Angioedema Attacks Research Articles

Pharmacokinetics (PK), Pharmacodynamics (PD), and Exposure-Response (E-R) Analyses Confirm the Effectiveness of Lanadelumab in Patients 2 to

HAE is characterized by recurrent angioedema attacks. Lanadelumab is approved for HAE attack prevention in patients ≥12 years old (y.o.). Data across studies were integrated to evaluate the similarity of the PK/PD and E-R relationships between patients 2–<12 and ≥12 y.o. to support the dosing recommendation for patients 2–<12 y.o.

Reporting of Adverse Drug Reactions with Parenteral Drugs for the On-Demand Treatment of Hereditary Angioedema Attacks – Analysis of the FAERS Database 2009 to 2022

Analysis assessed the post-marketing reporting rates for adverse drug reactions (ADRs) in patients treated with parenteral on-demand hereditary angioedema (HAE) drugs utilizing the FDA’s Adverse Event Reporting System (FAERS).

Health and well-being implications of insurance coverage delays and denials for patients with hereditary angioedema

Hereditary angioedema (HAE) is a rare, debilitating and potentially fatal genetic disease associated with recurrent and unpredictable episodes of angioedema attacks. Modern therapies have dramatically increased quality of life. HAE treatments, similar to other rare conditions, are expensive and insurance approval is often a protracted process. This study examines the impact of delays and denials on health and well-being.

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.

Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in a Cohort of Patients with Hereditary Angioedema.

Many factors may trigger hereditary angioedema (HAE) attacks. This study aims to gain insights into the benefits and potential risks of COVID-19 vaccination in HAE patients, focusing particularly on the possibility of triggering attacks. We enrolled 31 patients with HAE undergoing two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine. To evaluate the possible influence of the vaccine on disease control and attack frequency, we administered the angioedema control test (AECT) 4-week version before (T0), 21 days after the first dose (T1), and between 21 and 28 days after the second dose (T2). Despite 5 patients (16.1%) experiencing attacks within 72 h of the first dose administration, no significant variation in attack frequency was observed before and after vaccination [F(2,60) = 0.123; p = 0.799]. In addition, patients reported higher AECT scores at T1 and T2 compared to T0 [F(2,44) = 6.541; p < 0.05; post hoc p < 0.05)], indicating that the disease was rather more controlled after vaccinations than in the previous period. All patients showed a positive serological response to the vaccine without significant differences from healthy controls (U = 162; p = 0.062). These observations suggest that the vaccine administration is safe and effective in HAE patients.

Consensus on diagnosis and management of Hereditary Angioedema in the Middle East: A Delphi initiative

BackgroundHereditary angioedema (HAE), a potentially life-threatening genetic disorder due to C1 inhibitor deficiency in most cases, is characterized by sudden and/or recurrent attacks of angioedema (subcutaneous/submucosal swellings). The global World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) International guideline for HAE management is comprehensive, but the implementation of this guideline may require regional adaptation considering the diversity in disease awareness, type of medical care systems, and access to diagnostics and treatment. The aim of this Delphi initiative was to build on the global guideline and provide regional adaptation to address the concerns and specific needs in the Middle East. MethodsThe Consensus panel comprised 13 experts from the Middle East (3 from the United Arab Emirates, 3 from Saudi Arabia, 2 from Lebanon, 2 from Kuwait, 2 from Oman and 1 from Qatar) who have more than 2 decades of experience in allergy and immunology and are actively involved in managing HAE patients. The process that was carried out to reach the consensus recommendation included: 1.) A systematic literature review for articles related to HAE management using Ovid MEDLINE. 2.) The development of a questionnaire by an internationally acclaimed expert, with 10 questions specific to HAE management in the Middle East. 3.) Experts received the questionnaire via email individually and their answers were recorded (email/interview). 4.) A virtual consensus meeting was organized to discuss the questionnaire, make amends if needed, vote, and achieve consensus. ResultsThe questionnaire comprised 10 questions, each with 2 or more statements/recommendations on which the regional experts voted. A consensus was reached based on a 70% agreement between the participants. The key highlights include: 1) HAE experts in the Middle East emphasized the importance of a positive family history for arriving at a diagnosis of HAE. 2) The number of episodes per month or per 6-month period and severity should be used, together with other markers, to determine the need for prophylaxis. 3) Disease status should be monitored by periodic visits and the use of patient-reported outcome measures such as the angioedema activity score and the angioedema control test. 4) Attenuated androgens and tranexamic acid may be considered for long-term prophylaxis, if lanadelumab, C1-Inhibitor or berotralstat are not available. ConclusionThis consensus recommendation may help to educate healthcare practitioners in the Middle East and unify their approach to the diagnosis and management of HAE.

