Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects.

PURPOSE/BACKGROUND: Daridorexant is a dual orexin receptor antagonist in development for the treatment of sleep disorders. Thus far, it has not yet been studied in Japanese subjects. Study objectives were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of single- and multiple-dose administration of daridorexant in healthy Caucasian and Japanese subjects. METHODS/PROCEDURES: This was a double-blind, placebo-controlled, randomized study. Subjects received once-daily doses of daridorexant (25 or 50 mg) or placebo for 5 days. Pharmacokinetics and safety were investigated using standard assessments. To assess PD effects, a battery of tests (saccadic peak velocity, body sway, adaptive tracking performance, and visual analog scales for alertness, mood, and calmness), known to be sensitive to sleep-promoting drugs was used. FINDINGS/RESULTS: On day 1, PK variables were similar between Caucasian and Japanese subjects. On day 5, slight accumulation occurred in Japanese but not in Caucasian subjects, resulting in a higher maximum concentration (1403 vs 1006 ng/mL) and area under the curve (8256 vs 6306 ng·h/mL) at a dose of 50 mg, whereas values for time to maximum concentration and half-life were similar. Daridorexant dose-dependently reduced vigilance, attention, visuomotor coordination, and postural stability. Pharmacokinetic effects were detectable within 1 hour after drug administration and returned to baseline 4 to 8 hours postdose. Overall, Japanese showed slightly larger PD effects and reported more adverse events than Caucasians. The most frequently reported were somnolence, fatigue, and headache. Changes in other safety assessments were unremarkable. IMPLICATIONS/CONCLUSIONS: The PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin.RESULTSGene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected.CONCLUSIONTo our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation.TRIAL REGISTRATIONClincalTrials.gov NCT02493816.FUNDINGCure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, and Fondation René Touraine Short-Exchange Award.