Medical Literature - 2021

A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab

McKenzie A, Roberts A, Malandkar S, Feuersenger H, Panousis C, Pawaskar D 12/2021 Clinical and translational science

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19). Copyright © 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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Analysis of cold activation of the contact system in hereditary angioedema with normal C1 inhibitor

Larrauri B, Hester CG, Jiang H, Miletic VD, Malbran A, Bork K, Kaplan A, Frank M 8/2021 Molecular immunology

Hereditary angioedema (HAE) attacks are caused by excessive activation of the contact system. Understanding how the contact system is activated in HAE, especially in patients with normal C1 inhibitor (HAEnCI), is essential to effectively treat this disease. Contact system activation involves the cleavage of several proteins including Factor XII (FXII), high molecular weight kininogen (HK), prekallikrein, sgp120 (ITIH4) and C1 inhibitor (C1-INH) before the subsequent generation of bradykinin that mediates HAE. In this study, we evaluated the fragmentation and enzymatic activity of contact system proteins in HAEnCI plasma samples before and after contact system activation induced by incubation in the cold. Our results show that in contrast to normal plasma, cold activation induced contact system activation in the majority of the HAEnCI patient samples we tested, in which each contact system protein exhibited fragmentation, FXII and kallikrein enzymatic activity increased, and C1-INH functional activity decreased. HAEnCI samples with low FXII concentrations or functional activity were not affected by cold activation. One HAEnCI sample with a plasminogen gene mutation activated the fibrinolytic system, as shown by an increase in concentration of plasma D dimers. Our results suggest that cold activation seems to be initiated by the cleavage of prekallikrein, and that it needs FXII in order to occur. Reported to be susceptible to excessive contact system activation after incubation in the cold, we further applied this system of study to the evaluation of plasma from women undergoing estrogen treatment. Similar to plasma from HAEnCI patients, excessive contact system activation was demonstrated. Copyright © 2021. Published by Elsevier Ltd.

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Androgen use in hereditary angioedema: A critical appraisal and approaches to transitioning from androgens to other therapies

Johnston DT, Henry Li H, Craig TJ, Bernstein JA, Anderson J, Joseph K, Riedl MA 1/2021 Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) is a rare genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. Attenuated androgens have been a prophylactic treatment option to reduce the frequency of HAE attacks for > 4 decades. However, the advent of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies has led to a decline in the use of attenuated androgens for the management of HAE in regions where newer therapies are available. A consensus about the best approach for discontinuing or tapering off attenuated androgen therapy does not exist. Objective: To develop a consensus on androgen tapering for patients with HAE. Methods: We sent an open-ended survey about androgen tapering to 21 physicians who treat HAE, 12 of whom responded. We reviewed the collective experience of the participating physicians in combination with results from a literature review on the topic. Results: The survey and literature review underscored potential concerns related to rapid androgen withdrawal in patients with HAE, including physician and patient concerns that the frequency and severity of attacks would abruptly worsen. In addition, discontinuation of attenuated androgens may have the potential for transient adverse effects, such as an increase in the rate of attacks or effects related to hormone withdrawal. Our survey showed that physicians often taper androgens to prevent increases in HAE attacks and possible withdrawal complications. Conclusion: Based on both experiences of the physicians who responded to our survey and reports in the endocrine literature, we provided recommendations for androgen tapering. However, we noted that the likelihood of adverse effects due to androgen withdrawal in patients with HAE is poorly understood and requires further study.

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Angioedema and fatty acids [Review]

Wada A, Sawada Y, Sugino H, Nakamura M 8/2021 International journal of molecular sciences

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid’s function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.

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Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema

Castaldo AJ, Jervelund C, Corcoran D, Boysen HB, Christiansen SC, Zuraw BL 3/2021 Allergy and asthma proceedings

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

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Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies [Review]

Manning ME, Kashkin JM 7/2021 Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient’s quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages >= 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

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Berotralstat (BCX7353): Structure-guided design of a potent, selective, and oral plasma kallikrein inhibitor to prevent attacks of hereditary angioedema (HAE)

Kotian PL, Wu M, Vadlakonda S, Chintareddy V, Lu P, Juarez L, Kellogg-Yelder D, Chen X, Muppa S, Chambers-Wilson R, Davis Parker C, Williams J, Polach KJ, Zhang W, Raman K, Babu YS 9/2021 Journal of medicinal chemistry

