[Long-term prophylactic therapy combined with on-demand therapy for the control of hereditary angioedema--Comment on the 2021 edition of the international WAO/EAACI guideline for the management of hereditary angioedema].

The 2021 edition of the international World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) guideline for the management of hereditary angioedema (HAE) is mainly based on high-quality randomized controlled trials. It provides clinical classification for HAE and offers graded recommendations for on-demand therapy, short-term prophylactic therapy, and long-term prophylactic therapy. Additionally, it provides management strategies for people with different HAE types. This article focused on the interpretation of short-term, long-term prophylactic therapy and on-demand therapy for HAE, supplemented with the latest clinical evidence, aiming to provide references for the long-term management of HAE.

[Case series of hereditary angioedema patients and use of tranexamic acid treatments in prophylaxis and acute crisis, experience in Perú]. / Serie de casos de pacientes con angioedema hereditario y uso de ácido tranexámico como tratamiento profiláctico, y en crisis agudas: experiencia en Perú.

BACKGROUND: Hereditary Angioedema (HAE) is a rare disease characterized by episodes of swelling, HAE crisis could cause death by suffocation, and also affect the quality of life in these patients. There exists an important disparity of HAE specific treatments between countries, inclusive in the same region, currently in Perú we use moderate and high doses of Tranexamic Acid (TA) in prophylaxis therapy and in acute HAE crisis respectively. OBJECTIVE: To report our experience with TA in three types of HAE patients and be a guide to other countries with this therapy, where HAE specific treatments are not registered. CASE REPORT: Patient 1: Woman. 49 years old. HAE-1. Symptoms began at the age of 12. Her final diagnosis was at age 45. Usually presents an acute crisis every two months approximately, she receives 2 g IV of TA when lips, tongue, facial episodes is beginning, eventually she needed other 1 - 2 g IV (after 4 hours). She receives Long-Term Prophylaxis (LTP) with TA (500 - 750 mg)/12 h. Patient 2: Woman 47 years old, HAE nC1INH-FXII. Symptoms began at the age of 19, during her first pregnancy, her definitive diagnosis was at the age of 41 years. She maintains a prophylaxis treatment of TA (750 mg-1,5 g)/daily; upper airway attacks are treated immediately with TA doses (1 - 2 g) when the crisis is beginning. Patient 3: Woman 43 years old, HAE-nC1INH-U. Genetic study did not recognize SERPING1, PLG1, ANGPT1, KNG1, FXII, mutations. Symptoms began at age 4, and her final diagnosis was at age 36. When the attack is beginning, she immediately receives TA (500 - 750 mg) orally / 12 hours during 2 to 3 days with acceptable tolerance and control of the HAE episodes. While the patients receive TA prophylaxis treatment doses (500 - 750 mg) every 8 or 12 hours respectively, the HAE episodes are less symptomatic and resolve in a few days. CONCLUSIONS: We found this systematic review, used TA orally, on-demand and prophylaxis therapy, maximum cumulative dose 3 g/24 h1. In our HAE patients, we used TA up to 4 g (2 g - 2 g) intravenous for control of acute crisis in a interval of 4 hours, when decreases the reaction, the orally maintenance dose should be prescribed, 1 g/8 h with a progressive decrease of the dose in the next days. Tranexamic Acid treatment was useful in our different types of HAE patients. Most of our patients use high doses of TA to slow down and stop slowly the HAE crisis. TA is probably an option in countries where specific treatments are not registered, it could be administered orally and/or intravenous. High doses of TA were well tolerated and with acceptable response in HAE attacks.

