Search

Background Methods Results Conclusion Hereditary angioedema (HAE) is a chronic, unpredictable disease. Long‐term prophylactic treatments that offer durable efficacy, safety, and convenience are required to assist patients in achieving complete disease control, per international guidelines. We report an interim analysis of an ongoing phase 3 (VANGUARD) open‐label extension (OLE) study evaluating the long‐term safety and efficacy of garadacimab for HAE prophylaxis.Adults and adolescents aged ≥12 years with HAE previously participating in phase 2 and pivotal phase 3 (VANGUARD) studies were rolled over to an OLE, alongside newly enrolled patients. Patients received garadacimab 200 mg subcutaneously, once monthly for ≥12 months. The primary endpoint was treatment‐emergent adverse events (TEAEs) in patients with C1 inhibitor deficiency/dysfunction.At data cut‐off (February 13, 2023; N = 161), median (interquartile range) exposure was 13.8 months (11.9–16.3). For the primary endpoint, 133/159 patients experienced ≥1 TEAE (524 events), equivalent to 0.23 events/administration and 2.84 events/patient‐year. Garadacimab‐related TEAEs (13% of patients, 52 events) were most commonly injection‐site reactions (ISRs). No deaths occurred. One patient discontinued treatment due to garadacimab‐related moderate ISR. Most TEAEs were mild/moderate; three events were serious (COVID‐19, two events; abdominal HAE attack, one event) and not garadacimab related. No abnormal bleeding, thromboembolic, severe hypersensitivity, or anaphylactic events were observed. Mean HAE attack rate decreased by 95% from the run‐in period; 60% of patients were attack‐free. Almost all patients (93%) rated their response to garadacimab as “good” or “excellent.”Garadacimab has a favorable safety profile suitable for long‐term use and provides durable protection against HAE attacks. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. CSL Behring. [ABSTRACT FROM AUTHOR]

Keywords: attacks; hereditary angioedema; patient-reported outcomes; prodromes EN attacks hereditary angioedema patient-reported outcomes prodromes 577 579 3 01/31/23 20230201 NES 230201 Hereditary angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.[1] Early signs, symptoms, and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.[[2]] Using a new HAE-specific instrument, we have recently shown that patients can identify prodromes and are able to predict oncoming attacks.[4] However, that study was retrospective, which might have been affected by recall bias. Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The study highlights the predictive value of prodromes as forecasters of attacks.[[2], [4]] It affirms that patients can clearly distinguish prodromes from attacks. [Extracted from the article]

We received 223 patient reports on attacks, with 92% experiencing a prodrome before at least one attack, and 64% said they are able to predict an oncoming attack by a prodrome. Keywords: attacks; dimensions; domains; hereditary angioedema; prodromes EN attacks dimensions domains hereditary angioedema prodromes 1309 1312 4 03/30/22 20220401 NES 220401 ACKNOWLEDGMENTS We thank our colleagues from other HAE centers in Israel and the Israeli HAE patient organization (EDEMA) for their collaboration. Orange bars = attacks, blue bars = prodromes gl These results indicate that HAE patients can distinguish prodromes from attacks and that prodromes foretell subsequent attack location and intensity. [Extracted from the article]

Abbreviations BMI body mass index C1-INH-HAE hereditary angio-oedema due to C1-inhibitor deficiency/dysfunction CI confidence interval FPS-R Faces Pain Scale - Revised tool HAE hereditary angio-oedema HCP healthcare professional SD standard deviation TEAE treatment-emergent adverse event TOSR time to onset of symptom relief TTMS time to minimum symptoms ACKNOWLEDGMENTS We thank all patients, investigators, and their study staff. HCP, healthcare professional; TOSR, time to onset of symptom relief gl Most attacks had a short time to initial symptom relief: ~80% and ~90% started to resolve by 1 and 2 hours, respectively, after second administration, and ~55% and ~90% by 1 and 2 hours, respectively, after third administration. 2 a In Part 1, three patients received icatibant in the absence of an HAE attack; their second icatibant administration in Part 2 was therefore treatment of their first on-study attack. All nine patients were included in the primary end-point analysis after second icatibant administration (for new attacks in Part 2), and eight patients after third administration (for subsequent attacks; one patient did not have baseline measurement for a cutaneous/abdominal attack); all experienced symptom relief after treatment. [Extracted from the article]

Background: Berotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE. Methods: APeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness. Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040). [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52–140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were ≤17 years old [mean (range) age, 13.3 (8–16) years, 3 subjects <12 years old; exposure range, 51–133 weeks]. All 10 pediatric subjects experienced ≥50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Conclusions: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE. [ABSTRACT FROM AUTHOR]

Background: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial. Methods: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period. Results: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities. Conclusions: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353. [ABSTRACT FROM AUTHOR]

Background: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods: This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). Results: Twenty children (aged 5‐14 years; 73 HAE attacks) were treated with rhC1‐INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1‐INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0‐65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0‐126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment‐related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. Conclusions: Recombinant human C1‐INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults. [ABSTRACT FROM AUTHOR]

