Development and Validation of a US HAE-C1INH Quality of Life Instrument.

BACKGROUND: Hereditary angioedema (HAE) attacks are unpredictable, cause a substantial and enduring burden of illness, and are potentially fatal. Due to issues unique to the US healthcare system, there is a need for a US-validated HAE-specific Quality of Life (QoL) instrument. OBJECTIVE: To develop and validate a US HAE-specific QoL instrument, following FDA guidelines and established methodologies. METHODS: We generated 41 QoL-related items likely relevant to US HAE-C1INH patients and performed a 10-patient pilot study to refine the question-wording. 415 HAE C1-inhibitor (C1INH) deficiency U.S. patients completed the initial 41-item instrument online, providing the data for item reduction, factor analysis, and the assessment of validity and reliability. We used multiple linear regression to identify the drivers of total and domain scores. Convergent validity analysis assessed the extent to which the HAE-C1INH-QoL is theoretically related to the angioedema-QoL (AE-QoL). RESULTS: Item reduction and factor analysis yielded a final instrument of 31 items across five domains, and the assessment analysis showed that the HAE-C1INH-QoL is valid and reliable. Attack frequency and severity were statistically significant factors influencing total and domain scores. Correlation analysis of the two instruments indicated that 8 items of the HAE-C1INH-QoL were not included or well-described in the AE-QoL. CONCLUSION: The HAE-C1INH-QoL is the first HAE-specific QoL tool validated in the US. Compared to the AE-QoL, the items in our instrument are more relevant to US HAE patients.

Current and Emerging Therapeutics in Hereditary Angioedema.

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.

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.).

Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved 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. METHODS: In 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. RESULTS: A 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. CONCLUSIONS: Oral 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.).

The future of therapeutic options for hereditary angioedema.

Hereditary angioedema (HAE) is a rare genetic condition causing unpredictable and severe episodes of angioedema that are debilitating and life-threatening. Moreover, HAE can be classified into HAE due to C1-esterase inhibitor deficiency (HAE-C1INH) or HAE with normal C1INH. Moreover, HAE-C1INH is subcategorized as types I and II based on deficient or dysfunctional circulating C1INH protein resulting from inherited or spontaneous mutations in the SERPING1 gene leading to uncontrolled factor XII/plasma kallikrein activation and excessive bradykinin production. Bradykinin-2 receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in subcutaneous or submucosal fluid extravasation that can affect the face, extremities, airway, and gastrointestinal and genitourinary systems. Furthermore, HAE with normal C1INH is caused by either a known or unknown genetic mutation, and the mechanisms are less well-established but most forms are thought to be related to bradykinin signaling with a similar presentation as HAE-C1INH despite normal levels of C1INH protein and function. Current HAE management strategies include on-demand and prophylactic treatments which replace C1INH, reduce kallikrein activity, or block bradykinin binding to the bradykinin B2 receptor. With the advent of additional small molecule inhibitors, monoclonal antibodies, RNA-targeted therapies, gene therapies, and gene modification approaches, preclinical studies and human clinical trials are underway to further expand therapeutic options in HAE. This review article will briefly summarize current HAE treatments and provide an overview of potential future therapies for HAE.

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

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, 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. RESULTS: A total of 58 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% or greater 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, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

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.

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.

Hereditary angioedema outcomes in US patients switched from injectable long-term prophylactic medication to oral berotralstat.

BACKGROUND: Berotralstat, a first-line, once-daily, oral plasma kallikrein inhibitor for long-term prophylaxis of hereditary angioedema (HAE), is an effective and well-tolerated treatment option. OBJECTIVE: To summarize the safety, effectiveness, and impact on treatment satisfaction in patients who switched from injectable long-term prophylactics to oral berotralstat monotherapy (150 mg daily) at US sites in the international open-label APeX-S study. METHODS: APeX-S was an open-label, Phase II study of berotralstat conducted in 22 countries. Here, we focus on APeX-S patients enrolled at US sites who switched from injectable long-term prophylactics to berotralstat 150 mg once-daily monotherapy. RESULTS: A total of 34 patients discontinued lanadelumab (n = 21), subcutaneous C1 esterase inhibitor (n = 11), or intravenous C1 esterase inhibitor (n = 2) and switched to berotralstat 150 mg monotherapy. Vomiting, diarrhea, and upper respiratory tract infection were the most common adverse events (each 11.8%). Mean monthly attack rates were consistently low after the switch to berotralstat. The mean (SEM) monthly attack rate was 0.29 (0.11) at Month 1, 0.48 (0.15) at Month 6, and 0.58 (0.23) at Month 12. The median attack rate was 0 attack/mo throughout 12 months of treatment. Improvements were observed in the Treatment Satisfaction Questionnaire for Medication from baseline to Month 12 after the switch to berotralstat monotherapy, with the greatest improvements in convenience. CONCLUSION: The transition from injectable prophylactic medication to berotralstat was generally well tolerated. Patients switching to berotralstat monotherapy maintained good control of their HAE symptoms and reported improved treatment satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03472040.

