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

Abstract

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.

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

“…The striking beneficial effects of GBZ in VWM mice have led to the first clinical trial in VWM (https://www.trialregister.nl/trial/7260 and https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL). Translating GBZ treatment into clinical studies comes with concerns regarding α2‐adrenergic side effects, 59 although rapid habituation is also seen in clinic 60 and dose levels with similar exposure as used in the current study have proven safe in adults. Our study makes clear that S1 is not simply a GBZ replacement without α2‐adrenergic effects for the treatment of VWM.…”

The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

“…In a recent clinical trial in which sporadic patients were treated with guanabenz to evaluate safety and efficacy, there was a surprising result that showed that patients with bulbar onset did not progress to a higher stage during the course of the study [ 151 ]. However, some patients drop the treatment due to secondary effects of Guanabenz [ 151 ]. Nevertheless, some of these drugs have secondary effects in other tissues.…”

“…GSK2606414 showed some weight loss and mild hyperglycemia in a mouse prion model [ 152 , 153 ] whereas, in ALS patients, guanabenz showed adverse effects such as hypotension, fatigue, and drowsiness that could be related with its alpha-2 adrenergic receptor activity. However, no serious adverse events were observed with respect to the placebo group [ 151 ]. For those reasons, clinical trials have evaluated the safety, availability, and tolerability of ISR modulation with sephin1 (IFB-088, that lacks the alpha-2 adrenergic receptor activity and blood pressure lowering adverse effects have not been observed [ 154 ]) instead of with guanabenz.…”

Creation and Research of Cell Models of Hereditary Neurodegenerative Diseases Using Directed Genome Editing

“…The next, no less important point is the phenomenon of endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded, defective proteins in the ER lumen [43]. This pathophysiological process is typical of most neurodegenerative diseases and may be a therapeutic target [44][45][46][47][48][49]. For the formation of the tertiary structure of a protein, disulfide bonds are important, the formation of which is mediated by the enzyme protein disulfide isomerase, which, in turn, is activated by oxidation.…”