ANTECEDENTES: El Angioedema Hereditario (AEH) se caracteriza por episodios de hinchazón a niveles cutáneo y submucoso, una crisis podría causar muerte por asfixia. Además, afecta la calidad de vida de las personas que la padecen. Existe una disparidad importante de medicamentos específicos para el AEH entre países, inclusive en nuestra misma región. En Perú donde no son viables estos tratamientos, se utiliza el Ácido Tranexámico (AT) para las Profilaxis de Largo y Corto Plazo (PLP / PCP), y para las crisis agudas de AEH. OBJETIVO: Reportar la experiencia con el tratamiento de AT en tres tipos de pacientes con AEH, para que pueda ser usada como referencia en otros países en los que aún no se cuenta con medicamentos específicos para la enfermedad. REPORTE DE CASO: Paciente 1: Mujer de 49 años, AEH Tipo 1. Inició síntomas a los 12 años de edad. Diagnóstico definitivo a los 45 años. Actualmente, presenta crisis cada dos meses. Se le administran dosis de 2 g por IV de AT, cuando empieza crisis en cara, lengua y labios. Eventualmente ha necesitado entre 1 y 2 g por IV (después de cuatro horas), ella recibe PLP con AT (500 ­ 750 mg) cada 12 horas. Paciente 2: Mujer de 47 años, AEH-nC1INH-FXII. Inició síntomas a los 19 años durante su primer embarazo. Diagnóstico definitivo a los 41 años. Ella mantiene PLP con AT (750 mg ­ 1,5 g) diariamente. Los ataques de vía respiratoria alta son tratados inmediatamente con AT cuando la crisis inicia, con dosis de 1 a 2 g por IV. Paciente 3: Mujer de 43 años, AEH-nC1INH-D. Estudio genético no detecta mutación en SERPING1, PLG1, ANGPT1, KNG1 y FXII. Inició síntomas a los 4 años. Diagnóstico definitivo a los 36 años. Al iniciar las crisis, se administra AT por VO, entre 500 a 750 mg/12 horas durante dos o tres días con aceptable respuesta y tolerancia a los episodios de AEH. Mientras las pacientes reciban dosis de mantenimiento de AT, entre 500 y 750 mg cada 8 o 12 horas, las crisis suelen ser de menor intensidad y se resuelven en menos días. CONCLUSIONES: En esta revisión sistemática, utilizaron AT vía oral, a demanda y en tratamiento profiláctico, dosis máxima acumulada 3 g/24 h1. En nuestros pacientes con AEH, hemos utilizado AT hasta 4 g vía intravenosa en un intervalo de cuatro horas (2 g - 2 g); para el control de crisis agudas, cuando la reacción está cediendo, prescribimos la dosis de mantenimiento, 1 g/8 h con disminución progresiva de la dosis en los días siguientes. El tratamiento con ácido tranexámico ha sido de utilidad en nuestros pacientes con los distintos tipos de AEH. La mayoría de ellos utilizan altas dosis de AT para disminuir lentamente las crisis agudas de AEH. Se puede administrar vía oral o intravenosa. Es un medicamento que puede ser de ayuda en países donde no se tiene registro de tratamientos específicos para la enfermedad. Las dosis de AT han sido bien toleradas y con una respuesta aceptable en las crisis de estos pacientes con AEH.

Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.

BACKGROUND: Symptoms of hereditary angioedema (HAE) often first occur during childhood, and HAE attacks in children can be severe and substantially affect health-related quality of life (HRQoL). However, there are no approved long-term prophylaxis treatments for children aged less than 6 years. OBJECTIVE: The SPRING Study (NCT04070326) evaluated the safety, pharmacokinetics, and efficacy of lanadelumab and HRQoL in patients aged 2 to less than 12 years. METHODS: Over 52 weeks of treatment, patients aged 2 to less than 6 years received lanadelumab 150 mg every 4 weeks (Q4W) and patients aged 6 to less than 12 years received 150 mg every 2 weeks (Q2W) but could switch to Q4W if they were attack-free for 26 weeks. RESULTS: We enrolled 21 patients (aged 2 to less than 6 years: n = 4; aged 6 to less than 12 years: n = 17), 20 of whom completed the study. There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events. Treatment-emergent adverse events were reported for 17 patients (81.0%). The most common TEAE was injection site pain. Overall systemic exposure was comparable for both age groups. The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free. The attack rate reduction in both age groups was similar during the first 26-week fixed-dosing treatment. Seven patients switched from Q2W to Q4W and remained attack-free. A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score and a large increase in the Pediatric Quality of Life Inventory Generic Core Scale-Family Impact Module Total Score from baseline to end of study (better HRQoL) were observed. CONCLUSIONS: Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.

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.

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.

Once-Daily Oral Berotralstat for Long-Term Prophylaxis of Hereditary Angioedema: The Open-Label Extension of the APeX-2 Randomized Trial.

BACKGROUND: Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. OBJECTIVE: This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat. METHODS: APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL). RESULTS: Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n = 70), the mean (standard error) change in attack rate from baseline was -2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain. CONCLUSION: Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.

A clinical evaluation of patients with known mutations (plasminogen and factor XII) with a focus on prophylactic treatment.

BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE. METHODS: An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires. RESULTS: Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy-efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime. CONCLUSION: This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.

An expert panel's review on patients with hereditary angioedema switching from attenuated androgens to oral prophylactic therapy.