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration’s approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

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Berotralstat (Orladeyo) for prevention of hereditary angioedema [Review]

Anonymous 7/2021 The Medical letter on drugs and therapeutics

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Berotralstat: First approval [Review]

Lee A 2/2021 Drugs

Berotralstat (ORLADEYO TM) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The inhibition of kallikrein by berotralstat decreases the production of bradykinin, which prevents the localised tissue oedema that occurs during attacks of HAE. Berotralstat has been approved in the USA, and subsequently in Japan, for prophylaxis to prevent attacks of HAE in adults and paediatric patients aged 12 years or older. This article summarises the milestones in the development of berotralstat leading to this first approval for prophylaxis to prevent attacks of HAE.

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Clinical manifestations of hereditary angioedema and a systematic review of treatment options [Review]

Rosi-Schumacher M, Shah SJ, Craig T, Goyal N 6/2021 Laryngoscope investigative otolaryngology

Objective: This study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and specific therapies.

Methods: A literature search of PubMed and Embase databases was conducted from start of the database to February 2021. Inclusion criteria included relevant systematic reviews, randomized control clinical trials, prospective and retrospective cohort studies, and outcomes research published in English and available in full-text. Out of 310 candidate articles, a total of 55 articles were included in our study.

Results: The most common genetic form of HAE in up to 85% of cases is caused by low levels of C1 esterase inhibitor (C1-INH) protein, leading to a bradykinin-mediated increase in vascular permeability. During an attack of HAE, abortive treatment with C1-INH replacement is most commonly described, however, icatibant, ecallantide, or fresh frozen plasma are also used. Long-term prophylaxis in the form of C1-INH replacement (subcutaneous or intravenous), monoclonal antibodies targeting plasma kallikrein, attenuated androgens, and transexemic acid should be considered for those who suffer from frequent, severe attacks.

Conclusion: Progressively distal involvement of the upper airway, especially the larynx, has been shown to pose an increased risk of asphyxiation and death in the acute presentation of HAE. Evaluation by an otolaryngologist is often sought during the emergent clinical management of HAE; therefore, it is prudent that the consulting physician is well-versed in the prompt recognition, triage of patients, and appropriate treatment modalities.

Level of Evidence: 1A. Copyright © 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.

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Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2 [Review]

Fijen LM, Bork K, Cohn DM 8/2021 Clinical reviews in allergy & immunology

Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema. Copyright © 2021. The Author(s).

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Current medical management of hereditary angioedema: Follow-up survey of US physicians

Riedl MA, Banerji A, Gower R 3/2021 Annals of Allergy, Asthma, & Immunology

BACKGROUND: Physician surveys on hereditary angioedema (HAE) management in 2010 and 2013 revealed important trends in HAE care.

OBJECTIVE: To evaluate current HAE management and the impact of new treatment options on physician practice patterns over time.

METHODS: During June and July 2019, 5382 physicians were contacted by means of postal mail to complete a 47-question survey; 177 responded (3%).

RESULTS: Across the 3 surveys, the home replaced the emergency department as the most typically reported setting for HAE attack treatment (54.3% vs 11.6% in 2010 and 32.5% in 2013; P < .001). Physicians reported C1 esterase inhibitor (C1-INH) as the most typically prescribed long-term prophylactic treatment (LTP) (60.0% vs 20.4% in 2010 and 56.7% in 2013; P < .001). Subcutaneous LTP medications were most typically prescribed over intravenous (C1-INH, 41.4%; subcutaneous lanadelumab, 21%; intravenous C1-INH, 18.6%). Danazol, the most frequently prescribed LTP treatment, dropped to 6.4% (55.8% in 2010 and 23.4% in 2013; P < .001). The strongest nonefficacy factor influencing clinician treatment choice changed over time, with cost and (or) insurance coverage increasing to 43.7% (from 24.4% in 2010 and 40.5% in 2013; P = .001), whereas the concern over adverse effects dropped to 16.2% (from 55.8% in 2010 and 29.5% in 2013; P < .001). Physician-reported patient satisfaction remains high, with only 1.5% of physicians indicating patients are not satisfied with treatment.