Background: Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources. Objective: This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks. Methods: In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of ≥50 mm, with severe attacks defined as ≥75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed <84 kg; 4200 IU for patients who weighed ≥84 kg) or placebo. Also, in an open-label extension (OLE) study of rhC1-INH, oropharyngeal-laryngeal attacks were analyzed. Rescue therapy with rhC1-INH 50 IU/kg (≤4200 IU) was permitted after 4 hours or for life-threatening symptoms (in the RCT) or after 1 hour (in the OLE study). The primary end point measured the time to the beginning of symptom relief by using the Treatment Effects Questionnaire. Results: Of 75 adults in the RCT, 43 had severe attacks and received either rhC1-INH (n = 24) or placebo (n = 19). The median (95% confidence interval) time to the onset of symptom relief totaled 90.0 minutes (95% confidence interval, 47.0 -120.0 minutes) versus 334.0 minutes (95% confidence interval, 105.0 to not calculable minutes; hazard ratio, 2.5; p = 0.02), for rhC1-INH and placebo, respectively. Open-label rhC1-INH rescue therapy was administered to 1 of 24 in the rhC1-INH group (4.2%) and 10 of 19 in the placebo group (52.6%). During the OLE study, the median onset of symptom relief with rhC1-INH for eight oropharyngeal-laryngeal HAE attacks was 69.0 minutes (95% confidence interval, 59.0-91.0 minutes). Conclusion: In the current study, rhC1-INH was efficacious in resolving severe HAE attacks, including oropharyngeal-laryngeal attacks. The rhC1-INH rescue treatment rapidly improved symptoms for patients who received placebo and who experienced worsening or sustained symptoms. [ABSTRACT FROM AUTHOR]

In patients with hereditary angioedema (HAE), premonitory symptoms ('prodromes') may appear hours to days before attack onset. It remains to be determined if prodromes could be useful indicators for early treatment initiation. Most published reports of prodromes have been limited to case reports or small case series. The common objective of several recent survey-based studies was to collect information relevant to prodromal patterns in patients with HAE. Three separate surveys solicited prodromal data from HAE patients. Although differences in survey methodologies permit only descriptive analysis of data, responses to the surveys provide the largest compilation of observational data on this topic to date. Prodromes were reported by 82.5-95.7% of patients surveyed. In one survey, about two-thirds of subjects reported experiencing prodromes before all or most acute HAE attacks, and only 6% of subjects noted the appearance of prodromes in <10% of all attacks. The most common types of prodromal symptoms were related to skin/soft tissue and gastrointestinal tract. Most prodromes were experienced hours to days before the onset of angioedema. A large percentage of surveyed subjects indicated being able to predict an impending HAE attack all or most of the time; <10% reported being rarely or never able to predict an attack. Although insufficient to establish the clinical role of prodromal symptoms, results of these surveys provide additional data on the scope of prodromes and could stimulate further research into the potential efficacy and cost-effectiveness of HAE attack prediction and prodrome-triggered interventions. [ABSTRACT FROM AUTHOR]

Background We analyzed the clinical response of pediatric and adolescent hereditary angioedema ( HAE) patients to pd C1- INH in the International Multicenter Prospective Angioedema C1- INH Trials ( I.M.P.A.C.T.) 1 and 2. Methods Patients included in this post hoc analysis of prospectively collected data were between 10 and 18 yr old with type I or II HAE and a documented history of abdominal or facial attacks. Patients received a single injection of pd C1- INH concentrate ( Berinert®, CSL Behring, Marburg, Germany) 20 U/kg. Efficacy end-points were time from the administration of study drug to onset of symptom relief and time to complete relief of all symptoms. Results Seven pediatric patients were included in I.M.P.A.C.T.1 with only 1 attack analyzed per patient. Median time to onset of relief was 0.42 h and to complete resolution was 8.08 h. No patient experienced a worsening of symptoms during the 0-4-h assessment period. Nine patients who experienced a total of 115 attacks were included in the analysis of I.M.P.A.C.T.2. Abdominal attacks were rated as 'severe' more frequently than were other types of attacks. The number of attacks per patient ranged from 2 to 42, and study participation ranged from 1 to 38 months. Median times to onset of symptom relief and to complete symptom resolution were 0.49 h and 14.1 h, respectively. Of 4 treatment-emergent adverse events in both studies, only 2 were considered related to treatment. Conclusions Study results showed that outcomes with pd C1- INH treatment of HAE in pediatric patients are comparable with outcomes in adults. [ABSTRACT FROM AUTHOR]

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. Objective: To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. Methods: This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. Results: Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. Conclusion: C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article about the use of recombinant human (rh) C1INH concentrate in the prevention of acute hereditary angioedema (HAE) attacks, discussing issues arising from the investigation that may be considered in more detail.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life- threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophy- laxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifi- Amcally reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with heredi. tary 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), donidal- orsen 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°/0 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°/0 in the placebo group. The mean attack rate during weeks 5 to 25 was 87°6 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 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. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. Methods: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. Results: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. Conclusions: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.) N Engl J Med 2010;363:532-41. [ABSTRACT FROM AUTHOR]