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PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.
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BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).
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Angioedemas Hereditários , Humanos , Masculino , Feminino , Método Duplo-Cego , Angioedemas Hereditários/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Injeções Subcutâneas , Adulto Jovem , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/uso terapêutico , Idoso , Adolescente , Qualidade de VidaRESUMO
BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).
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Estudos Cross-Over , Humanos , Feminino , Método Duplo-Cego , Masculino , Adulto , Administração Oral , Pessoa de Meia-Idade , Angioedemas Hereditários/tratamento farmacológico , Adolescente , Adulto Jovem , Idoso , Angioedema Hereditário Tipos I e II/tratamento farmacológico , PirazóisRESUMO
BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.
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Angioedemas Hereditários , Humanos , Angioedemas Hereditários/tratamento farmacológico , Resultado do Tratamento , Técnica Delphi , Inquéritos e Questionários , Ensaios Clínicos como Assunto , Consenso , Feminino , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.
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Angioedema , Consenso , Terminologia como Assunto , Humanos , Angioedema/classificação , Angioedema/diagnóstico , Abreviaturas como Assunto , Técnica DelphiRESUMO
BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.
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Angioedema , Estudos Cross-Over , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Angioedema/tratamento farmacológico , Método Duplo-Cego , Idoso , Proteína Inibidora do Complemento C1/uso terapêutico , Adulto , Resultado do Tratamento , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêuticoRESUMO
BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).
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Angioedemas Hereditários , Sistemas CRISPR-Cas , Edição de Genes , Adulto , Humanos , Angioedema , Angioedemas Hereditários/sangue , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/uso terapêutico , Relação Dose-Resposta a Droga , Edição de Genes/métodos , Calicreína Plasmática/genética , Resultado do TratamentoRESUMO
BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
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Angioedemas Hereditários , Oligonucleotídeos , Humanos , Angioedemas Hereditários/tratamento farmacológico , Pré-Calicreína , Qualidade de Vida , Resultado do Tratamento , Proteína Inibidora do Complemento C1/uso terapêuticoRESUMO
Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.
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Angioedemas Hereditários , Humanos , Angioedemas Hereditários/genética , Angioedemas Hereditários/prevenção & controle , Bradicinina/uso terapêutico , Bradicinina/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Fígado/metabolismo , Pré-CalicreínaRESUMO
Most cases of angioedema are mast cell mediated. We present three patients with angioedema, who were admitted to our emergency room or outpatient clinic. One of them did have mast cell mediated angioedema, despite insufficient response to initial antihistamine treatment. The other patients had more rare cases of angioedema, i.e. hereditary angioedema with C1-inhibitor deficiency and angiotensin converting enzyme inhibitor associated angioedema. We discuss similarities and differences in symptoms, diagnosis and treatment between these causes of angioedema. We recommend keeping the differential diagnosis of angioedema in mind when a patient with angioedema is presented, including rarer pathophysiological explanations.
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Angioedema , Angioedemas Hereditários , Humanos , Mastócitos , Angioedema/diagnóstico , Angioedema/etiologia , Angioedemas Hereditários/complicações , Angioedemas Hereditários/diagnóstico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Diagnóstico DiferencialRESUMO
BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE-C1-INH. METHODS: To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation-based approach using phase 2 data. RESULTS: Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI-C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI-C rating of at least "A Little Better" for two time points in a row. CONCLUSIONS: Patient feedback and phase 2 data support PGI-C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on-demand treatment for HAE-C1-INH attacks.
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Hereditary angioedema (HAE) is a rare disease characterized by sudden and often unprovoked episodes of swelling that can be potentially life-threatening when it involves the upper airway. The treatment options for both acute episodes of HAE and LTP, used to minimize the frequency and severity of angioedema attacks, were limited historically to very few options, had considerable side effects, and/or had considerable burden of treatment. Fortunately, through the elucidation of the pathophysiology of HAE, the development of newer targeted therapies has been possible both for acute therapy and long-term prophylaxis and even more are on the horizon. Because of the rapid development of these therapies, it can be challenging for clinicians to keep abreast of newer and developing treatments for HAE. This review article will outline the current and potential future treatments for HAE. It will also highlight important considerations when treating special HAE patient populations including women and pediatric patients.