CONCLUSION: The US physician survey data reflect improvements in the HAE management in recent years. Therapeutic advances in HAE have led to reported higher rates of home treatment of HAE attacks, reduced concern for adverse treatment effects, and high levels of patient satisfaction. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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Efficacy of lanadelumab in acquired angioedema with C1-inhibitor deficiency

Belbezier A, Boccon-Gibod I, Bouillet L 6/2021 The journal of allergy and clinical immunology. In practice

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Hereditary angioedema: How to approach it at the emergency department?

Serpa FS, Mansour E, Aun MV, Giavina-Bianchi P, Chong Neto HJ, Arruda LK, Campos RA, Motta AA, Toledo E, Grumach AS, Valle SOR 4/2021 Einstein (Sao Paulo, Brazil)

Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

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Impact of lanadelumab on health-related quality of life in patients with hereditary angioedema in the HELP study

Lumry WR, Weller K, Magerl M, Banerji A, Longhurst HJ, Riedl MA, Lewis HB, Lu P, Devercelli G, Jain G, Maurer M, HELP Study Investigators 4/2021 Allergy

BACKGROUND: An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health-related quality of life (HRQoL) in patients with hereditary angioedema (HAE).

METHODS: Patients with HAE-1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0-182). The Angioedema Quality of Life Questionnaire (AE-QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ-5D-5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab-treated patients and (b) individual lanadelumab groups for changes in scores (day 0-182) and proportions achieving the minimal clinically important difference (MCID, -6) in AE-QoL total score.

RESULTS: Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE-QoL total and domain scores (mean change, -13.0 to -29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ-5D-5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.

CONCLUSION: Patients with HAE-1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE-QoL following lanadelumab treatment in the HELP Study. Copyright © 2020 Takeda Pharmaceuticals Company Limited. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

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Indirect comparison of lanadelumab and intravenous C1-INH using data from the HELP and CHANGE studies: Bayesian and frequentist analyses

Mendivil J, Malmenas M, Haeussler K, Hunger M, Jain G, Devercelli G 3/2021 Drugs in R&D

BACKGROUND: Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is a rare disease associated with painful, potentially fatal swelling episodes affecting subcutaneous or submucosal tissues. HAE attacks recur with unpredictable severity and frequency throughout patients’ lives; long-term prophylaxis is essential for some patients. In the absence of head-to-head studies, indirect treatment comparison (ITC) of long-term prophylactic agents is a valid approach to evaluate comparative efficacy.

METHODS: We conducted an ITC using data from the placebo-controlled HELP study (assessing patients receiving lanadelumab 300 mg every 2 or 4 weeks) and the 12-week, parallel arm, crossover CHANGE study (assessing intravenous C1-INH). Outcomes of interest were attack rate ratio (ARR) and time to attack after day 0 (TTA0) and after day 70 (TTA70). Two ITC methodologies were used: a Bayesian approach using study results to update non-informative prior distributions to posterior distributions on relative treatment effects, and a frequentist approach using patient-level data from HELP and CHANGE to generate Poisson regressions (for ARR) and Cox models (for TTA0 and TT70).

RESULTS: Both Bayesian and frequentist analyses suggested that lanadelumab reduced HAE attack rate by 46-73% versus intravenous C1-INH. Relative to intravenous C1-INH, risk of first attack after day 0 was comparable between intravenous C1-INH and both lanadelumab doses; risk of first attack after day 70 was reduced by 81-83% with lanadelumab 300 mg every 2 weeks, compared with C1-INH.

CONCLUSIONS: Findings from these two ITC methodologies support the favorable efficacy of lanadelumab in reducing the HAE attack rate and extending attack-free intervals in patients with HAE.

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Lanadelumab (Takhzyro) for prevention of hereditary angioedema [Review]

Anonymous 3/2021 The Medical letter on drugs and therapeutics

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Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: Findings from the COMPACT open-label extension study

Lumry WR, Zuraw B, Cicardi M, Craig T, Anderson J, Banerji A, Bernstein JA, Caballero T, Farkas H, Gower RG, Keith PK, Levy DS, Li HH, Magerl M, Manning M, Riedl MA, Lawo JP, Prusty S, Machnig T, Longhurst H, on behalf of the COMPACT Investigators 2/2021 Orphanet journal of rare diseases

BACKGROUND: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.

