100 research outputs found
Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial
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 (Clinicaltrials.gov 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 \u3c .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
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences
Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development
Hereditary Angioedema: The Dawn of a New Era of Hereditary Angioedema Management
This symposium provided an overview of past, current, and future therapies and routes of administration for patients with hereditary angioedema (HAE). Prof Cicardi opened the symposium by welcoming attendees and introducing the main topics of the session. Prof Magerl then focussed on treatments that are currently used for acute and prophylactic management of patients with HAE and highlighted that there is an unmet medical need in terms of better prophylactic treatment options. Prof Craig summarised the clinical evidence gathered over the last decades and shared the key findings and insights that led to our current understanding of the disease and laid the foundations for current and future treatment approaches. Prof Zuraw presented the findings from the pivotal Phase III COMPACT trial that explored the efficacy and safety of a self-administered subcutaneous (SC) nanofiltered C1-esterase inhibitor concentrate (C1-INH[SC]) for the prevention of HAE attacks
WAO guideline for the management of hereditary angioedema
Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists
Development and content validity testing of a patient-reported outcomes questionnaire for the assessment of hereditary angioedema in observational studies
Background Hereditary Angioedema (HAE), a rare genetic disease, manifests as
intermittent, painful attacks of angioedema. Attacks vary in frequency and
severity and include skin, abdominal and life-threatening laryngeal swellings.
This study aimed to develop a patient reported outcome (PRO) tool for the
assessment of HAE attacks, including their management and impact on patients’
lives, for use in clinical studies, or by physicians in general practice.
Methods The results of open-ended face to face concept elicitation interviews
with HAE patients in Argentina (n = 10) and the US (n = 33) were used to
develop the first draft questionnaire of the HAE patient reported outcomes
questionnaire (HAE PRO). Subsequently, in-depth cognitive debriefing
interviews were performed with HAE patients in the UK (n = 10), Brazil (n =
10), Germany (n = 11) and France (n = 12). Following input from eight
multinational clinical experts further cognitive interviews were conducted in
the US (n = 12) and Germany (n = 12). Patients who experienced abdominal,
cutaneous or laryngeal attacks of varying severity levels were included in all
rounds of interviews. Across the rounds of interviews patients discussed their
HAE attack symptoms, impacts and treatments. Cognitive debriefing interviews
explored patient understanding and relevance of questionnaire items. All
interviews were conducted face to face following a pre-defined semi-structured
interview guide in the patient’s native language. Results Patients reported a
variety of HAE symptoms, attack triggers, warning signs, attack impacts and
treatment options which were used to develop the HAE PRO. The HAE PRO was
revised and refined following input from patients and clinical experts. The
final 18-item HAE PRO provides an assessment of the HAE attack experience
including symptoms, impacts, treatment requirements, healthcare resource use
and loss of productivity caused by HAE attacks. Conclusions Patient and expert
input has contributed to the development of a content valid questionnaire that
assesses concepts important to HAE patients globally. HAE patients across
cultures consider the HAE PRO a relevant and appropriate assessment of HAE
attacks and treatment
Bradykinin receptors in GtoPdb v.2021.3
Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [91]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema
Bradykinin receptors in GtoPdb v.2023.1
Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023
Bradykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [76]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema
HAE therapies: past present and future
Advances in understanding the pathophysiology and mechanism of swelling in hereditary angioedema (HAE) has resulted in the development of multiple new drugs for the acute and prophylactic treatment of patients with HAE. This review will recap the past treatment options, review the new current treatment options, and discuss potential future treatment options for patients with HAE
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