Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary 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. METHODS: In 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. RESULTS: A 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. CONCLUSIONS: Donidalorsen 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.).

Inhibition of Prekallikrein for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease. METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety. RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo. CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.).

Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

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.

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Plasma microRNAs as biomarkers in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease with variable expression. In some families with identical genetic abnormalities, the expression can range from several attacks per month to no attacks at all. It is hypothesized that post-transcriptional gene regulation accounts for the variable expression of the disease. OBJECTIVE: To identify candidate microRNAs (miRNAs) that could play a role in HAE by determining whether miRNAs are differentially expressed in patients with HAE vs non-HAE individuals and whether expression profiles are tracked with severity. METHODS: This study compared serum miRNA expression in patients with HAE vs non-HAE using RNA sequencing. Associations between miRNA expression and HAE severity were assessed in patients with mild disease (<6 attacks a year) vs severe disease (>1 attack per month). The functions of candidate miRNAs were analyzed using in silico methods. RESULTS: There were robust miRNA expression differences between patients with HAE and non-HAE controls. A cluster analysis identified subgroups of patients with HAE having unique miRNA profiles that tracked with frequency of attacks. Two miRNAs, miR-99b-5p and miR-127-3p, were differentially expressed between mild and severe HAE (adjusted P < .05). In silico analysis revealed a function of differentially expressed miRNAs in regulation of C1 esterase inhibitor, kininogen, the bradykinin B2 receptor, and adherens junction function. CONCLUSION: Candidate microRNAs were identified that could distinguish patients with and without HAE and may be used to identify phenotypes of HAE.

Hereditary angioedema in older adults: Understanding the patient perspective.

BACKGROUND: Hereditary angioedema (HAE) is a rare condition characterized by potentially fatal, recurrent episodes of painful swelling. Whereas there are limited studies evaluating the quality of life of individuals with HAE, none have evaluated the impact of HAE on older adults. OBJECTIVE: To evaluate the effect of HAE on older adults through qualitative methodology. METHODS: A group of 3 physicians with extensive research and clinical experience in HAE developed a focus group guidebook highlighting issues of importance to older adults. A total of 17 patients with HAE (type I or II) aged 60 years and older participated in focus groups. Three independent reviewers coded each focus group transcript using a thematic saturation approach. RESULTS: Reviewers identified 7 core themes from the focus groups. The themes identified encompassed the following: (1) challenges with securing medications and insurance concerns; (2) the experience of living with HAE before the advent of newer and more effective therapeutic options; (3) a worsening of HAE attack frequency and severity with aging; (4) the effects of comorbid conditions such as arthritis, memory loss, and irritable bowel syndrome; (5) changes in HAE with menopause; and (6) changing perspective on HAE with age, the effect of HAE on interpersonal relationships including the decision to have children, and goals for future care and research including support groups and a desire to be included in clinical trials. CONCLUSION: Older adults with HAE have specific challenges and concerns that may be unique compared with younger populations. Health care providers should address these to provide optimal care.

Long term outcome of C1-esterase inhibitor deficiency.

Hereditary angioedema (HAE) is a rare hereditary disorder characterized by episodic swelling and life-threatening airway obstruction caused by laryngeal angioedema. In most HAE patients, reduced level of serum C1-Inhibitor (type-I-HAE) or presence of aberrant C1-Inhibitor (type-II-HAE) result in the lost of regulation of the complementary system and contact activation system with downstream over-activation of bradykinin - the chief mediator leading to angioedema. Type-III HAE (HAE-nl-C1INH) is rare without deficient or dysfunction of C1-Inhibitor, often with genetic aberrant related to the contact activation system. The prevalence of HAE in the population is estimated at 1 in 50,000 individuals, often with early onset, but due to the heterogeneity of the disease, there is frequently a significant delay in diagnosis. Recently, better awareness by physicians, more access to diagnostic tools, better management and prophylaxis has decreased morbidity and mortality. A focus in HAE patient care shift from management of attacks with on-demand medication, to use of prophylaxis to reduce attacks has improved the overall quality of life of patients with HAE. One area in HAE research that has not been emphasized is the long-term consequence of C1-INH deficiency in HAE patients, other than the typical manifestations of HAE, as evidence have emerged linking this disorder with increased risk of cardiovascular diseases, auto-immune disorders, and malignancy. This review aims to gather the current knowledge and evidence of potential consequence of C1-Inhibitor deficiency in HAE aside from angioedema with emphasis in the improvement of long-term care and overall quality of life for HAE patients.

Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH. METHODS: In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228. FINDINGS: Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed. INTERPRETATION: Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation. FUNDING: CSL Behring.

Small molecule drugs for atopic dermatitis, rheumatoid arthritis, and hereditary angioedema.

OBJECTIVE: To review recent trends in the development of targeted small molecule drugs (SMDs) for the treatment of immunologically driven disorders, including atopic dermatitis, rheumatoid arthritis, and hereditary angioedema. DATA SOURCES: Data sources included peer-reviewed published literature from the PubMed database, published abstracts from scientific and medical meetings, and medication information from the Drugs@FDA database. STUDY SELECTIONS: Articles with primary or retrospective trial results, articles with patient or physician survey results, articles providing expert perspectives, and commentary on chronic immunologic disorders, Food and Drug Administration package inserts, and abstracts from scientific meetings were selected. RESULTS: Targeted biological therapies have greatly improved response rates and symptom relief for patients with long-term immunologically driven disorders over the past 2 decades. However, recent advances in the understanding of molecular pathways involved in the pathogenesis of these disorders have led to the development of novel targeted SMDs, such as tofacitinib and berotralstat, that can be delivered orally or topically. Few head-to-head studies that compare the safety and efficacy of biologics to SMDs in immunologically driven disorders exist, although some studies suggest that oral and topical modes of administration are preferred by patients and may improve patient quality of life over time. CONCLUSION: Scientific advances have led to an increase in the development of targeted SMDs for the treatment of chronic immunologic disorders, which may revolutionize the management of these diseases. Head-to-head studies and real-world evidence are needed to fully compare treatment attributes between biologics and SMDs, including safety, efficacy, adherence, impact on quality of life, and cost-effectiveness.

Prophylactic therapy with subcutaneous C1-inhibitor is associated with sustained symptom control in patients with hereditary angioedema.

Background: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare genetic disorder characterized by disabling episodes of edema that commonly affect the skin as well as the gastrointestinal tract and upper airway. Prophylactic therapy can decrease the severity and number of attacks. Long-term symptom control and rescue medication use were evaluated in patients with HAE who received subcutaneous (SC) C1-INH enrolled in an open-label extension (OLE) of the phase III COMPACT (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) trial, including a subgroup analysis of patients treated for ≥12 months. Methods: The OLE study evaluated patients ≥ 6 years old who had had four or more attacks over 2 consecutive months before enrollment. Patients naive for C1-INH (SC) and patients in the COMPACT rollover trial were included. The patients were randomized to receive C1-INH (SC) 40 or 60 IU/kg twice weekly for 52 weeks. U.S. patients were eligible to continue for up to 140 weeks. Results: A total of 63 patients were randomized to the U.S. Food and Drug Administration approved dose of 60 IU/kg; 24 subjects were treated for at least 12 months. For the 63 subjects, the median (range) attacks per month were 0.09 (0.0-4.0) and per year were 1.0 (0.0-48.0). Two-thirds of the patients used rescue medication fewer than once per year. For the 24 patients with ≥ 12 months of exposure, the median (range) attacks per month and per year were 0.017 (0.000-2.4) and 0.199 (0.000-28.94), respectively. Of these patients, 12 (50%) were attack free throughout the duration of the study, and 3 (12.5%) had fewer than one attack per year. Conclusion: Prophylaxis with C1-INH (SC) provided sustained reductions in attack frequency and decreased rescue medication use, with a substantial proportion of patients being attack free.

Management of pediatric hereditary angioedema types 1 and 2: A search for international consensus.