RESULTS: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within “normal” range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], – 1.23 [- 2.08, – 0.38]), HADS depression scale (- 0.95 [- 1.57, – 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], – 23.33% [- 34.86, – 11.81]), work productivity loss (- 26.68% [- 39.92, – 13.44]), and activity impairment (- 16.14% [- 26.36, – 5.91]). Clinically important improvements were achieved in >= 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.

CONCLUSIONS: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014,

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Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks [Review]

Hide M, Horiuchi T, Ohsawa I, Andresen I, Fukunaga A 1/2021 Allergology international : official journal of the Japanese Society of Allergology

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies. Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

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Managing chronic urticaria and recurrent angioedema differently with advancing age

Longhurst HJ, Goncalo M, Godse K, Ensina LF 6/2021 The journal of allergy and clinical immunology. In practice

Angioedema and urticaria affect people of all ages. Accurate diagnosis and optimum management is essential for healthy aging. Older people continue to experience mast cell-mediated urticaria and angioedema, with a higher prevalence of autoimmune and a lower prevalence of autoallergic disease. Bradykinin-mediated angioedemas are more common in the elderly because of their association with angiotensin-converting enzyme inhibitor (ACEI) treatment. Acquired C1-inhibitor deficiency, another bradykinin-mediated angioedema, occurs predominantly in older people, whereas hereditary angioedema due to C1-inhibitor deficiency continues to cause symptoms, even in old age. Drug-induced angioedemas disproportionately affect older people, the most frequent users of ACEIs, aspirin, and nonsteroidal anti-inflammatory drugs. Accurate diagnosis and targeted treatment prevent unnecessary morbidity and mortality. Second-generation antihistamines with omalizumab if required are effective and well tolerated in older people with mast cell-mediated urticaria. For bradykinin-mediated angioedemas, these drugs are ineffective. C1-inhibitor replacement or blockade of kallikrein or the bradykinin B2 receptor of the contact pathway is required to treat hereditary angioedema and may be considered in other bradykinin-mediated angioedemas, if supportive treatment is insufficient. For aspirin-related angioedema and urticaria, alternative medications or, exceptionally, desensitization may be required. Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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Medicinal use of testosterone and related steroids revisited [Review]

Tauchen J, Jurasek M, Huml L, Rimpelova S 2/2021 Molecules (Basel, Switzerland)

Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.

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Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial

Ohsawa I, Honda D, Suzuki Y, Fukuda T, Kohga K, Morita E, Moriwaki S, Ishikawa O, Sasaki Y, Tago M, Chittick G, Cornpropst M, Murray SC, Dobo SM, Nagy E, Van Dyke S, Reese L, Best JM, Iocca H, Collis P, Sheridan WP, Hide M 6/2021 Allergy

BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.

METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with >=2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (>=2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period.

RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).

CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan. Copyright © 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

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Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial

Zuraw B, Lumry WR, Johnston DT, Aygoren-Pursun E, Banerji A, Bernstein JA, Christiansen SC, Jacobs JS, Sitz KV, Gower RG, Gagnon R, Wedner HJ, Kinaciyan T, Hakl R, Hanzlikova J, Anderson JT, McNeil DL, Fritz SB, Yang WH, Tachdjian R, Busse PJ, Craig TJ, Li HH, Farkas H, Best JM, Clemons D, Cornpropst M, Dobo SM, Iocca HA, Kargl D, Nagy E, Murray SC, Collis P, Sheridan WP, Maurer M, Riedl MA 7/2021 The Journal of allergy and clinical immunology

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.

OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).

METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo ( identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.

RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.

CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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Orladeyo (Berotralstat): A novel oral therapy for the prevention of hereditary angioedema

Powell J, Piszczatoski C, Rubido E 7/2021 The Annals of pharmacotherapy

OBJECTIVE: The purpose of this article is to review the available trials that led to the Food and Drug Administration (FDA) approval of berotralstat, an oral kallikrein inhibitor, for the prevention of hereditary angioedema (HAE) attacks.

DATA SOURCES: PubMed and were searched using key term berotralstat to identify phase III clinical trials related to the FDA approval of berotralstat from April 2018 to May 2021.

