First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat

Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. EUDRACT No. 2015-003721-33, filed 30 October 2015. The online version contains supplementary material available at 10.1007/s40263-021-00797-x

Salvatore Di Giacomo, La fiera commedia lirica in 3 atti musica di Nicola D'Arienzo

Edition of Salvatore Di Giacomo's La fiera, music by Nicola D'Arienz

Francesco Florimo e l'Ottocento musicale, Atti del Convegno (Morcone, 19-21 aprile 1990

Conference proceedings: Francesco Florimo e l\u2019Ottocento musicale, Morcone, 19-21 aprile 199

«Io conosco un dilettante il quale è pazzo per te». Giuseppe Sigismondo e la collezione di musiche di Niccolò Jommelli

Il saggio mette a fuoco la collaborazione fra Giuseppe Sigismondo e Niccolò Jommelli e la creazione della collezione musicale di Sigismondo, primo bibliotecario (dal 1794) del Conservatorio di Santa Maria della Pietà dei Turchini a Napoli

"Io conosco un dilettante il quale è pazzo per te": Giuseppe Sigismondo e la collezione di musiche di Niccolò Jommeli

Il saggio mette a fuoco la collaborazione fra Giuseppe Sigismondo e Niccolò Jommelli e la creazione della collezione musicale di Sigismondo, primo bibliotecario (dal 1794) del Conservatorio di Santa Maria della Pietà dei Turchini a Napoli

Un capitolo di storia dell\u2019editoria musicale fra Milano e Napoli: lo Stabilimento musicale Clausetti (1847\u20131864)

The paper focuses on the music publishing firm Clausetti from 1847 to 1864, when its catalogue beacame part of the wider Ricordi productio

\uabVi prego di rimandarmi la Biografia della Calata del Gigante, che tenni altra volta, per riscontrare alcune cose del Jommelli, e del Piccinni\ubb: l\u2019Apoteosi della musica nello scriptorium di Giuseppe Sigismondo

Il saggio inquadra il ruolo di Giuseppe Sigismondo come collezionista, musicista, intellettuale

Sigismondo, Giuseppe

Voce biografica

La trattatistica musicale

The paper focuses on the tradition of harmony and counterpoint teaching in Naples in the 18th century