Hereditary Angioedema Attacks Research Articles

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor (C1-INH), a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized immunoglobulin G1 (IgG1) antibody with a long circulating half-life (t1/2) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor (FcRn) binding, resulting in a prolonged t1/2 in vivo (⁓34 days in cynomolgus monkeys) compared to antibodies without this modification. A single subcutaneous dose of STAR-0215 ({greater than or equal to} 100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic (mPBPK) model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t1/2, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. Significance Statement STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

Efficacy and safety of lanadelumab in Japanese patients with hereditary angioedema: A phase 3 multicenter, open-label study.

The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open-label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged ≥12 years with ≥1 investigator-confirmed HAE attack during the 4-week run-in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26-week treatment period if patients had well-controlled symptoms (e.g., attack-free) for 6 months. The primary efficacy endpoint was no investigator-confirmed HAE attacks (attack-free status) during days 0-182. Other outcomes included the rate of investigator-confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean ± SD age 41.9 ± 12.4 years) were enrolled. During the first 26 weeks (days 0-182), five (41.7%) patients were attack-free. The mean ± SD HAE attack rate per month decreased by 74.0%, from 3.8 ± 2.4 during baseline to 1.2 ± 2.6 during the overall 52-week treatment period. There were no deaths or discontinuations due to treatment-emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti-drug antibody results. The most frequent TEAEs were injection-site reactions (37 events in six patients). Most of the injection-site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE.

Preferred Therapy for Patients with Hereditary Angioedema during Pregnancy

Hereditary angioedema (HAE) is a rare, inherited disease caused by a deficiency (HAE-1) or lack of functional (HAE-2) C1 inhibitor protein. The symptoms present with mucocutaneous swelling of various organ systems, such as the respiratory and gastrointestinal systems, which can manifest as stridor and abdominal pain, respectively. HAE can present with increased frequency and severity of attacks during the pregnancy and lactation period. This is thought to be due to hormonal changes, which may trigger HAE attacks. The management of this condition in pregnant and lactating patients can be challenging for providers due to disease rarity and the lack of data regarding the management of this specific population. This review aims to provide insights for HAE management regarding rescue therapy, short-term prophylaxis, and long-term prophylaxis via the consolidation of the current literature and various international consensus guidelines. Furthermore, this review discusses when to initiate treatment and at what frequency and dosing, as well as the possible side effects that may occur as a result of therapy.

Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open-label study.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

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 IIItrials, was performed using a frequentist weighted regression-based approach following Rücker et al. Efficacy outcomes of interest were HAE attack rate per 28days and ≥90% reduction in monthly HAE attacks. Results & conclusion: In this NMA, lanadelumab 300mg administered every 2weeks or every 4weeks was associated with statistically significantly higher effectiveness versus berotralstat 150mg once daily (q.d.) or 110mg q.d. for both efficacy outcomes assessed.

Current challenges and future opportunities in patient-focused management of hereditary angioedema: Anarrative review.

Patients with hereditary angioedema (HAE) experience a high burden of disease due to unpredictable, painful, disfiguring, and potentially life-threatening HAE attacks. Multiple HAE-specific medications for the on-demand treatment, short-term and long-term prophylaxis of HAE attacks have entered the market in recent years; however, the availability and access to these medications may vary between different countries. For this review, PubMed and EMBASE databases were searched for guidelines, consensus statements, and other publications on HAE management as well as publications on quality of life in patients with HAE. The current guidelines and recent literature on HAE management in specific countries are summarized with the aim to highlight the similarities and differences between guideline recommendations and the country-specific clinical practice. Improvement in quality of life, which is a key goal in HAE management, is also discussed and the country-specific trends are highlighted. Finally, the ways to achieve a more patient-centric approach to HAE management within the framework set by the clinical management guidelines are examined.

Bradykinin receptors in GtoPdb v.2023.1

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023.