STUDY SELECTION AND DATA EXTRACTION: Trials selected were those that influenced the FDA approval of berotralstat or provided novel information regarding the safety and efficacy of this therapy in the treatment of HAE.

DATA SYNTHESIS: Both APeX-2 and ApeX-J found clinically significant benefit with berotralstat 150 mg daily for reduction in HAE attacks when compared with placebo (1.31 vs 2.35, P < 0.001, and 1.11 vs 2.18, P < 0.001, attacks in the APeX-2 and APeX-J trials, respectively). APeX-2 also showed a statistically significant benefit for berotralstat 110 mg daily (1.65 vs 2.35 attacks [1.65 attacks, P = 0.024]).

RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: An advantage berotralstat has over the other approved therapies is that it is administered orally, which may garner patient preference because of ease of administration. Berotralstat has also shown a potential benefit in reducing the need for standard-of-care treatment for HAE attacks, which has not been studied with alternative agents.

CONCLUSIONS: Berotralstat 150 mg daily has been proven safe and effective in clinical studies and appears to be a viable oral alternative to parenteral medications currently used in HAE prophylaxis.

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Periodic severe angioedema without exogenous hormone exposure

Nabavi M, Bahrami S, Arshi S, Rezaeifar A, Bemanian MH, Fallahpour M, Shokri S, Tehrani H 2/2021 Iranian journal of allergy, asthma, and immunology

Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine/corticosteroid or adrenaline. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1-INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1-INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.

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Population Pharmacokinetics and Exposure-Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema

Wang Y, Jomphe C, Marier JF, Martin P 4/2021 Journal of clinical pharmacology

Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE. Copyright © 2020 Takeda Pharmaceutical Company Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

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Population pharmacokinetics of recombinant human C1 esterase inhibitor in children with hereditary angioedema

Hayes S, Farrell C, Relan A, Anderson J 6/2021 Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for the treatment of acute hereditary angioedema (HAE) attacks in adolescents and adults; it is also indicated in Europe for children aged 2 years and older. A need exists for further insight into potential pharmacokinetic (PK) differences in functional C1-INH levels by age (ie, children, adolescents, and adults).

OBJECTIVE: To perform population PK modeling to predict C1-INH levels by age after by age rhC1-INH administration.

METHODS: Data from a phase 2 pediatric trial (children aged 4-13 years at screening) were added to a database of 6 trials in adults and adolescents. An unpublished population PK model was refined and used to simulate C1-INH exposure.

RESULTS: Analysis included 153 individuals (14 healthy volunteers; 139 patients with HAE) and 1788 functional C1-INH measurements (59 from 20 patients in the pediatric trial). Bodyweight (population weight, 16-128 kg) was a key predictor of C1-INH volume of distribution. Age was not a predictor of C1-INH PK after the inclusion of bodyweight in the model. Simulations of the recommended rhC1-INH dosing regimen (bodyweight <84 kg, 50 U/kg; >=84 kg, 4200 U) revealed that overall C1-INH exposure was comparable among age groups. Predicted peak functional C1-INH concentrations were at or above the lower level of normal (>=0.7 U/mL) for 99.8% of adults (>=18 years), 99.8% of adolescents (14-17 years), and 96.0% of children (2-13 years).

CONCLUSION: The analyses support the same weight-based rhC1-INH dosing for HAE attacks in children as currently recommended for adolescents and adults. These results support clinical trial data, which revealed similar safety and efficacy profiles across these age groups. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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Preventive treatment of hereditary angioedema: A review of phase III clinical trial data for subcutaneous C1 inhibitor and relevance for patient management [Review]

West JB, Poarch K, Lumry WR 12/2021 Clinical therapeutics

PURPOSE: Hereditary angioedema (HAE), most often caused by a genetically mediated deficiency in the activity of C1 inhibitor (C1INH) protein, is characterized clinically by recurrent episodes of localized swelling without wheals. HAE attacks can be painful, debilitating, and even fatal, resulting in physical discomfort, emotional stress, and interruptions of work, school, and/or social activities, all of which can affect health-related quality of life (HRQoL). Subcutaneous C1INH (C1INH[SC]) is recommended as a first-line option for long-term prophylaxis (LTP) in HAE. This narrative review provides a concise but comprehensive overview of all published data generated from the pivotal Phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) study program, which evaluated the use of C1INH(SC) as LTP.

