Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis ...and management of HAE provides up‐to‐date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on‐demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast‐feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.
Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
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).
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.
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.
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.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable localized episodes of edema, which is frequently managed with long-term prophylactic medications. Until recently, ...long-term prophylaxis has predominantly required regular intravenous or subcutaneous administration, however the recent approval of berotralstat (Orladeyo™) offers an orally administered prophylactic which may be associated with a lower burden of treatment compared to injectable options for some patients.
This report describes four participants in the APeX-S trial who transitioned from subcutaneously administered lanadelumab (Takhzyro
) to daily oral berotralstat for long-term HAE prophylaxis. Lanadelumab dosing continued after berotralstat commencement in all patients and was tapered before discontinuation in three of the four patients. No substantial increases in HAE attack rates were observed after the transition to berotralstat monotherapy. One patient experienced a treatment-related adverse event (dyspepsia), which was mild and self-resolving.
All four patients described in this case series successfully transitioned from lanadelumab to berotralstat monotherapy for long-term prophylaxis without significant complications and without the use of a complex transition protocol. The decision to transition to berotralstat monotherapy and how the transition should be achieved was discussed between patient and physician, ensuring that the comfort and perspectives of the patients were considered during the treatment transition. This report highlights the importance of individualization of HAE management plans to address both the disease and treatment burdens of HAE, and thus to provide the best possible quality of life for each patient.
Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a ...nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks.
We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.
Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval CI, -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo.
In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).
Background
Topical treatments for atopic dermatitis (AD) used reactively often fail to achieve lasting disease control; many of these therapies are associated with safety concerns that limit ...long-term use. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD that has potential as a long-term maintenance therapy.
Objective
The aim was to evaluate the long-term efficacy and safety of crisaborole once daily (QD) compared to vehicle QD as a maintenance therapy to reduce the incidence of flares in patients with AD who previously responded to crisaborole twice daily (BID).
Methods
CrisADe CONTROL was a randomized, double-blind, vehicle-controlled, 52-week, phase III study of patients aged ≥ 3 months with mild-to-moderate AD involving ≥ 5% treatable body surface area. Eligible patients received crisaborole BID during an open-label run-in period of up to 8 weeks. Responders were randomly assigned in the double-blind maintenance period to receive either crisaborole QD or vehicle QD. Responders were defined as patients who achieved Investigator’s Static Global Assessment (ISGA) success (ISGA score of 0 clear or 1 almost clear with a ≥ 2-grade improvement) and ≥ 50% improvement in Eczema Area and Severity Index total score (EASI-50) from baseline. Patients who experienced a flare (ISGA score ≥ 2) during the double-blind maintenance period switched to crisaborole BID for up to 12 weeks. During this period, patients were assessed every 4 weeks; if the flare resolved (ISGA score ≤ 1), patients resumed their assigned treatment. The primary endpoint was flare-free maintenance until onset of the first flare. Key secondary endpoints were number of flare-free days, number of flares, and maintenance of pruritus response until onset of the first flare. The incidence of treatment-emergent adverse events was also analyzed.
Results
Overall, 497 patients entered the open-label run-in period with crisaborole BID, of which 270 patients were randomized into the 52-week double-blind maintenance period of the study. Of the 270 patients, 135 were randomly assigned to the crisaborole QD group and 135 were randomly assigned to the vehicle QD group. Median time of flare-free maintenance was longer for patients who received crisaborole versus vehicle (111 vs 30 days, respectively;
p
= 0.0034). The mean number of flare-free days was higher for patients who received crisaborole versus vehicle (234.0 vs 199.4 days, respectively;
p
= 0.0346). The mean number of flares was lower for patients who received crisaborole versus vehicle (0.95 vs 1.36, respectively;
p
= 0.0042). No clear trend was observed in maintenance of pruritus response between crisaborole- and vehicle-treated patients. Crisaborole was well tolerated, with no new or unexpected safety findings when used as maintenance treatment.
Conclusions
Crisaborole QD was effective and well tolerated for long-term maintenance treatment and flare reduction in adult and pediatric patients with mild-to-moderate AD.
Trial Registration
ClinicalTrials.gov, NCT04040192, 31 July 2019.
Plain Language Summary
Atopic dermatitis (AD) is an immuno-inflammatory skin disease that can last a long time. It causes skin lesions and intense itching. Topical AD treatments used reactively often fail to control the disease over a long period of time. Many are associated with safety concerns that limit long-term use. Crisaborole ointment is a nonsteroidal treatment for the skin and is used to treat mild-to-moderate AD. Previous studies showed that using crisaborole twice daily was effective and had few side effects in patients with mild-to-moderate AD. This study evaluated how effective and safe long-term treatment with once-daily crisaborole was compared with an ointment with no drug (vehicle). The study included patients aged ≥ 3 months with mild-to-moderate AD whose AD improved after previous treatment with twice-daily crisaborole. This study was designed to investigate how much crisaborole reduced the incidence of AD flares over 52 weeks in these patients.
The study included 270 patients whose AD had improved after treatment with twice-daily crisaborole. Of these patients, 135 were randomly assigned to receive crisaborole once a day and 135 to receive vehicle once a day. Patients who received crisaborole had a significantly longer time before experiencing AD flares than those who received vehicle. Crisaborole was well tolerated, and no new or unexpected side effects were found when used as a once-daily maintenance treatment for 52 weeks. These results indicate that once-daily treatment with crisaborole could be a potential long-term maintenance treatment option in children and adults with mild-to-moderate AD.
Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INHSC; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an ...open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.
Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change 95% CI, 0.07 0.01, 0.12 and Visual Analog Scale (7.45 3.29, 11.62). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change 95% CI, - 1.23 - 2.08, - 0.38), HADS depression scale (- 0.95 - 1.57, - 0.34), and WPAI-assessed presenteeism (mean change 95% CI, - 23.33% - 34.86, - 11.81), work productivity loss (- 26.68% - 39.92, - 13.44), and activity impairment (- 16.14% - 26.36, - 5.91). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.
Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .
Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL).
The objective of this study was to assess HRQoL outcomes in patients self-administering ...subcutaneous C1-INH (C1-INHSC; HAEGARDA) for routine prevention of HAE attacks.
Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM).
Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a “good/excellent” response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo.
In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).
Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by deficient or dysfunctional C1 inhibitor (C1 INH). HAE patients experience recurrent episodes of angioedema affecting the ...extremities, face, genitalia or submucosal edema in the abdomen or upper airway. Laryngeal attacks can be fatal. The determination of optimal therapy should be based on individualization of patient history and preferences. The parameters include attack frequency, location, severity and burden of illness on quality of life. Patients with HAE need medications for acute attacks; some also require prophylaxis. This is an overview of HAE treatments currently available in the US and how to individualize therapy for patients based on their circumstances. A literature search was performed for HAE and therapeutic modalities currently available. HAE guidelines and randomized, controlled clinical trials were evaluated. There are several options for acute and prophylactic treatment of HAE that have been approved by the Food and Drug Administration. Acute treatments include C1 INH, a replacement therapy; ecallantide, a kallikrein inhibitor; and icatibant, a bradykinin-2 receptor antagonist. Prophylactic treatments include attenuated androgens and C1 INH. These options have been proven safe and effective in clinical trials. Optimal therapy is based on the individual patients need regarding on-demand therapy and/or prophylactic therapy, short-term or long-term. Patients with HAE have individual requirements, based on the nature and frequency of past attacks, occupation, proximity to trained medical personnel, and patient preference. These factors should be used to create a patient-centered approach to management of HAE.
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