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

EE681 Costs of Treating Acute Hereditary Angioedema (HAE) Attacks With C1 Inhibitors in Five Central and Eastern European Countries

Hereditary angioedema (HAE) is a rare genetic disease caused by the deficiency or dysfunction of C1 esterase inhibitor (C1-INH), and characterized by recurring episodes of severe swelling, which can be life-threatening. Frequency and severity of attacks vary. Replacement C1-INH therapies provide effective relief; however, there is a lack of comparative data on economic outcomes in Central and Eastern European countries (CEE).

A review of berotralstat for the treatment of hereditary angioedema

ABSTRACT Introduction Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) imposes a significant disease burden on patients and their families. Unpredictable episodes of angioedema, which can lead to life-threatening conditions, have a significant impact on the quality of life of the patient. The fundamental aim of the treatment of C1-INH-HAE is to ensure that patients can lead a normal life. The most effective way to do this is to prevent the onset of angioedema attacks. Areas covered This review gives a brief overview of the safety and efficacy of the oral kallikrein inhibitor berotralstat in C1-INH-HAE disease. It provides a comprehensive synopsis of the results of the first clinical trials with a targeted oral kallikrein inhibitor (APeX-1 [NCT02870972]; ZENITH-1 [NCT03240133]; APeX-2 [NCT03485911]; APeX-S [NCT03472040]; APeX-J [NCT03873116]), reviewing evidence on the efficacy and safety of the drug, and placing berotralstat on the spectrum of long-term prophylactic therapeutic options. Expert opinion The availability of the first targeted oral prophylactic drug, the kallikrein inhibitor berotralstat, in 2021, is a milestone in the treatment of patients with hereditary angioedema.

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation.

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

Interventions for the long-term prevention of hereditary angioedema attacks.

Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE. To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE. We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021. We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks. We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome. We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE. The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Hereditary angioedema is associated with an increased risk of venous thromboembolism

MODELING AND SIMULATION PREDICTS ROBUST HAE ATTACK SUPPRESSION WITH EVERY 3 MONTH DOSING OF STAR-0215

<h3>Introduction</h3> Inhibition of plasma kallikrein is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. STAR-0215 is a long-acting monoclonal antibody inhibitor of plasma kallikrein. We sought to generate a mechanistic quantitative systems pharmacology (QSP) model to explore the potential for reduction of HAE attacks with different dosing regimens of STAR-0215. <h3>Methods</h3> A simplified QSP model was established based on published reaction parameters for the plasma kallikrein-kininogen pathway in the vascular space and adjacent to the endothelial surface. The pharmacokinetic (PK) parameters of STAR-0215 were derived from cynomolgus monkey PK studies and scaled to estimate human PK parameters. Variability in PK parameters was simulated using a standard deviation of 50% and a Poisson distribution was applied to randomly determine the timing of trigger events with an average attack frequency of 3 per month. <h3>Results</h3> A long circulating half-life of STAR-0215 in humans (108 days) was predicted from empirically obtained PK parameters in cynomolgus monkeys. The QSP model predicted long-term robust HAE attack suppression following a single subcutaneous administration of STAR-0215 at dose levels of ≥300 mg. The QSP model simulations also showed subcutaneously administered STAR-0215 could provide a potential prolonged HAE attack suppression with a once every 3 months maintenance dose regimen. <h3>Conclusions</h3> STAR-0215 is a novel, potent and selective long-acting monoclonal antibody plasma kallikrein inhibitor for the potential treatment of HAE. Results from the QSP model support STAR-0215 dosing once every 3 months or longer for robust suppression of HAE attacks.

CONSISTENTLY LOW HEREDITARY ANGIOEDEMA ATTACK RATES OBSERVED WITH BEROTRALSTAT REGARDLESS OF PREVIOUS PROPHYLAXIS: REAL-WORLD OUTCOMES

