First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica

Abstract

Objective: To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica.

Methods: This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28.

Results: Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase.

Conclusions: These data support the development of BG00010 for the treatment of neuropathic pain.

Trial registration: ClinicalTrials.gov NCT00961766.

Conflict of interest statement

Competing Interests: Gilmore O’Neill, Jitesh Rana, and Gerald Galluppi are employees of Biogen Idec Inc, Eve Versage and Yongqiang Tang were employed by Biogen Idec Inc, during the course of the study and are now employees of Novartis Vaccines and GlaxoSmithKline respectively. Ernesto Aycardi was employed by Biogen Idec Inc. during the course of the study. Eve Versage and Yongqiang Tang own shares of BIIB stock. The study was sponsored by Biogen Idec Inc. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Subject disposition. i.v., intravenous; s.c., subcutaneous.

Fig 2. Incidence and duration of temperature perception, pruritus and rash AEs.

Subjects were treated as follows: intravenous BG00010 (a) 50 μg/kg, (b) 100 μg/kg, (c) 200 μg/kg, (d) 400 μg/kg, (e) 800 μg/kg, or (f) placebo. AE, adverse event.

Fig 3. Pain outcomes over time.

Mean (standard deviation) scores on the Likert numerical pain scale over (a) 56 days and (b) 7 days (expanded time axis), and (c) mean (standard deviation) scores on the 100 mm VAS of the Short-Form McGill Pain Questionnaire over 56 days, following i.v. or s.c. administration of BG00010 or placebo. Note that Likert data were missing at day 21 for one placebo-treated subject, and both Likert and McGill data were missing at day 56 for six placebo-treated subjects and all subjects treated with BG00010 0.3, 1, 3, 10, 25 or 50 μg/kg. i.v., intravenous; s.c., subcutaneous; VAS, visual analog scale.

Fig 4. Change in IEFND between baseline and day 28.

Data points indicate data for individual subjects following intravenous administration of BG00010 or placebo; lines indicate mean and range. IEFND, intra-epidermal nerve fiber density.

Fig 5. BG00010 serum concentrations over time.

Mean (standard deviation) BG00010 serum concentrations over (a) 120 h and (b) 15 h (expanded time axis) following i.v. administration of BG00010. Note that data were only available for two subjects treated with BG00010 25 μg/kg at 9, 12, 18 and 48 h. Where data points are not shown, the mean BG00010 serum concentration was equal to 0.00 ng/ml. h, hours; i.v., intravenous.