The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial

Strong evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits ER stress-induced eIF2α-phosphatase allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. Its efficacy and safety in ALS patients are unknown. To address these issues, we conducted a multicentre, randomised, double-blind trial, with futility design. ALS patients with onset of symptoms within the previous 18 months were randomly assigned to receive in a 1:1:1:1 ratio guanabenz 64 mg, 32 mg, 16 mg or placebo daily for 6 months as add-on therapy to riluzole. The purpose of the placebo group blinding was safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease in 6 months as measured by the ALS Milano-Torino staging compared to a historical cohort of 200 ALS patients. The secondary outcomes were the rate of decline in ALSFRS-R total score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary analysis of efficacy was performed by intention-to-treat. Guanabenz 64 mg and 32 mg arms, both alone and combined, reached the primary hypothesis of non-futility with proportions of patients who progressed to higher stage of disease at 6 months significantly lower than that expected under the hypothesis of non-futility and significantly lower difference in the median rate of change of the ALSFRS-R total score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those in guanabenz 16 mg (4/8; 50%), historical cohort alone (21/49; 43%; p = 0.001) or plus placebo (25/60; 42%; p = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having significantly higher proportion of drug-related side effects and the 64 mg arm significantly higher drop-out rate. The number of serious adverse events did not significantly differ between guanabenz arms and placebo. Our findings indicate that a larger trial with a molecule targeting the UPR pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.