<h3>Introduction</h3> Clinical trial data showed patients who switched to oral berotralstat monotherapy reported consistently low hereditary angioedema (HAE) attack rates. Here we present preliminary efficacy data of patients in the United States who initiated berotralstat treatment in the real-world clinical setting and were previously on another prophylactic therapy. <h3>Methods</h3> Data was collected through the sole-source pharmacy and included patients with confirmed HAE Type I/II who actively received berotralstat 110 or 150mg from 12/16/2020-5/20/22 and were stratified by previous prophylaxis. Baseline attack rates were reported for the 90 days prior to berotralstat initiation. While on therapy, median attacks/month(25^th,75^th percentile) were calculated over each 90-day period by averaging each patient's monthly reported attack rate (1 month=∼28 days). Some patients did not report attack rates at each refill. <h3>Results</h3> In patients treated with prior prophylaxis(n=129) the median baseline attack rate was 1.7 attacks/month which decreased to 0.3(0,1.31) from days 1-90; 0.6(0,1.00) from days 91-180; 0.5(0.25,1.00) from days 181-270; and 0.5(0,1.50) from days 271-360. Specifically, in the lanadelumab group(n=53), the baseline attack rate of 1.0 attack/month decreased to 0(0,0.50) from days 1-90; 0.3(0,0.75) from 91-180; 0.5(0,1.00) from 181-270; and 0.5(0,1.38) from 271-360. In the subcutaneous C1-inhibitor group(n=31), the baseline attack rate of 1.7 attacks/month decreased to 0.8(0,2.00) from days 1-90; 0.7(0,2.08) from 91-180; 1.0(0.54,1.50) from 181-270; and 1.0(0.29,2.17) from 271-360. Patients without prior prophylaxis(n=112) had similar attack rate reductions. The most common adverse events reported were consistent with clinical trials. <h3>Conclusions</h3> Patients previously treated with another prophylactic therapy reported consistently low HAE attack rates when treated with once daily berotralstat.

REAL-WORLD TREATMENT BURDEN ASSOCIATED WITH PARENTERAL ON-DEMAND THERAPIES FOR HEREDITARY ANGIOEDEMA

<h3>Introduction</h3> The objective of the current study is to describe treatment burden associated with FDA-approved on-demand therapies for hereditary angioedema (HAE) attacks using the real-world frequency of administration site reactions reported in the FDA's Adverse Event Reporting System (FAERS). <h3>Method</h3> : We searched FAERS data from 10/01/2009 to 3/31/2021 for human C1-inhibitor (H-C1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (R-C1-INH). The number of administration site adverse drug reactions (ADRs), where the drug was listed as "primary suspect" were recorded for each drug. ADR preferred terms were then grouped into an ADR domain based on semantic and/or clinical similarity. This process resulted in 15 overarching ADR domains. For each ADR domain, the number of reports for each drug were calculated per year from the time of their approval through March 2021. Descriptive results are presented. <h3>Results</h3> The most frequently reported ADR domains included injection site pain, erythema, swelling as well as access site complications or malfunctions. Icatibant had the highest rate of ADRs per year for site pain (16.6), erythema (7.08), and swelling (6.35). Access site complications/malfunctions (7.75) were highest for R-C1-INH. ADR rates per year for H-C1-INH and ecallantide were under 2. <h3>Conclusion</h3> Results generally support those found in clinical trials, particularly for icatibant, for which 97% of patients experience injection-site reactions. ADR rates are not exposure-adjusted and are based on spontaneous reporting. These real-world descriptive results suggest that patients experience significant treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks.

MATCHING-ADJUSTED INDIRECT TREATMENT COMPARISON BETWEEN LANADELUMAB AND BEROTRALSTAT FOR HEREDITARY ANGIOEDEMA PROPHYLAXIS

<h3>Introduction</h3> To date, no head-to-head studies compared the efficacy of lanadelumab and berotralstat for the prevention of hereditary angioedema (HAE) attacks. In this analysis, matching-adjusted indirect comparison (MAIC) was used to estimate comparative effectiveness of lanadelumab versus berotralstat over 48 weeks of treatment as there were no common comparators to link a network of evidence. <h3>Methods</h3> The MAIC used the data from the HELP open-label extension (HELP OLE; NCT02741596) and APeX-2 (NCT03485911) studies. To preserve randomization, patients from the HELP OLE Study were re-weighted to match the clinically relevant baseline characteristics from the APeX-2 study. The efficacy outcome of interest was the HAE attack rate per 28 days. <h3>Results</h3> In this analysis, lanadelumab 300 mg every 2 weeks (Q2W) was associated with a statistically significantly 73% lower HAE attack rate per 28 days compared with berotralstat 150 mg QD over 48 weeks of treatment (rate ratio [RR] 0.27; 95% CI 0.24, 0.31; p<0.00001). In a subgroup analysis that only considered patients from the HELP OLE Study who rolled over from lanadelumab 300 mg Q2W arm in the HELP Study, lanadelumab 300 mg Q2W was associated with a statistically significantly 81% lower HAE attack rate per 28 days compared with berotralstat 150 mg QD over 48 weeks of treatment (RR 0.19; 95% CI 0.12, 0.29; p<0.0001). <h3>Conclusion</h3> In this MAIC, lanadelumab 300 mg Q2W was associated with a statistically significantly lower rate of HAE attacks per 28 days versus berotralstat 150 mg QD at 48 weeks of treatment.