Background: Hereditary angioedema (HAE) is a rare condition marked by swelling episodes in various body parts, including the extremities, upper airway, face, intestinal tract, and genitals. Long-term prophylaxis (LTP), prescribed to control recurring HAE attacks, is integral to its management. Previously, attenuated androgens (AAs) were the only oral LTP options. However, in 2020, berotralstat, an oral plasma kallikrein inhibitor, was approved in the United States. A 2018 survey of adults with HAE type I or type II showed that almost all the patients who used prophylactic HAE medication preferred oral treatment (98%) and felt that it fit their lifestyle better than injectable treatment (96%). Still, guidelines lack consensus on transitioning patients from AAs to alternative oral prophylactic therapy. Objective: This paper aims to share expert insights and patient feedback on transitioning from AAs to berotralstat, an alternative oral prophylactic therapy, from the perspective of clinicians with extensive experience in treating patients with HAE. Methods: A panel of five HAE specialists convened for a virtual half-day roundtable discussion in April 2023. Results: Discussions about transitioning from AAs to berotralstat were prompted by routine consultations, patient inquiries based on independent research, ineffective current treatment, or worsening AA-related adverse effects. For patients who switched from AAs, the physicians reported that the decision was influenced by the alternative therapy's ability to prevent HAE attacks, its safety, and the once-daily administration schedule. All expert panel members identified fewer AA-related adverse effects; better quality of life; and less severe, shorter, and less frequent HAE attacks as clinical or patient goals they hoped to achieve through the treatment switch. Conclusion: The emergence of new, highly specific LTP drugs for HAE calls for the development of comprehensive recommendations and guidelines for transitioning from AAs to alternative oral prophylactic therapy. The expert panel highlighted key factors to consider during the development of such guidelines.

A Retrospective Analysis of Long-Term Prophylaxis with Berotralstat in Patients with Hereditary Angioedema and Acquired C1-Inhibitor Deficiency-Real-World Data.

Hereditary angioedema (HAE) and acquired C1-inhibitor deficiency (AAE-C1-INH) are orphan diseases. Berotralstat is a recently licensed long-term prophylaxis (LTP) and the first oral therapy for HAE patients. No approved therapies exist for AAE-C1-INH patients. This study is the first to report real-world clinical data of patients with AAE-C1-INH and HAE who received Berotralstat. All patients treated with Berotralstat were included in this retrospective, bi-centric study. Data was collected from patients' attack calendars and the angioedema quality of life (AE-QoL) and angioedema control test (AECT) questionnaires before treatment, and at 3, 6, and 12 months after treatment and was then analyzed. Twelve patients were included, 3 patients with AAE-C1-INH, 7 patients with HAE type I, and 2 patients with HAE-nC1-INH. One patient (HAE I) quit treatment. Berotralstat was associated with fewer attacks in all groups. After 6 months of treatment, a median decrease of attacks per month was noted for HAE type I patients (3.3 to 1.5) and AAE-C1-INH patients (2.3 to 1.0). No aerodigestive attacks were noted for AAE-C1-INH patients. For HAE-nC1-INH patients, a mean decrease from 3.8 to 1.0 was noted (3 months). For HAE I patients, the total AE-QoL lowered a mean of 24.1 points after 6 months, for HAE-nC1-HAE patients 8.0 points, and for AAE-C1-INH patients 13.7 points. AECT scores increased for HAE I patients (mean: 7.1), HAE-nC1-INH patients (9.0), and AAE-C1-INH patients (4.2) after 6 months. Patients with HAE, HAE-nC1-INH, and AAE-C1-INH treated with Berotralstat showed reduced angioedema attacks and improved AE-QoL and AECT scores.

Real-world changes in costs over time among patients in the United States with hereditary angioedema on long-term prophylaxis with lanadelumab.

AIMS: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period. METHODS: Patients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a ≥ 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t-tests and McNemar's test. RESULTS: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively (p < .01). LIMITATIONS: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance. CONCLUSIONS: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

Initial use of subcutaneous plasma-derived C1 inhibitor in prophylaxis of acute attacks of hereditary angioedema in pregnant patients in Slovakia.

Hereditary angioedema (HAE) is a rare, inborn disease manifested with recurrent attacks of angioedema. They can affect the skin and subcutaneous tissue, mucous membranes (gastrointestinal, respiratory, and uropoietic tracts), and submucous tissue. Women in reproductive age require specific management of the disease regarding both the course of the disease and treatment options. It is not only the treatment in female patients that is specific, but also the situations (pregnancy, breastfeeding). We present a case report of the initial use of a subcutaneous C1 inhibitor in the long-term prophylaxis of HAE attacks in two pregnant patients.

A safety review of prophylaxis drugs for adolescent patients with hereditary angioedema.