METHODS: A PubMed search was performed using the search terms subcutaneous C1 inhibitor plus COMPACT with no filters, and another search was performed using the term subcutaneous C1 inhibitor, with output limited to clinical trial data only. All publications that reported data generated during the Phase III COMPACT study were included. Data presentation focused on the US Food and Drug Administration-approved dose of 60 IU/kg.

FINDINGS: The search strategy identified a total of 11 publications that reported data and analyses from the Phase III COMPACT study. Publications reported overall findings from the double-blind, placebo-controlled, crossover COMPACT study and a subsequent long-term open-label extension (OLE) study. Other published analyses included pharmacokinetic/pharmacodynamic data, HRQoL assessments, and findings in patient subgroups including women, pediatric patients, and patients >=65 years of age. Subgroup analyses reported good safety and efficacy profiles among age-based subgroups from the COMPACT OLE, including pediatric patients, patients >=65 years of age with comorbidities, and among female patients, despite a tendency for HAE to be more severe in women. A number of significant HRQoL improvements were noted with C1INH(SC) use, including better overall health status, less anxiety, and less work- and activity-related impairment versus placebo (double-blind study), and compared with baseline (OLE).

IMPLICATIONS: This review provides a concise overview of all published COMPACT study data with C1INH(SC). The data reviewed here portray a high level of efficacy and tolerability with C1INH(SC), even during periods of treatment that exceed 2 years, which does not appear to vary based on patient age or sex. Clinically relevant improvements in multiple facets of HRQoL were also reported, including better overall HRQoL, less anxiety and depression, and less disruptions in work attendance and productivity. These data should be useful for assessing the appropriateness of C1INH(SC) therapy for individual patients. Copyright © 2021. Published by Elsevier Inc.

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Psychiatric and clinical characteristics of hereditary angioedema patients who experienced attacks during COVID-19

Mete Gokmen N, Kuman Tuncel O, Bogatekin G, Bulut G, Demir S, Gelincik A, Tunakan Dalgic C, Mungan D 7/2021 Journal of investigational allergology & clinical immunology

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Randomized trial of the efficacy and safety of berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: Results of APeX-2 through 48 weeks (Part 2)

Wedner HJ, Aygoren-Pursun E, Bernstein J, Craig T, Gower R, Jacobs JS, Johnston DT, Lumry WR, Zuraw BL, Best JM, Iocca HA, Murray SC, Desai B, Nagy E, Sheridan WP, Kiani-Alikhan S 6/2021 The journal of allergy and clinical immunology. In practice

BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile.

OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks.

METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability.

RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (+/-standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (+/-0.25) and 1.06 (+/-0.25) in the berotralstat 150mg 48-week group and 2.97 (+/-0.21) and 1.35 (+/-0.33) in the berotralstat 110mg 48-week group.

CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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Recombinant human C1 esterase inhibitor for hereditary angioedema attacks: A European registry

Valerieva A, Staevska MT, Grivcheva-Panovska V, Jesenak M, Kohalmi KV, Hrubiskova K, Zanichelli A, Bellizzi L, Relan A, Hakl R, Farkas H 4/2021 The World Allergy Organization journal

Background: Hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks. A European treatment registry was established to review the adverse event profile and efficacy of recombinant human C1 esterase inhibitor (rhC1-INH) for HAE attacks.

Methods: Individuals with C1-INH-HAE were enrolled following a decision to treat with rhC1-INH and provision of written informed consent. Medical history and baseline HAE information were collected at screening. Healthcare providers entered data on HAE attacks, response to treatment, and adverse events using a web-based questionnaire.

Results: From July 1, 2011, through December 1, 2019, 71 patients with C1-INH-HAE (30 male/41 female; mean age, 47.3 years; age range, 19-78 years) in 9 countries reported 2356 attacks and were treated with rhC1-INH. Before registry entry, patients, including 20 (28.2%) who were on maintenance therapy/prophylaxis at registry enrollment, experienced a mean of 25 HAE attacks per year (median, 16 [range, 0-185]). Most treated HAE attacks were abdominal (46.1%), followed by peripheral (38.3%), oro-facial-pharyngeal (14.8%), urogenital (3.2%), and laryngeal (2.6%). The mean rhC1-INH dose was 3307 U (43.3 U/kg). Patients reported symptom improvement within 4 h for 97.8% of attacks (2305/2356) with rhC1-INH; most attacks (99.8%; 2351/2356) required only 1 dose. Five attacks were treated with a second dose (total rhC1-INH dose administered for attack, 4200 U). No hypersensitivity, thrombotic/thromboembolic events, or drug-related serious adverse events were reported.

