A controlled trial of recombinant methionyl human BDNF in ALS

Objective: To replicate the beneficial effect of brain-derived neurotrophic factor (BDNF) in 1,135 ALS patients in a multicenter trial.

Background: In a phase I through II study, BDNF appeared to increase survival and retard loss of pulmonary function in ALS patients.

Methods: Patients were randomized to placebo, or 25 or 100 μg/kg BDNF for 9 months.

Results: The study failed to show benefit of BDNF treatment for the primary end points. Survival in patients treated with 25 μg/kg BDNF was identical to placebo, but there was a trend toward increased survival in the 100-μg/kg group. As a whole, survival was better than anticipated when planning the study. The 9-month probability of survival was approximately 85% across all groups. This diminished the power of the study. Among the 60% of patients with baseline forced vital capacity of ≤91%, survival was significantly greater for 100 μg/kg BDNF versus placebo. For the 20% of patients treated with 100 μg/kg BDNF reporting altered bowel function as an adverse effect of BDNF in the first 2 weeks of dosing, defined as BDNF “responders,” 9-month survival was significantly better than for placebo (97.5% versus 85%).

Conclusions: Although the primary end point analysis failed to demonstrate a statistically significant survival effect of BDNF in ALS, post hoc analyses showed that those ALS patients with early respiratory impairment and those developing altered bowel function showed statistically significant benefit. Further clinical trials of BDNF using either intrathecal delivery or high-dose subcutaneous administration are in progress.