By Dr Isabella Colonna
For January we have selected Dalla Bella E., et al The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial. Brain 2021 Sep doi:10.1093/brain/awab167
Our research paper of the month is a multicentre, randomised and double-blind phase 2 study with a futility design, exploring the efficacy and the safety of guanabenz in patients with probable or definite amyotrophic lateral sclerosis (ALS).
Guanabenz is an FDA-approved alpha-2 adrenergic receptor agonist which, according to preclinical studies, may selectively inhibit endoplasmic reticulum stress-induced eIF2α-phosphatase, preventing misfolded protein accumulation, and may reduce neuronal death, delay disease onset and prolong survival, as has been shown in in vitro and in vivo ALS models.
After screening for eligibility, 200 patients were enrolled in this trial. Study participants were randomised with 1:1:1:1 allocation to the four treatment arms: (i) guanabenz 16 mg plus riluzole 100 mg, (ii) guanabenz 32 mg plus riluzole 100 mg, (iii) guanabenz 64 mg plus riluzole 100 mg, (iiii) placebo plus riluzole 100 mg. The placebo group was included in order to assess safety and tolerability only, while the treatment arms were compared to a historical cohort of 200 patients, treated with riluzole 100 mg only.
The primary end point was the proportion of patients who worsened at six months after the start of full allocation dose, as assessed by the ALS Milano-Torino (MITOS) system. The null hypothesis was that guanabenz reduced the number of patients progressing to higher stage of disease at six months by 35%, compared to the historical cohort. If the null hypothesis was rejected, this would indicate that guanabenz was not sufficiently promising for a phase 3 randomised controlled trial. Secondary end points were the rate of decline in the total ALSFR-R score, the change in slow vital capacity, the time to death, tracheostomy or permanent ventilation, the serum light neurofilament level and the number of withdrawals due to adverse events.
The groups of patients who received guanabenz 64 mg and 32 mg reached the primary hypothesis of non-futility. All patients with bulbar onset enrolled in this trial were at stage 0 of disease at the baseline and none of them in the arms treated with guanabenz 64 mg and 32 mg worsened after six months of follow-up, while 50% of those in the guanabenz 16 mg arm, 43% in the historical cohort and 36% on the placebo did. No statistically significant differences were seen for patients with spinal onset among the groups.
With regard to safety and tolerability, the number of patients who experienced at least one adverse event was greater in the guanabenz arms than in the placebo group, showing a greater proportion of withdrawals among the patients treated with guanabenz 64 mg and 32 mg; however, the number of serious adverse events did not statistically differ significantly between groups.
The authors conclude that ALS patients with bulbar onset who received guanabenz 16 mg and 32 mg showed a slower disease progression than the other groups, suggesting that endoplasmic reticulum stress may play an important role in the ALS pathogenesis. Thus, the findings of this work point out that a phase 3 trial, using a molecule which targets the unfolded protein response pathway and does not cause the alpha-2 adrenergic related side-effects of guanabenz, is warranted.