Conclusion: The rhC1-INH treatment registry provided real-world data on the treatment of 2356 HAE attacks that were consistent with clinical trial data of rhC1-INH in patients with C1-INH-HAE. Copyright © 2021 The Authors.

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Recurrent and acute abdominal pain as the main clinical manifestation in patients with hereditary angioedema

Cao Y, Liu S, Zhi Y 3/2021 Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) is a rare disease that often leads to misdiagnosis. The delay of diagnosis is > 10 years in China. Recurrent and acute abdominal pain is one of the common symptoms of HAE. Because of the high misdiagnosis rate, it usually results in unnecessary surgical procedures. This study focused on the clinical symptoms and management of HAE-related abdominal attacks in Chinese patients to provide some new insight for the emergency department (ED) physicians and gastroenterologists. Methods: A Web-based survey was conducted among 107 patients with HAE from 94 unrelated families. Detailed questions with respect to the abdominal attacks were asked, including the frequency, symptoms, and duration before and after confirmed diagnosis. The demographic characteristics, diagnosis process, and treatment outcomes were also included. Results: Approximately 70% of the patients with HAE presented with abdominal symptoms during the onset of edema, mostly characterized by pain (94.8%), nausea (83.1%), vomiting (83.1%), diarrhea (59.7%), and constipation (23.4%). The patients were easily misdiagnosed as having gastroenteritis (35.1%) and appendicitis (10.4%), and 24.7% of them received unnecessary appendectomy or laparotomy. Danazol, a widely used drug for long-term prophylaxis of HAE in China, can reduce the attack frequency and alleviate the abdominal symptoms, but the adverse effects are also significant and more severe in women. Conclusions: Abdominal symptoms are common and important clinical features of HAE but are easily confused with other gastrointestinal diseases. ED physicians and gastroenterologists should consider HAE when patients experience recurrent and unexplained abdominal pain. Proper medical treatment should be administered in a timely manner if an HAE diagnosis is confirmed and efforts are required to increase access in China to medications both for on-demand treatment and long-term prophylaxis.

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Safety and outcomes associated with the pharmacological inhibition of the kinin-kallikrein system in severe COVID-19

Mansour E, Palma AC, Ulaf RG, Ribeiro LC, Bernardes AF, Nunes TA, Agrela MV, Bombassaro B, Monfort-Pires M, Camargo RL, Araujo EP, Brunetti NS, Farias AS, Falcao ALE, Santos TM, Trabasso P, Dertkigil RP, Dertkigil SS, Moretti ML, Velloso LA 2/2021 Viruses

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

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Short review of SEC, a potential dexamethasone-sparing regimen for glioblastoma: Spironolactone, ecallantide, clotrimazole

Kast RE, Burns TC, Halatsch ME 9/2021 Neuro-Chirurgie

This paper presents a short review of data supporting a dexamethasone sparing regimen, SEC, to reduce glioblastoma related brain edema. The conclusion of the reviewed data is that the rationale and risk/benefit ratio favors a pilot study to determine if the three drug regimen of SEC can reduce need for corticosteroid use during the course of glioblastoma. Details of how selected pathophysiological aspects of brain edema occurring during the course of glioblastoma and its treatment intersect with the established action of the three old drugs of SEC indicate that they can be repurposed to reduce that edema. Current first-line treatment of this edema is dexamethasone or related corticosteroids. There are multiple negative prognostic implications of both the edema itself and of dexamethasone, prime among them shortened survival, making a dexamethasone sparing regimen highly desirable. SEC uses spironolactone, an antihypertensive potassium-sparing diuretic acting by mineralocorticoid receptor inhibition, ecallantide acting to inhibit kallikrein activation marketed to treat hereditary angioedema, and clotrimazole, an old antifungal drug that inhibits intermediate conductance Ca++ activated K+ channel (KCa3.1). These three old drugs are well known to most clinicians, have a well-tolerated safety history, and have a robust preclinical database showing their potential to reduce the specific edema of glioblastoma. Additionally, these three drugs were chosen by virtue of each having preclinical evidence of glioblastoma growth and/or migration inhibition independent of their edema reduction action. A clinical study of SEC is being planned. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