Background: The management of hereditary angioedema has rapidly changed over the past decade. With these changes there has been increased recognition of the unique challenges of diagnosing and managing hereditary angioedema in pediatric populations. The objective of this review was to identify and compare recently published consensus guidelines for the management of hereditary angioedema types 1 and 2 to identify areas of agreement and conflict. Methods: A MEDLINE database search was performed to identify guidelines that offered guidance on diagnosing or managing hereditary angioedema in pediatric populations. A limitation was placed on guidelines published in the past 5 years to reflect the most recent literature. Results: Six clinical practice guidelines were included in the analysis. Early detection of disease status, coordination with specialists, and empowering patients with self-administered medications are emphasized, with use of plasma derived C1 esterase inhibitor as first line therapy for aborting attacks. The guidelines are shifting away from attenuated androgens and tranexamic acid for long-term prophylaxis toward medications such as subcutaneous C1 esterase inhibitor, lanadelumab, and berotralstat. Conclusion: Although some differences exist based on geographic region and health system where an included guideline was published, they have very minimal differences on close review.

Global perceptions of the current and future impacts of COVID-19 on hereditary angioedema management.

Background: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected health-care provision across the globe. Management of chronic ailments has become challenging because of the strained health-care resources and social distancing measures that prevent on-site clinical visits and treatments. Hereditary angioedema (HAE) is a debilitating, chronic disease characterized by unpredictable swelling attacks in various parts of the body. Controlling HAE symptoms often requires long-term prophylactic medication use and regular medical care; however, limited scientific information has been published about HAE medical care during the COVID-19 pandemic. Objective: To gather patient and health-care professional (HCP) perspectives on the global impact that COVID-19 has had, and the future impact it will have on HAE medical care and to identify differences in perceptions across economic and geographic boundaries. Methods: We conducted two independent but similar online global surveys to capture patient and HCP perspectives on the impact that COVID-19 has had, and the future impact it will have on HAE medical care. Results: Both patients and HCPs globally reported that the pandemic has limited the availability of HAE medical care, and they expect the restrictions to continue far beyond the pandemic. In addition, the results of our study suggested that telehealth use has increased across the globe but has been more successfully implemented in high-income countries. Conclusion: Patients and HCPs expect that HAE-related care will be negatively impacted by the pandemic for many years. Disparities in medical care and technologic infrastructure may exacerbate these challenges in non-high-income countries. Supportive tools and global infrastructure should be established to provide aid to non-high-income countries throughout the pandemic and several years after.

Hereditary angioedema in children and adolescents.

Hereditary angioedema is a genetic disease with autosomal dominant inheritance and, in most cases, caused by C1 inhibitor deficiency. Patients present with recurrent edema affecting sub-cutaneous and mucus membranes with variable onset and severity. More than 50% of patients may become symptomatic before 10 years of age. Family history can help with the diagnosis; however, approximately 25% of the cases are de novo mutations. Biochemical diagnosis should be delayed until after 1 year of age. Children were often excluded from advances in therapy for hereditary angioedema since most of the new medicines were tested in adults and thus excluded by the Food and Drug Administration (FDA) and other agencies for approval to be used in children. Treatment of attacks is available for the pediatric patient; however, barriers still exist for the use of long-term prophylaxis in young children. © 2022 Codon Publications. Published by Codon Publications.

Consensus on treatment goals in hereditary angioedema: A global Delphi initiative.

BACKGROUND: Hereditary angioedema (HAE) is a rare, life-threatening genetic disorder characterized by recurrent episodes of subcutaneous or submucosal angioedema. The ultimate goals of treatment for HAE remain ill-defined. OBJECTIVES: The aim of this Delphi process was to define the goals of HAE treatment and to examine which factors should be considered when assessing disease control and normalization of the patient's life. METHODS: The Delphi panel comprised 23 participants who were selected based on involvement with scientific research on HAE or coauthorship of the most recent update and revision of the World Allergy Organization/European Academy of Allergy and Clinical Immunology guideline on HAE. The process comprised 3 rounds of voting. The final round aimed to aggregate the opinions of the expert panel and to achieve consensus. RESULTS: Two direct consensus questions were posed in round 2, based on the responses received in round 1, and the panel agreed that the goals of treatment are to achieve total control of the disease and to normalize the patient's life. For the third round of voting, 21 statements were considered, with the participants reaching consensus on 18. It is clear from the wide-ranging consensus statements that the burdens of disease and treatment should be considered when assessing disease control and normalization of patients' lives. CONCLUSIONS: The ultimate goal for HAE treatment is to achieve no angioedema attacks. The availability of improved treatments and disease management over the last decade now makes complete control of HAE a realistic possibility for most patients.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

Short-term prophylaxis for children and adolescents with hereditary angioedema.

