Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment.

INTRODUCTION/AIMS: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone. METHODS: This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone. RESULTS: The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug. DISCUSSION: This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.

Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US. METHODS: Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date). RESULTS: As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported. CONCLUSION: In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.

Electron-Deficient Polycyclic π-System Fused with Multiple B←N Coordinate Bonds.

An extensive polycyclic π-system with 23 fused rings is synthesized via a highly efficient borylation reaction, in which four B-N covalent bonds and four B←N coordinate bonds are formed in one pot. B←N coordinate bonds not only lock the backbone into a near-coplanar conformation but also decrease the LUMO energy level to around -3.82 eV, demonstrating the dual utility of this strategy for the synthesis of extensive rigid polycyclic molecules and the development of n-type conjugated materials for organic electronics and organic photovoltaics.

Covalent and Noncovalent Approaches to Rigid Coplanar π-Conjugated Molecules and Macromolecules.

Molecular conformation and rigidity are essential factors in determining the properties of individual molecules, the associated supramolecular assemblies, and bulk materials. This correlation is particularly important for π-conjugated molecular and macromolecular systems. Within such an individual molecule, a coplanar conformation facilitates the delocalization of not only molecular orbitals but also charges, excitons, and spins, leading to synergistically ensembled properties of the entire conjugated system. A rigid backbone, meanwhile, imposes a high energy cost to disrupt such a favorable conformation, ensuring the robustness and persistence of coplanarity. From a supramolecular and material point of view, coplanarity and rigidity often promote strong intermolecular electronic coupling and reduce the energy barrier for the intermolecular transport of charges, excitons, and phonons, affording advanced materials properties in bulk. In this context, pursuing a rigid and coplanar molecular conformation often represents one of the primary objectives when designing and synthesizing conjugated molecules for electronic and optical applications. Two general bottom-up strategies-covalent annulation and noncovalent conformational control-are often employed to construct rigid coplanar π systems. These strategies have afforded various classes of such molecules and macromolecules, including so-called conjugated ladder polymers, graphene nanoribbons, polyacenes, and conformationally locked organic semiconductors. While pursuing these targets, however, one often confronts challenges associated with precise synthesis and limited solubility of the rigid coplanar systems, which could further impede their large-scale preparation, characterization, processing, and application. To address these issues, we developed and utilized a number of synthetic methods and molecular engineering approaches to construct and to process rigid coplanar conjugated molecules and macromolecules. Structure-property correlations of this unique class of organic materials were established, providing important chemical principles for molecular design and materials applications. In this Account, we first describe our efforts to synthesize rigid coplanar π systems fused by various types of bonds, including kinetically formed covalent bonds, thermodynamically formed covalent bonds, N→B coordinate bonds, and hydrogen bonds, in order of increasing dynamic character. The subsequent section discusses the characteristic properties of selected examples of these rigid coplanar π systems in comparison with control compounds that are not rigid and coplanar, particularly focusing on the optical, electronic, and electrochemical properties. For systems bridged with noncovalent interactions, active manipulation of the dynamic bonds can tune variable properties at the molecular or collective level. Intermolecular interactions, solid-state packing, and processing of several cases are then discussed to lay the foundation for future materials applications of rigid coplanar π conjugated compounds.

Assembly and Chiral Memory Effects of Dynamic Macroscopic Supramolecular Helices.

Macroscopic enantiomerically pure helical supramolecular fibers are bottom-up assembled in aqueous media from a chiral π-electron donor template and an achiral π-electron acceptor. The helices can be assembled to the sub-millimeter scale with controlled handedness. These dynamic supramolecular architectures allow for a quantitative exchange of the chiral donor template with achiral analogues. During this process, a chiral memory effect was observed, affording enantiomerically pure helices composed entirely of achiral components.

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies.

BACKGROUND: There continues to be a need for new therapies to treat ALS. OBJECTIVE: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. METHODS: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. RESULTS: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at ≥2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. CONCLUSION: Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.

Extended Ladder-Type Benzo[k]tetraphene-Derived Oligomers.

Well-defined, fused-ring aromatic oligomers represent promising candidates for the fundamental understanding and application of advanced carbon-rich materials, though bottom-up synthesis and structure-property correlation of these compounds remain challenging. In this work, an efficient synthetic route was employed to construct extended benzo[k]tetraphene-derived oligomers with up to 13 fused rings. The molecular and electronic structures of these compounds were clearly elucidated. Precise correlation of molecular sizes and crystallization dynamics was established, thus demonstrating the pivotal balance between intermolecular interaction and molecular mobility for optimized processing of highly ordered solids of these extended conjugated molecules.

Fully conjugated ladder polymers.

Fully conjugated ladder polymers (cLPs), in which all the backbone units on the polymer main-chain are π-conjugated and fused, have attracted great interest owing to their intriguing properties, remarkable chemical and thermal stability, and potential suitability as functional organic materials. The synthesis of cLPs can be, in general, achieved by two main strategies: single-step ladderization and post-polymerization ladderization. Although a variety of synthetic methods have been developed, the chemistry of cLPs must contend with structural defects and low solubility that prevents complete control over synthesis and structural characterization. Despite these challenges, cLPs have been used for a wide range of applications such as organic light emitting diodes (OLEDs) and organic field effect transistors (OFETs), paralleling developments in processing methods. In this perspective, we discuss the background of historical syntheses including the most recent synthetic approaches, challenges related to the synthesis and structural characterization of well-defined cLPs with minimum levels of structural defects, cLPs' unique properties, and wide range of applications. In addition, we propose outlooks to overcome the challenges limiting the synthesis, analysis, and processing of cLPs in order to fully unlock the potential of this intriguing class of organic materials.