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.

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema.

Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.

Refractory Status Epilepticus Associated With a Pathogenic Variant in TNFRSF13B.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis.

BACKGROUND: Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. METHODS: The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. RESULTS: Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains. CONCLUSIONS: These real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients' lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.

Validation of a suspicion index to identify patients at risk for hereditary angioedema.

Background: Hereditary angioedema (HAE) is a genetic condition characterized by dysregulation of the contact (kallikrein-bradykinin) pathway, leading to recurrent episodes of angioedema. Objective: This project sought to determine whether a suspicion index screening tool using electronic health record (EHR) data can identify patients with an increased likelihood of a diagnosis of HAE. Methods: A suspicion index screening tool for HAE was created and validated by using known patients with HAE from the medical literature as well as positive and negative controls from HAE-focused centers. Through the use of key features of medical and family history, a series of logistic regression models for 5 known genetic causes of HAE were created. Top variables populated the digital suspicion scoring system and were run against deidentified EHR data. Patients at 2 diverse sites were categorized as being at increased, possible, or no increased risk of HAE. Results: Prediction scoring using the strongest 13 variables on the "real-world" EHR-positive control data identified all but 1 patient with C1 inhibitor deficiency and patient with non-C1 inhibitor deficiency without false-positive results. The 2 missed patients had no documented family history of HAE in their EHR. When the prediction scoring variables were expanded to 25, the screening algorithm approached 100% sensitivity and specificity. The 25-variable algorithm run on general population EHR data identified 26 patients at the medical centers as being at increased risk for HAE. Conclusions: These results suggest that development, validation, and implementation of suspicion index screening tools can be useful to aid providers in identifying patients with rare genetic conditions.

Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat.

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.

Healthcare utilization of patients with hereditary angioedema treated with lanadelumab and subcutaneous C1-inhibitor concentrate.

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.

Long-term lanadelumab treatment improves health-related quality of life in patients with hereditary angioedema.

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).

Hereditary Angioedema: Impact of COVID-19 pandemic stress upon disease related morbidity and well-being.

Background: Individuals with hereditary angioedema (HAE) experience stress-related sequelae, including enhanced disease morbidity and reduced quality of life. The pervasive societal strain that surround the coronavirus disease 2019 (COVID-19) pandemic may theoretically pose a disproportionate risk for patients with HAE. Objective: To dissect the interrelationship(s) among the COVID-19 pandemic, stress, and HAE disease-related morbidity and overall well-being. Methods: Subjects with HAE (either due to C1-inhibitor deficiency or with normal C1 inhibitor) as well as non-HAE household members (normal controls) completed online questionnaires that covered the impact of the COVID-19 pandemic on attack frequency, observed effectiveness of HAE medications, stress, and perceived quality of life and/or well-being. The subjects scored each of the questions to reflect their current status as well as their status before being aware of the pandemic. Results: Disease morbidity and psychologic stress outcomes were significantly worse in patients with HAE during the pandemic compared with before they were aware of the pandemic. A COVID-19 infection further increased attack frequency. Control subjects also experienced deterioration of well-being and optimism. A comorbid diagnosis of anxiety, depression, or posttraumatic stress disorder (PTSD) was generally associated with worse outcomes. Women consistently showed greater decrements in wellness during the pandemic compared with men. Women also reported higher levels of comorbid anxiety, depression, or PTSD than men and experienced a higher rate of job loss during the pandemic. Conclusion: The results implicated a deleterious impact of stress in the aftermath of COVID-19 awareness on HAE morbidity. The female subjects were universally more severely affected then were the male subjects. Overall well-being and/or quality of life, and optimism for the future deteriorated after awareness of the COVID-19 pandemic for the subjects with HAE and non-HAE household controls.