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.

Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial.

BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

[Facial swelling due to angioedema: often mast cell mediated, but not always]. / Gelaatszwellingen door angio-oedeem.

Most cases of angioedema are mast cell mediated. We present three patients with angioedema, who were admitted to our emergency room or outpatient clinic. One of them did have mast cell mediated angioedema, despite insufficient response to initial antihistamine treatment. The other patients had more rare cases of angioedema, i.e. hereditary angioedema with C1-inhibitor deficiency and angiotensin converting enzyme inhibitor associated angioedema. We discuss similarities and differences in symptoms, diagnosis and treatment between these causes of angioedema. We recommend keeping the differential diagnosis of angioedema in mind when a patient with angioedema is presented, including rarer pathophysiological explanations.

Sensitivity to change and minimal clinically important difference of the angioedema control test.

BACKGROUND: The Angioedema Control Test (AECT) is a patient-reported outcome measure developed and validated for the assessment of disease control in patients with recurrent angioedema. Its sensitivity to change and minimal clinically important difference (MCID) have hitherto not been established. METHODS: Patients with recurrent angioedema due to chronic spontaneous urticaria, hereditary angioedema, or acquired C1-inhibitor deficiency were repeatedly asked to complete the AECT along with the Angioedema Quality of Life Questionnaire (AE-QoL), Dermatology Life Quality Index (DLQI), and anchors for disease control and whether treatment was sufficient during routine care visits. The sensitivity to the change of the AECT was determined by correlating changes in its scores over time with changes in the applied anchors. The MCID was determined using anchor-based and distributional criterion-based approaches. RESULTS: Eighty-six cases were used for this analysis. Changes in AECT scores correlated well with AE-QoL changes (but less with changes in the DLQI) as well as other applied anchors, demonstrating its sensitivity to change. The MCID was found to be three points for improvement of angioedema control. The available number of cases with meaningful deterioration in our dataset was too low to reach a definite conclusion on the MCID for deterioration of angioedema control. CONCLUSION: The AECT is a valuable tool to assess changes in disease control in patients with recurrent angioedema over time. The lowest AECT score change that reflects a meaningful improvement of disease control to patients (MCID) is three points.

The Disease Burden and Societal Costs of Hereditary Angioedema.

BACKGROUND: According to the current treatment guidelines, the goals of treatment of patients with hereditary angioedema (HAE) are to achieve total control of the disease and to normalize patients' lives. OBJECTIVE: This study aims to establish the entire burden of HAE comprising disease control, treatment satisfaction, reductions in quality of life, and societal costs. METHODS: Adult patients with HAE under treatment at the Dutch national center of reference completed a cross-sectional survey in 2021. The survey consisted of different questionnaires: angioedema-specific questionnaires (4-week Angioedema Activity Score and Angioedema Control Test), quality of life questionnaires (Angioedema Quality of Life [AE-QoL] questionnaire and EQ-5D-5L), the Treatment Satisfaction Questionnaire for Medication (TSQM), and societal costs questionnaires (iMTA Medical Consumption Questionnaire and iMTA Productivity Cost Questionnaire). RESULTS: The response rate was 78% (69 of 88). The entire sample had a mean Angioedema Activity Score of 16.61, and 36% of participants had poorly controlled disease as expressed by the Angioedema Control Test. The mean quality of life in the entire sample was 30.99 as expressed by the AE-QoL and 0.873 as expressed by the EQ-5D-5L utility value. Utilities dropped by 0.320 points during an angioedema attack. TSQM scores ranged from 66.67 to 75.00 across its 4 domains. On average, total costs per year incurred €22,764, predominantly existing of HAE-medication costs. Total costs showed substantial variation between patients. CONCLUSIONS: This study describes the entire burden of HAE among Dutch patients comprising disease control, quality of life, treatment satisfaction, and societal costs. These results can inform cost-effectiveness analyses that can aid reimbursement decisions for HAE treatments.

Case report: Recurrent angioedema: Diagnosing the rare and the frequent.

Hereditary angiodema with normal C1 inhibitor and unknown mutation (HAE-nC1INH-UNK), an exceedingly rare subtype of HAE, appears to be often diagnosed in patients who do not have this condition, but have mast cell-mediated angioedema. Here, we report two patients diagnosed with HAE-nC1INH-UNK by their physicians, who referred them to our center for treatment continuation with costly kallikrein-kinin-system targeted therapies. We describe how we established the correct diagnosis of recurrent mast cell-mediated angioedema after thorough investigation of both patients and initiated effective treatment with omalizumab. Also, we present and discuss the consensus criteria for diagnosing the very rare condition HAE-nC1INH in light of recent research and based on our own clinical experience. In conclusion, HAE-nC1INH-UNK should only be considered after more common differential diagnoses, i.e., mast cell-mediated angioedema, have thoroughly been investigated and ruled out. This approach reduces both the patients' disease burden and healthcare costs and contributes to meaningful research.

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation.

Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives. The fundamental cause of hereditary angioedema in almost all patients is a mutation in the SERPING1 gene leading to a deficiency in C1-inhibitor. Subsequently, the contact activation cascade and kallikrein-kinin pathway are insufficiently inhibited, resulting in excessive bradykinin production triggering vascular leakage. While C1-inhibitor is an important regulator of the intrinsic coagulation pathway, fibrinolytic system and complement cascade, patients do not have an increased risk of coagulopathy, autoimmune conditions or immunodeficiency disorders. Hereditary angioedema is diagnosed based on C1-inhibitor level and function. Genetic analysis is only required in rare cases where hereditary angioedema with normal C1-inhibitor is found. In recent years, new, highly specific therapies have greatly improved disease control and angioedema-related quality of life. This article reviews the clinical picture of hereditary angioedema, the underlying pathophysiology, diagnostic process and currently available as well as investigational therapeutic options.

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.).

Severe acquired hypertriglyceridemia following COVID-19.

Severe hypertriglyceridemia is a major risk factor for acute pancreatitis. In exceptional cases, it is caused by plasma components inhibiting lipoprotein lipase activity. This phenomenon is predominantly associated with autoimmune diseases. Here, we report a case of severe hypertriglyceridemia due to a transient reduction in lipoprotein lipase activity following an episode of COVID-19 in an otherwise healthy 45-year-old woman. The lipoprotein lipase activity of the patient was markedly reduced compared with a healthy control and did recover to 20% of the healthy control's lipoprotein lipase activity 5 months after the COVID-19 episode. Mixing tests substantiated reduced lipolytic capacity in the presence of the patient's plasma at presentation compared with a homozygous lipoprotein lipase-deficient control, which was no longer present at follow-up. Western blotting confirmed that the quantity of lipoprotein lipase was not aberrant. Fibrate treatment and a strict hypolipidemic diet improved the patient's symptoms and triglyceride levels.