АНАЛИЗ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ ПРИМЕНЕНИЯ ПАТОГЕНЕТИЧЕСКОЙ ТЕРАПИИ С ЦЕЛЬЮ КУПИРОВАНИЯ АТАК У ДЕТЕЙ С НАСЛЕДСТВЕННЫМ АНГИОНЕВРОТИЧЕСКИМ ОТЕКОМ

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare (orphan) autosomal-dominant disease related to primary immunodeficiencies with a defect in the complement system and is characterized by recurrent, unpredictable edema attacks involving various organs and tissues. The recurrent episodes of edema are not amenable to the usual therapy methods and often are life-threatening conditions, especially in pediatric patients. The most pressing issue for the attending physician is the choice of the drug from the available range, taking into consideration its mechanism of action, route of administration and other parameters. This Article summarizes the properties of drugs currently available for the HAE attacks relief in pediatric patients in Russia, including the results of clinical trials, and the Authors’ own experience in the use of Icatibant and a human C1-esterase inhibitor as drugs of choice for the edema relief in the pediatric patient cohort. The purpose of this retrospective study was to evaluate the equivalence and safety of Icatibant and a C1-inhibitor concentrate for the edema management. Materials and methods used: the study included 34 HAE-C1-INH patients who had experienced 302 attack episodes in total. The inclusion criteria were a registered episode of angioedema in a patient aged 0 up to 18 y/o, confirmed HAE diagnosis and one of the two studying drugs intake within 24 hours after the onset of the first edema symptoms. Patients were administered with Icatibant, subcutaneously, or with C1-esterase inhibitor, intravenously. The efficacy was evaluated by comparing the presence of relief and/or relief of symptoms during the mentioned therapy. All of the adverse reactions during the therapy were also recorded in order to assess the drugs’ safety. Results: a total of 302 attack episodes were analyzed in 34 patients in the period from 2016 to 2021. Icatibant was used in 225 (74.5%) cases in 34 patients, and human C1-esterase inhibitor was used in 77 (25.5%) cases in 27 patients. It was allowed to use both drugs in the same patient in different angioedema episodes. The age of the children included in the analysis at the time of the first episode ranged from 1 to 14 y/o (Me 4.5 y/o). The edema was peripheral in most of the studied cases. The drugs were found to be equivalent in terms of duration until the edema symptoms’ relief (Me duration was 30 min. in both drugs, p=0.005), but not in terms of duration until the symptoms cut-off, - with greater values for Icatibant compared to the C1-inhibitor human esterase (p=0.394). Conclusion: a relatively similar efficacy and safety of both drugs as well as the possibility for their use in all age groups were recorded. It is therefore necessary to take into consideration the availability of the satisfactory venous access when choosing a drug for stopping the edema; the patient’s age (in order to ensure the fastest possible administration of the drug counting from the onset of edema); the remoteness of a patient’s location during the attack from the nearest available and satisfying medical facility; the patient’s and/or his/her parent(s)/caretaker(s) preferences. The study demonstrated that both Icatibant and the C1-inhibitor concentrate have high safety profile.

The impact of puberty on the onset, frequency, location, and severity of attacks in hereditary angioedema due to C1-inhibitor deficiency: A survey from the Italian Network for Hereditary and Acquired Angioedema (ITACA).

Hereditary angioedema due to C1-inhibitor deficiency is influenced by hormonal factors, with a more severe course of disease in women. Our study aims to deepen the impact of puberty on onset, frequency, location and severity of attacks. Retrospective data were collected through a semi-structured questionnaire and shared by 10 Italian reference centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). The proportion of symptomatic patients increased significantly after puberty (98.2% vs 83.9%, p=0.002 in males; 96.3% vs 68,4%, p<0.001 in females); the monthly mean of acute attacks was significantly higher after puberty, and this occurred both in females (median (IQR) = 0.41(2) in the three years before puberty vs 2(2.17) in the three years after, p<0.001) and in males (1(1.92) vs 1.25(1.56) respectively, p<0.001). The increase was greater in females. No significant differences were detected in attack location before and after puberty. Overall, our study confirms previous reports on a more severe phenotype in the female gender. Puberty predisposes to increased numbers of angioedema attacks, in particular in female patients.