Background: Hereditary Angioedema (HAE) is a rare, autosomal dominant, life threatening disease, secondary to the deficiency of C1-inhibitor, dysfunction of C1-inhibitor or inadequate control of the contact pathway. Presentation includes recurrent swelling of the skin, upper airway and the abdomen. Trauma can precipitate attacks, which in the airway can lead to asphyxia. For this reason, short term prophylaxis (STP) may be indicated before medical, surgical and dental procedures. The goal of the manuscript is to review short term prophylaxis for children of all ages. Methods: We searched the following search words: children, pediatric, adolescent, plasma derived C1-inhibitor, recombinant C1-inhibitor, surgery, medical procedures, prophylaxis, dental, Hereditary Angioedema, tranexamic acid, androgens, fresh frozen plasma, short term prophylaxis, lanadelumab, subcutaneous C1-inhibitor in Google Scholar and in PubMed to develop our results. Results: STP should be discussed at every visit. Plans should be individualized based upon the procedure, therapies available and shared decision making with patient/parent. For high risk procedures plasma derived C1-inhibitor should be used at 20 units/kg just prior to the procedure. Alternative agents for STP include recombinant C1-inhibitor, fresh frozen plasma, androgens, or tranexamic acid. In all cases, with or without the use of STP, 2 doses of on-demand therapy should be available in case of an attack. Conclusion: Herein, we review the published data on STP for pediatric patients with HAE and discuss first-line options, and off label use of medications, as well as review the guidelines pertaining to short term prophylaxis.

The need for continuous quality assessment for providing optimal comprehensive care for patients with alpha-1 antitrypsin deficiency.

Background: Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that mainly affecting the liver and the lung. This creates difficulties to ensure that comprehensive care is administered to both organ systems. Past assessments of care delivered to patients with AATD demonstrated that improvements are needed. For that reason, we reassessed a population of patients with AATD in a large health care system to see if past findings affected present care. Methods: We performed electronic health record (EHR) reviews on all patients with documented AATD and confirmed the diagnosis by evidence of genotyping. We then selected the patients with the ZZ genotype to review comprehensive care. We further compared the findings in patients treated by different specialists (allergy immunology, gastroenterology, and pulmonary). The data were captured and assessed by using a secure web application for building and managing online surveys and data bases. REDCap. Results: We found a total of 329 patients with diagnostic codes for AATD, of these, 203 patients had a confirmed abnormal genotype. Confirmed genotypes were MZ (n = 69), ZZ (n = 48), MS (n = 22), SZ (n = 22). Further focus was applied to the care of the ZZ population secondary to a predisposition to potential severe lung and liver disease. The findings suggest that care can be improved no matter which specialist cares for the patient. Conclusion: Our study demonstrated that all three subspecialty groups had room for improvement in providing care to patients with AATD. Our study further demonstrated the need for recurrent quality-assurance programs that may be aided by care suggestions built into the EHR.

Androgen use in hereditary angioedema: A critical appraisal and approaches to transitioning from androgens to other therapies.

Background: Hereditary angioedema (HAE) is a rare genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. Attenuated androgens have been a prophylactic treatment option to reduce the frequency of HAE attacks for > 4 decades. However, the advent of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies has led to a decline in the use of attenuated androgens for the management of HAE in regions where newer therapies are available. A consensus about the best approach for discontinuing or tapering off attenuated androgen therapy does not exist. Objective: To develop a consensus on androgen tapering for patients with HAE. Methods: We sent an open-ended survey about androgen tapering to 21 physicians who treat HAE, 12 of whom responded. We reviewed the collective experience of the participating physicians in combination with results from a literature review on the topic. Results: The survey and literature review underscored potential concerns related to rapid androgen withdrawal in patients with HAE, including physician and patient concerns that the frequency and severity of attacks would abruptly worsen. In addition, discontinuation of attenuated androgens may have the potential for transient adverse effects, such as an increase in the rate of attacks or effects related to hormone withdrawal. Our survey showed that physicians often taper androgens to prevent increases in HAE attacks and possible withdrawal complications. Conclusion: Based on both experiences of the physicians who responded to our survey and reports in the endocrine literature, we provided recommendations for androgen tapering. However, we noted that the likelihood of adverse effects due to androgen withdrawal in patients with HAE is poorly understood and requires further study.