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 randomiz ed to placebo, or 25 or 100 mu g/kg BDNF for 9 months. Results: The study f ailed to show benefit of BDMF treatment for the primary end points. Surviva l in patients treated with 25 mu g/kg BDNF was identical to placebo, but th ere was a trend toward increased survival in the 100-mu g/kg group. As a wh ole, survival was better than anticipated when planning the study. The 9-mo nth probability of survival was approximately 85% across all groups. This d iminished the power of the study. Among the 60% of patients with baseline f orced vital capacity of less than or equal to 91%, survival was significant ly greater for 100 mu g/kg BDNF versus placebo. For the 20% of patients tre ated with 100 mu g/kg BDNF reporting altered bowel function as an adverse e ffect 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 8 5%). Conclusions: Although the primary end point analysis failed to demonst rate a statistically significant survival effect of BDNF in ALS, post hoc a nalyses showed that those ALS patients with early respiratory impairment an d 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.