Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines.

Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly.

CRISPR-Based Therapy for Hereditary Angioedema.

Background: Hereditary angioedema is a rare genetic disease characterized by severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy that is based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 ().

Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial.

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.

Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

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.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

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.

CRISPR-Cas9 In Vivo Gene Editing of for Hereditary Angioedema.

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 (), with the goal of lifelong control of angioedema attacks after a single dose.

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema.

Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification.

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

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).

[Facial swelling due to angioedema: often mast cell mediated, but not always].

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.

Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat.

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.

Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape.

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.

The Disease Burden and Societal Costs of Hereditary Angioedema.

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.

Severe Dyslipidemia Mimicking Familial Hypercholesterolemia Induced by High-Fat, Low-Carbohydrate Diets: A Critical Review.

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.

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

Background: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks.

Methods: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA.

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation.

Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives.

Inhalation of Low Molecular Weight Heparins as Prophylaxis against SARS-CoV-2.

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.