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The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey

Iwamoto K, Yamamoto B, Ohsawa I, Honda D, Horiuchi T, Tanaka A, Fukunaga A, Maehara J, Yamashita K, Akita T, Hide M 4/2021 Allergology international : official journal of the Japanese Society of Allergology

BACKGROUND: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs.

METHODS: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis.

RESULTS: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect.

CONCLUSIONS: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues. Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

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The importance of complement testing in acquired angioedema related to angiotensin-converting enzyme inhibitors

Balla Z, Zsilinszky Z, Polai Z, Andrasi N, Kohalmi KV, Csuka D, Varga L, Farkas H 2/2021 The journal of allergy and clinical immunology. In practice

BACKGROUND: Angiotensin-converting enzyme inhibitors may cause angioedema. Currently, no laboratory method is available for identifying acquired angioedema related to angiotensin-converting enzyme inhibitors. However, establishing the diagnosis is possible from the medical history and the preexisting angiotensin-converting enzyme inhibitor therapy, as well as by excluding other angioedema types.

OBJECTIVE: To evaluate the results of complement testing in patients experiencing angioedema while taking angiotensin-converting enzyme inhibitors.

METHODS: Between 2005 and 2019, a total of 149 patients taking angiotensin-converting enzyme inhibitors were referred to our Angioedema Center for the diagnostic evaluation of recurrent angioedema episodes. Complement measurement was performed on these patients.

RESULTS: The mean age of the 149 patients treated with angiotensin-converting enzyme inhibitors at the onset of the index angioedema episode was 55.8 years. The mean interval between the introduction of angiotensin-converting enzyme inhibitor therapy and the occurrence of the initial symptoms of angioedema was 43 months. The most commonly used angiotensin-converting enzyme inhibitor was perindopril (32.9% of the patients). The initial angioedema episode involved the face in 50.3%, the lips in 40.9%, and the tongue in 33.5% of the patients. Angiotensin-converting enzyme inhibitors were discontinued in all 149 patients, and at the same time, a complement test was performed. The complement tests confirmed hereditary angioedema with C1-inhibitor deficiency in 2 patients and an additional 12 family members. Acquired angioedema with C1-inhibitor deficiency was found in 3 patients.

CONCLUSIONS: Excluding hereditary angioedema and acquired angioedema with C1-inhibitor deficiency is indispensable for establishing the diagnosis of acquired angioedema related to angiotensin-converting enzyme inhibitors. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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Treatment of hereditary angioedema [Review]

Caballero T 2/2021 Journal of investigational allergology & clinical immunology

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action.

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What’s new in the treatment of urticaria and angioedema

Khan DA, Kocaturk E, Bauer A, Aygoren-Pursun E 6/2021 The journal of allergy and clinical immunology. In practice

Chronic urticaria and angioedema are diseases often managed by Allergy and Immunology specialists. Recent international guidelines have outlined a stepwise approach to management of patients using dose escalation of second-generation antihistamines followed by use of omalizumab and finally cyclosporine in more refractory cases. In select patients (those with refractory chronic urticaria), nonbiologic alternative medications with anti-inflammatory or immunosuppressant activity may be considered. Angioedema without wheals may have several different pathophysiologic mechanisms. Optimal management of mast cell-mediated angioedema is less clear but is often managed similar to chronic spontaneous urticaria. Drug-induced angioedema due to angiotensin-converting enzyme inhibitors is a common cause of angioedema in the emergency department. Although bradykinin is thought to be a primary mediator for this type of angioedema, studies of targeted therapies have been generally disappointing. In contrast, several targeted therapies have been proven successful using acute and preventive approaches for management of hereditary angioedema. Further developments, including novel biologics, novel oral therapies, and gene therapy approaches, may hopefully continue to broaden therapeutic options to ensure optimal individual management of patients with hereditary angioedema. Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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