REMISSION OF HEREDITARY ANGIOEDEMA ATTACKS ASSOCIATED WITH STARTING TERIFLUNOMIDE IN A PATIENT WITH MULTIPLE SCLEROSIS.

Hereditary angioedema is a rare hereditary and potentially life-threatening disorder characterized by recurrent attacks of cutaneous and submucosal swelling. In spite of the advances made in terms of pathophysiology, underlying mechanisms are not fully clear and this, in turn, hinders the development of effective therapies. Currently, on demand treatment is considered first-class, with few cost-effective, long-term prophylactic options. Here we describe the case of a 34-year-old man diagnosed with hereditary angioedema at the age of 10, who used to suffer several angioedema attacks per month. He was given prophylactic treatment with antifibrinolytic agents and androgens without improvement. Moreover, he was treated with plasma-derived C1-INH concentrate or icatibant for on-demand treatment of moderate and severe angioedema attacks. At the age of 33, after suffering sudden vision loss and lower limb paresthesia, he was studied and diagnosed with multiple sclerosis. Teriflunomide was administered at a dosage of 14 mg/day. Angioedema attacks disappeared 40 days after starting treatment. Thus, we suggest considering the pathophysiologic mechanisms on which teriflunomide could be active and consider this drug carefully as an option for prophylaxis purposes. Yet, its effectiveness on this condition should be further studied. Underlying mechanisms in hereditary angioedema lack clarity and hence hinder the development of effective therapies.On-demand treatment of hereditary angioedema is considered first class, with few cost-effective, long-term prophylactic options.The mechanisms of action and effectiveness of teriflunomide on hereditary angioedema should be studied further.

Berotralstat (Orladeyo)

&#x0D; CADTH recommends that Orladeyo be reimbursed by public drug plans for routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older, if certain conditions are met.&#x0D; Orladeyo should only be reimbursed for adults and adolescents with HAE according to the criteria used by public drug plans for lanadelumab for the prevention of HAE attacks.&#x0D; In addition to following pre-existing criteria for lanadelumab, Orladeyo should not be used in combination with other medications for long-term prevention of angioedema. Orladeyo should only be reimbursed if its cost is reduced.&#x0D;

A Review of Randomized Controlled Trials of Hereditary Angioedema Long-Term Prophylaxis with C1 Inhibitor Replacement Therapy: Alleviation of Disease Symptoms Is Achievable.

Through its fluctuating disease activity and unpredictable attacks, hereditary angioedema (HAE) imposes a substantial patient burden. To minimize HAE burden and improve quality of life, treatment should involve individualized management strategies that address on-demand therapy and short-term/long-term prophylaxis. Goals of long-term prophylaxis include reducing the number, severity, and burden of HAE attacks. The best characterized forms of HAE arise from deficiency or dysfunction of C1-inhibitor (C1-INH; types I/II), and C1-INH replacement therapy is a first-line intervention for on-demand (acute) treatment of HAE attacks, short-term prophylaxis before high-risk procedures, and long-term prophylaxis. Randomized, double-blind, placebo-controlled crossover trials have shown dose-dependent efficacy with plasma-derived C1-INH (pdC1-INH) 40-60 IU/kg subcutaneously, pdC1-INH 1000 U intravenously, and recombinant human C1-INH (rhC1-INH) 50 IU/kg (maximum 4200 IU) intravenously, all administered twice weekly, as long-term prophylaxis in patients with a history of 2 to ≥4 attacks/month. Overall, up to 83% (pdC1-INH 60 IU/kg) of patients experienced an HAE attack reduction threshold of ≥70%, and up to 58% (pdC1-INH 60 IU/kg) achieved an attack reduction threshold of ≥90%. Lower-dose intravenous pdC1-INH therapy (1000 U) was seemingly less effective, with 45% of 22 patients experiencing an HAE attack reduction threshold of ≥70%, and up to 23% achieving an attack reduction threshold of ≥90%. Higher-dose intravenous rhC1-INH 50 IU/kg (maximum, 4200 IU) twice weekly was of intermediate benefit. Despite a baseline mean attack frequency of 17.9 (during the 3 months prior to study treatment) and a mean attack frequency during a 4-week placebo period of 7.2, 52% of 23 patients experienced ≥70% reduction in attack frequency and 26% of 23 patients experienced ≥90% reduction in attack frequency. The increasing patient percentages treated with C1-INH replacement therapy as long-term prophylaxis meeting these high thresholds reinforces hopes and expectations that "attack freedom" is achievable, including for those with moderate or severe disease.

