Preliminary safety evaluation in study BIA-102474-101

H. Gama1, M. Vieira1, J. Graça1, D. Chassard2, J. Massano3, H. Charfi2, A. Patat2, A. Santos1, F. Rocha1, P. Soares-da-Silva1,4. 1Dept. Research & Development, BIAL – Portela & Cª, S.A., 4745-457 Coronado (S. Romão e S. Mamede), PORTUGAL, 2Biotrial, Rennes, FRANCE, 3Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University Porto, Porto, PORTUGAL, 4Dept. Pharmacology & Therapeutics, Faculty of Medicine, University Porto, Porto, PORTUGAL.

Background and Aims:

This study evaluated the safety information in healthy subjects enrolled in study BIA 10-2472-101: a double blind, randomised, placebo-controlled single (SAD) and multiple (MAD) ascending dose or open-label food effect (FI) trial with BIA 10-2474 (3-(1-(cyclohexyl (methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide).

Summary of work and outcomes:

A total of 116 healthy volunteers, 69 male and 47 female, aged 19 to 53 years, were randomized to SAD, FI and MAD parts. Ninety subjects received at least one dose of BIA 10-2474 and 26 placebo. In each SAD cohort (0.25 to 100 mg), 6 subjects received verum and 2 placebo. In FI part, 12 subjects received a single dose (40 mg) in both fasting and fed state. In each MAD cohort (2.5 to 50 mg), 6 subjects received 10 once-daily administrations of a single dose of BIA 10-2474 or placebo (6 verum and 2 placebos), except in last group, due to its early termination. Up to 20 mg MAD part, 20 subjects reported at least one treatment emergent adverse event (TEAE): 15 (17.9%) on verum vs. 5 (20.8%) on placebo. Most frequent AE were orthostatic hypotension and headache (each n=3, verum). No other AE occurred in more than 2 subjects. No serious AE was recorded during the course of study; no withdrawal due to TEAE did occur. Central nervous system (CNS) disorders included dizziness (1), dizziness postural (2), sciatica (1), headache (3), and vision blurred (2), all mild in intensity and transient, with no dose relationship. During the 50 mg MAD part, 5 out of 6 subjects exposed to BIA 10-2474 reported unexpected CNS SAEs, for which causality cannot be excluded. One subject showed serious and sudden deterioration of clinical status with fatal outcome. No formal MRI diagnostic and autopsy report is currently available. One subject in verum and 2 in placebo remained asymptomatic. All 84 subjects previously treated with BIA 10-2474 were re-evaluated and no neurological symptoms or MRI abnormalities were observed, except one case of vascular cerebellar lesion with unknown exact date of occurrence.

Discussion: Tolerability was favourable in 84 subjects exposed to BIA 10-2474 up to 100 mg single dose or 20 mg for 10 days. The occurrence of several CNS SAEs, one with fatal outcome, in the 50 mg MAD led to study termination.

Conclusions: The available data does not allow discerning about specific reasons that could have caused the SAEs, which were considered unexpected and unpredictable.