Emmanuelle Abgueguen (France)
InFlectis BioScience NeuroscienceAuthor Of 1 Presentation
THE UNFOLDED PROTEIN RESPONSE IN AMYOTROPHIC LATER SCLEROSIS: RESULTS OF A PHASE 2 TRIAL
- Giuseppe Lauria (Italy)
Abstract
Background and Aims:
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 ALS models.
Methods:
In this multicentre RCT with futility design, ALS patients with onset <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. Primary outcome was the proportion of patients progressing to higher stages of disease measured by ALS-MITOs compared to a historical cohort of 200 patients. Secondary outcomes were rate of decline in ALSFRS-R, sVC change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level. Primary analysis of efficacy was by intention-to-treat.
Results:
Guanabenz 64/32 mg arms reached the primary hypothesis of non-futility with proportions of patients progressing to higher stage of disease significantly lower than that expected 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 higher stage of disease 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 experiencing at least one adverse event was higher in any guanabenz than placebo arm, with higher dosing having significantly higher proportion of side effects and drop-out rate.
Conclusions:
A larger trial with a molecule targeting the UPR pathway without alpha-2 adrenergic related side-effect profile is warranted.