INTRODUCTION: Hereditary angioedema (HAE) is characterized by recurrent subcutaneously and/or submucosally localized edematous swellings. The first symptoms often appear in childhood, and they may become more frequent and severe in puberty. Since the appearance of HAE attacks is unpredictable regarding the localization and the frequency, the attacks put a significant burden on the patients and crucially impacts their quality of life. AREAS COVERED: This review article analyzes the safety data acquired from the clinical trials conducted with the currently available medicinal products for the prophylactic treatment of hereditary angioedema due to C1 inhibitor deficiency and the safety data of observatory studies based on clinical practice. A review of the published literature was conducted using the PubMed database, clinical trials from ClinicalTrials.gov, and abstracts published at scientific conferences. EXPERT OPINION: The currently available therapeutic products have a good safety and efficiency profile and the international guidelines recommend them as first-line treatments. The choice should be made based on the evaluation of the availability and the preference of the patient.

Network meta-analysis for indirect comparison of lanadelumab and berotralstat for the treatment of hereditary angioedema.

Aim: With no head-to-head studies comparing the effectiveness of lanadelumab and berotralstat for prevention of hereditary angioedema (HAE) attacks, this network meta-analysis (NMA) aimed to indirectly compare the effectiveness of these treatments. Materials & methods: The NMA, using the published data from Phase III trials, was performed using a frequentist weighted regression-based approach following Rücker et al. Efficacy outcomes of interest were HAE attack rate per 28 days and ≥90% reduction in monthly HAE attacks. Results & conclusion: In this NMA, lanadelumab 300 mg administered every 2 weeks or every 4 weeks was associated with statistically significantly higher effectiveness versus berotralstat 150 mg once daily (q.d.) or 110 mg q.d. for both efficacy outcomes assessed.

Successful treatment of post-pericardiotomy syndrome via C1 inhibitor replacement therapy in a hereditary angioedema patient with Marfan syndrome.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is caused by dysfunctional C1-INH protein due to mutations in the SERPING1 gene encoding C1-INH. Marfan syndrome is a genetic connective tissue disease that affects the cardiovascular and ocular systems along with the skeletal system. In this case, we present the successful treatment of post-pericardiotomy syndrome unresponsive to classical therapy, which has not been described in the literature. The syndrome developed in a patient with hereditary angioedema (HAE) who underwent open heart surgery due to cardiac involvement in Marfan syndrome. CASE: A nine-year-old male HAE-C1INH patient underwent open heart surgery secondary to cardiac involvement caused by Marfan syndrome. To prevent HAE attacks, 1000 units of C1 inhibitor concentrate therapy were given 2 hours before and 24 hours after the operation. Post-pericardiotomy syndrome was diagnosed on the postoperative second day and ibuprofen 15 mg/kg/day (3 weeks) was started. Since there was no response to classical treatment on the 21st postoperative day, C1 inhibitor concentrate treatment was planned as 1000 units/ dose for 2 days a week considering a prolonged hereditary angioedema attack. In the second week of treatment, complete recovery was achieved for pericardial effusion with a total of 4 doses. CONCLUSIONS: We emphasize that in patients with hereditary angioedema undergoing this treatment, care should be taken in terms of complications that may be associated with the disease even if short-term prophylaxis is given before operations and that longer-term use of C1 inhibitor concentrate has a place in treatment.

Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.

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

BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.

Living With Hereditary Angioedema in Australia: Findings From a National Observational Study Using Short Message Service to Monitor the Burden of Disease.

BACKGROUND: To understand the impact and burden of disease experienced by patients with hereditary angioedema (HAE). OBJECTIVE: To determine whether the use of short message service (SMS) to communicate with patients with HAE facilitates the collection of attack rate, medication use, and quality of life measurements. METHODS: Patients aged 12 years and older with doctor-confirmed HAE C1-inhibitor deficiency types I and II were invited to participate. We devised a novel method for monitoring attacks by using questions weekly via SMS to gain a more accurate picture of the burden of HAE in Australian patients in real time. RESULTS: A total of 2,648 weekly SMS messages were sent to 47 participants; 1,892 responses were received (71%). Participants reported 463 attacks across all treatment groups. Sixty percent of attacks were treated. Icatibant and C1-inhibitor concentrate were administered IV for 210 and 67 attacks, respectively. Of the 463 recorded attacks, 23 necessitated presentation to the hospital (5%), predominantly for facial and/or throat swelling. Several participants reported attacks (n = 186), which they chose not to treat. Most of those attacks were rated mildly severe. Twenty-one participants reported lost days owing to HAE attacks (44.7%). Fifty-eight attacks (17%) resulted in time away from work or school, equating to a total of 85.5 days lost. CONCLUSIONS: This study was a first of its kind, real-world, prospective, observational study of Australian patients living with HAE. Despite the availability of effective on-demand therapies, HAE remains burdensome. Wider access to safe and effective prophylactic therapies is needed for patients living with HAE.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.