SUSTAINED IMPROVEMENT IN HEALTH-RELATED QUALITY OF LIFE WITH CONTINUED LANADELUMAB TREATMENT IN HEREDITARY ANGIOEDEMA

<h3>Introduction</h3> Lanadelumab is approved for the prevention of hereditary angioedema attacks. Reduced attack rate is associated with improved health-related quality of life (HRQoL). HRQoL was assessed in patients who completed the HELP Study (NCT02586805) and rolled into the HELP OLE Study (NCT02741596) using the Angioedema Quality of Life Questionnaire (AE-QoL). <h3>Methods</h3> Rollover patients completed 26 weeks' treatment in HELP, where they received placebo or lanadelumab (150mg every 4 weeks [Q4W], 300mg Q4W, or 300mg every 2 weeks [Q2W]), then continued into HELP OLE with lanadelumab 300mg Q2W for ≤33 months. A decrease in AE-QoL total score of ≥6 was considered clinical meaningful improvement. <h3>Results</h3> From the baseline of HELP to the end of study (EOS) visit in HELP OLE, rollovers (n=98) had a mean(SD) change in AE-QoL total score of -25.1(19.8). The reduction of total score in rollovers (n=97) during HELP OLE was -10.2(17.9). Among patients who received lanadelumab 300mg Q2W in HELP (n=24), total scores for patients with baseline attack rates of 1–<2 (n=7), 2–<3 (n=5), and ≥3 (n=12) attacks/month were reduced from 23.1(27.3), 15.3(9.5), and 24.4(22.0), respectively, at HELP OLE baseline, to 10.3(8.9) 18.0(12.9), and 20.4(20.6), respectively, at EOS. For rollovers treated with placebo in HELP (n=33), total scores for patients with baseline attack rates of 1–<2 (n=10), 2–<3 (n=7), and ≥3 (n=16) attacks/month were reduced from 37.8(20.0), 36.3(14.2), and 43.2(23.4), respectively, at HELP OLE baseline, to 17.5(15.3), 8.6(8.4), and 27.4(24.6), respectively, at EOS. <h3>Conclusion</h3> These data demonstrate sustained clinically meaningful improvement in HRQoL with continued lanadelumab treatment.

Long term follow-up of complement parameters to improve the management of acquired angioedema due to C1-inhibitor deficiency

Acquired angioedema due to C1-inhibitor deficiency (C1–INH-AAE) is a rare disease that can be diagnosed via complement testing. It often accompanies lymphoproliferative underlying diseases. Our study aimed to examine if there is a connection between complement parameters and the clinical symptoms of C1–INH-AAE, and, in case of a known underlying disease, its activity. The other question is how a connection, if proven, could help in the development of the therapeutic strategy of C1–INH-AAE patients.In the past 30 years, out of the 3938 patients sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1–INH-AAE in 19 cases. An underlying disease was diagnosed in 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found.Angioedema specific long-term prophylaxis did not result in an improvement in neither the frequency of the attacks nor in the complement parameters.A connection has been found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Decreasing complement parameters warn about the appearance or the worsening of the underlying disease. The treatment of the underlying disease brings improvement in the complement parameters.Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Complement parameters supported the long-term efficacy of rituximab treatment for C1–INH-AAE.The change in complement parameters predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In C1–INH-AAE, it is essential to examine the patients for underlying diseases, and to regularly follow up the patient's complement parameters.

Clinical outcomes of hereditary angioedema on multiparous women.

Significant concerns for patients with hereditary angioedema (HAE) include hormonal fluctuations and drug safety during pregnancy. The impact of the disease on childbearing in multiparous women remains to be elucidated. We aimed to investigate the clinical course and impacts of multiparity on HAE patients. This observational study included 15 multiparous women with HAE; a total of 88 pregnancies were assessed using a questionnaire and the patient's medical records. The median age was 36 (IQR, 33-39). Of 72 resulted in healthy babies without any congenital abnormalities. In sixteen pregnancies, 12 (13.6%) ended with spontaneous abortion; three resulted in stillbirth and one neonatal death. Two-thirds of the patients (n= 10) enounced a worsening in the frequency of angioedema attacks during pregnancy. There was no statistically significant difference compared with the nonpregnant period (p= 0.283). One-fifth of the patients (n= 3) reported alleviation in attacks. While most deliveries were vaginally (n= 57 babies), 19 deliveries in six patients were by cesarean section. None of the patients were aware of the diagnosis of HAE prior to their first pregnancies. After the diagnosis was made, eight patients received 263 vials of plasma-derived C1-inhibitor concentrate during a total of 13 pregnancies. No adverse events were reported. We conclude that our results on clinical course and outcomes of HAE in multiparous patients are consistent with the literature. A greater focus on multiparous HAE patients could produce exciting findings.

Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.