Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.
Br J Clin Pharmacol
; 87(12): 4658-4669, 2021 12.
Article
em En
| MEDLINE
| ID: mdl-33931884
ABSTRACT
AIMS:
Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).METHODS:
This study included Part A 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27total HSP27, were assessed in muscle and sorbitol-stimulated blood.RESULTS:
PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited.CONCLUSION:
Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. CLINICAL TRIAL REGISTRATION Clinical trial identifier ToetsingOnline NL68539.056.18 Nederlands Trials Register NL8000.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Distrofia Muscular Facioescapuloumeral
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Ciclopropanos
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article