6 research outputs found
The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update
No full text© 2022 The Author(s)Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.N
Randomized trial of the efficacy and safety of Berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: results of APeX-2 ihrough 48 weeks (Part 2)
No full textBackground: 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
Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial
No full textBackground: 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 < .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
The Ion-Dipole Effect is a Force for Molecular Recognition and Biomimetic Catalysis
No full textChapter 1
In aqueous and organic media, electron-rich synthetic macrocycles serve as hosts for positively-charged guests. Binding studies in different solvents have quantified hydrophobic, donor/acceptor, and ion-dipole interactions as forces for molecular recognition. We have found clear evidence for substantial host-guest donor/acceptor π-stacking interactions (ca. 1.5 kcal/mol) in aqueous media only. The ion-dipole effect is an appreciable driving force (worth up to 3.5 kcal/mol) for molecular recognition in both aqueous and organic media.
Chapter 2
Variable-temperature binding studies were performed to assess enthalpic (ΔH°) and entropic (ΔS°) contributions to free energies (ΔG°) of host-guest complexation. The van't Hoff plots (RlnKₐ vs T⁻¹), which are clearly non-linear, have revealed significant values for the heat capacities (ΔCₚ) of complexation in both organic and aqueous media. The ΔCₚ values reflect a phenomenon generally overlooked in molecular recognition studies: both ΔH° and ΔS° are strongly temperature-dependent.
Hydrophobic, donor/acceptor, and ion-dipole interactions are tentatively partitioned into ΔH° and ΔS° contributions at 298K. "Classic" hydrophobic binding is characterized by a large, positive ΔS° and a near-zero ΔH° term. Strong donor/acceptor π-stacking interactions are typically balanced between large, favorable enthalpic and unfavorable entropic contributions. The ion-dipole effect is primarily an enthalpically-driven binding force.
Chapter 3
Electron-rich synthetic macrocyclic host 1 accelerates a class of alkylation reactions in aqueous media. Specifically, host 1 catalyzes the reactions of pyridine-type nucleophiles with alkyl halides in an aqueous pD~9 borate buffer. The rate constants of catalyzed versus uncatalyzed reactions and the binding affinities for substrates and products demand that host 1 binds transition states more tightly than ground states. This extension of molecular recognition through ion-dipole interactions to biomimetic catalysis provides compelling evidence for transition-state stabilization via favorable dipole-dipole interactions in aqueous media.
Chapter 4
A new class of high-symmetry, water soluble, hydrophobic binding sites is described that feature 1,5-substituents on a rigid ethenoanthracene (DEA) framework. These new 1,5-hosts are compared to the analogous 2,6-hosts described in the Ph.D. theses of Petti and Shepodd. Because of more favorable solvation (by water) of amide linker groups that line the cavity, the 1,5-hosts exhibit significantly reduced affinities for all guests considered: only positively-charged guests are bound to any appreciable extent.
While the binding sites designed herein are composed of topographically well-defined, rigid units to give a chiral host (with a "greater sense of twist"), the disposition of the 1,5-substituents allows the collapse of hosts into a "bowl" conformation. We therefore suggest that the more successful high-symmetry, hydrophobic binding sites are to be found with 2,6-DEA-constructed hosts rather than with 1,5-DEA-constructed hosts.
One benefit of the synthetic approach taken here is the development of a series of DEA building blocks for the construction of hosts with even more pronounced hydrophobic character.</p
