanadelumab in managing hereditary angioedema, usually offering patients a complete resolution of severe hereditary angioedema attacks and release from dependence on rescue medication. Our results support the current paradigm shift in hereditary angioedema treatment.