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Angioedema , Angioedemas Hereditários , Humanos , Feminino , Criança , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Angioedema/tratamento farmacológicoRESUMO
BACKGROUND: According to the current treatment guidelines, the goals of treatment of patients with hereditary angioedema (HAE) are to achieve total control of the disease and to normalize patients' lives. OBJECTIVE: This study aims to establish the entire burden of HAE comprising disease control, treatment satisfaction, reductions in quality of life, and societal costs. METHODS: Adult patients with HAE under treatment at the Dutch national center of reference completed a cross-sectional survey in 2021. The survey consisted of different questionnaires: angioedema-specific questionnaires (4-week Angioedema Activity Score and Angioedema Control Test), quality of life questionnaires (Angioedema Quality of Life [AE-QoL] questionnaire and EQ-5D-5L), the Treatment Satisfaction Questionnaire for Medication (TSQM), and societal costs questionnaires (iMTA Medical Consumption Questionnaire and iMTA Productivity Cost Questionnaire). RESULTS: The response rate was 78% (69 of 88). The entire sample had a mean Angioedema Activity Score of 16.61, and 36% of participants had poorly controlled disease as expressed by the Angioedema Control Test. The mean quality of life in the entire sample was 30.99 as expressed by the AE-QoL and 0.873 as expressed by the EQ-5D-5L utility value. Utilities dropped by 0.320 points during an angioedema attack. TSQM scores ranged from 66.67 to 75.00 across its 4 domains. On average, total costs per year incurred 22,764, predominantly existing of HAE-medication costs. Total costs showed substantial variation between patients. CONCLUSIONS: This study describes the entire burden of HAE among Dutch patients comprising disease control, quality of life, treatment satisfaction, and societal costs. These results can inform cost-effectiveness analyses that can aid reimbursement decisions for HAE treatments.
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Angioedemas Hereditários , Qualidade de Vida , Adulto , Humanos , Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/tratamento farmacológico , Estudos Transversais , Efeitos Psicossociais da Doença , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2â×â2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.
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Angioedemas Hereditários , Calicreína Plasmática , Adulto , Feminino , Humanos , Masculino , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Estudos Cross-Over , Método Duplo-Cego , Calicreína Plasmática/antagonistas & inibidores , Resultado do Tratamento , Pessoa de Meia-IdadeRESUMO
Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk.
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Dislipidemias , Hipercolesterolemia , Hiperlipidemias , Hiperlipoproteinemia Tipo II , Humanos , LDL-Colesterol , Colesterol , Dieta com Restrição de Carboidratos , Ácidos Graxos , Carboidratos da Dieta , Gorduras na DietaRESUMO
New SARS-CoV-2 variants of concern and waning immunity demonstrate the need for a quick and simple prophylactic agent to prevent infection. Low molecular weight heparins (LMWH) are potent inhibitors of SARS-CoV-2 binding and infection in vitro. The airways are a major route for infection and therefore inhaled LMWH could be a prophylactic treatment against SARS-CoV-2. We investigated the efficacy of in vivo inhalation of LMWH in humans to prevent SARS-CoV-2 attachment to nasal epithelial cells in a single-center, open-label intervention study. Volunteers received enoxaparin in the right and a placebo (NaCl 0.9%) in the left nostril using a nebulizer. After application, nasal epithelial cells were retrieved with a brush for ex-vivo exposure to either SARS-CoV-2 pseudovirus or an authentic SARS-CoV-2 isolate and virus attachment as determined. LMWH inhalation significantly reduced attachment of SARS-CoV-2 pseudovirus as well as authentic SARS-CoV-2 to human nasal cells. Moreover, in vivo inhalation was as efficient as in vitro LMWH application. Cell phenotyping revealed no differences between placebo and treatment groups and no adverse events were observed in the study participants. Our data strongly suggested that inhalation of LMWH was effective to prevent SARS-CoV-2 attachment and subsequent infection. LMWH is ubiquitously available, affordable, and easy to apply, making them suitable candidates for prophylactic treatment against SARS-CoV-2. IMPORTANCE New SARS-CoV-2 variants of concern and waning immunity demonstrate the need for a quick and simple agent to prevent infection. Low molecular weight heparins (LMWH) have been shown to inhibit SARS-CoV-2 in experimental settings. The airways are a major route for SARS-CoV-2 infection and inhaled LMWH could be a prophylactic treatment. We investigated the efficacy of inhalation of the LMWH enoxaparin in humans to prevent SARS-CoV-2 attachment because this is a prerequisite for infection. Volunteers received enoxaparin in the right and a placebo in the left nostril using a nebulizer. Subsequently, nasal epithelial cells were retrieved with a brush and exposed to SARS-CoV-2. LMWH inhalation significantly reduced the binding of SARS-Cov-2 to human nasal cells. Cell phenotyping revealed no differences between placebo and treatment groups and no adverse events were observed in the participants. Our data indicated that LMWH can be used to block SARS-CoV-2 attachment to nasal cells. LMWH was ubiquitously available, affordable, and easily applicable, making them excellent candidates for prophylactic treatment against SARS-CoV-2.