Prevention of Recurrent Attacks of Hereditary Angioedema (HAE): Berotralstat and Its Oral Bioavailability.

Hereditary angioedema (HAE) is a condition characterized by episodes of cutaneous and submucosal edema. Angioedema of the extremities and abdominal attacks are the most common manifestations of the disease. It can also affect the upper airways with the potential of becoming life-threatening. The two most common causes of HAE are a deficiency of C1 inhibitor (classified as type 1 HAE) or a dysfunction of C1 inhibitor (type 2 HAE). A malfunction or deficiency of C1 inhibitor leads to an overactivated plasma kallikrein (an inflammatory vasoactive peptide), that increases bradykinin, mediating the angioedema episodes in patients with HAE. To minimize the difficulties of this pathology and to improve patients' quality of life, prevention of this condition is essential. Berotralstat is a unique option for oral administration for routine prophylaxis. This drug acts by binding to kallikrein and reducing its plasma activity, lowering bradykinin levels. Open-label studies have demonstrated the effectiveness of a single daily dose of berotralstat 150 mg in preventing HAE attacks. This review aims to examine studies performed to elucidate the efficacy, safety, and tolerability of berotralstat.

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

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.

Patient Perspectives On Early Use Of On-demand Treatment For Hereditary Angioedema (HAE) Attacks to Reduce Severity and Duration.

Hereditary Angioedema (HAE) attacks are characterized by recurrent, unpredictable episodes of swelling throughout the body. On-demand treatment is effective but may be impacted by time to administration. This survey investigated perspectives of people living with HAE regarding on-demand treatment of HAE attacks and outcomes.

Phase 2 Open-Label Extension Study With Donidalorsen in Patients With Hereditary Angioedema: Updated Interim Analysis With Quality-of-Life Data

A phase 2 study (ISIS 721744-CS2, NCT04030598) of donidalorsen-treated patients with hereditary angioedema (HAE) reported a 90% reduction in HAE attacks and lower adverse event (AE) rates compared with placebo (71% vs 83%). Here, we report the results of the updated year 1 interim analysis of the open-label extension study (ISIS 721744-CS3, NCT04307381) with quality-of-life (QoL) data.

Treatment with Sebetralstat Reduces the Cumulative Symptom Severity of Hereditary Angioedema Attacks in a Phase 2 Trial

Sebetralstat is an investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema (HAE) attacks. This analysis investigates the effects of sebetralstat on cumulative HAE attack symptom severity in a phase 2 trial.

Efficacy and Safety of Subcutaneous Garadacimab for the Prophylaxis of Hereditary Angioedema Attacks in Adults and Adolescent Patients with HAE: Results from a Multicenter, Placebo-Controlled Phase 3 Trial

The efficacy and safety of garadacimab, a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII for the prevention of hereditary angioedema (HAE) attacks, were evaluated in a randomized, placebo-controlled, 6-month, Phase 3 trial (NCT04656418).

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

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. 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. 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. 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). KalVista Pharmaceuticals.