Boosting Cell Stress Response May Be Promising Therapy Approach

A combination of guanabenz — an approved therapy for high blood pressure — plus riluzole slowed disease progression in adults with early amyotrophic lateral sclerosis (ALS), particularly those with bulbar onset disease, a form of ALS, according to data from a Phase 2 clinical trial.

Despite these promising benefits, the highest doses of guanabenz were associated with significantly greater adverse events and drop-out rates, preventing its further clinical development in ALS, the researchers noted.

Still, as the therapy’s benefits are believed to be linked to the boosting of the unfolded protein response (UPR), a cellular stress-response mechanism thought to be associated with ALS, the findings support future clinical evaluation of safer UPR-targeting molecules.

One such molecule, IFB-088, being developed by InFlectis BioScience, showed a favorable safety profile in a previous Phase 1 trial (NCT03610334), and will be tested in ALS patients in an upcoming Phase 2 trial.

“These are early yet encouraging results that demonstrate clinical proof-of-concept for [UPR] modulators,” Philippe Guédat, PhD, InFlectis’ chairman and CEO, said in a press release.

“Based on this data, outcomes from our Phase 1 safety study, and the body of results from our preclinical studies, we are planning a prospective, controlled Phase 2 trial in ALS with IFB-088,” Guédat said.

The upcoming trial will involve the IRCCS Istituto Neurologico Carlo Besta, in Milan, Italy, whose researchers led the Phase 1 study.

“We look forward to participating at a trial center in InFlectis’ planned Phase 2 study of IFB-088,” said Giuseppe Lauria, MD, the study’s senior author and the head of the department of clinical neuroscience at the IRCCS.

The Phase 1 study findings were reported in “The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial,” published in the journal Brain.

Maintenance of protein balance — including the production, shaping (folding), and degradation of proteins — is essential for a cell’s function and survival. The endoplasmic reticulum (ER) is a key cellular structure for these events.

Excessive amounts of unfolded or misfolded proteins in the ER results in ER stress and in the activation of UPR, which aids in mitigating damage associated with such protein buildup. It works by promoting the reduction of protein production, and an increase in protein folding and degradation of unfolded proteins in the ER.

If this fails to restore protein and cellular balance and UPR activation is prolonged, cell death is induced.

Notably, protein unbalance, UPR impairment, and prolonged ER stress have been associated with the accumulation of toxic protein aggregates, or clumps, and the development of neurodegenerative diseases, such as ALS.

Therefore, therapeutic approaches targeting ER stress or UPR activation are thought to have the potential to slow ALS progression.

Originally sold under the brand name Wytensin (now discontinued), guanabenz was approved in the U.S. as an oral treatment for high blood pressure. Notably, it was previously shown to reduce motor neuron loss, and improve motor function and survival in a mouse model of ALS. It achieved success in mice by promoting UPR and thereby reducing ER stress.

The multicenter, Phase 2 trial evaluated the safety and effectiveness of guanabenz, in combination with riluzole (sold as Rilutek, Tiglutik, or Exservan), in 200 adults with early ALS. The patients’ symptoms had started in the prior 1.5 years.

Participants were randomly assigned to receive either guanabenz in one of three doses — 16 mg, 32 mg, or 64 mg — or a placebo, twice a day, in addition to riluzole, for six months.

The placebo group was included only for the purpose of safety analysis. Efficacy analyses compared data from the guanabenz groups with those of an external historical group of 200 ALS patients treated with riluzole only.

The results showed that the higher doses of guanabenz (32 and 64 mg) reduced the proportion of patients progressing to a higher disease stage by more than 35% relative to riluzole in the historical group, meeting the trial’s main goal. Disease progress was assessed with the ALS Milano-Torino staging system.

In addition, patients treated with these two doses had a significantly slower functional decline, as measured through the ALS Functional Rating Scale-Revised, than those given 16 mg of guanabenz or a placebo, or those in the historical group.

Notably, these benefits were particularly observed in participants with bulbar onset ALS, which first affects muscles involved in speaking, swallowing, and breathing.

Bulbar onset patients receiving the highest doses of guanabenz showed the slowest rate of functional decline and none progressed to a higher disease stage. Those results compared with 50% of patients on low-dose guanabenz, 42% of those given a placebo, and 43% in the historical group.

However, the proportion of patients who experienced at least one adverse event was higher in any guanabenz group than in the placebo group, with the higher doses being associated with a significantly greater rate of treatment-related adverse events and the 64 mg dose with a significantly higher drop-out rate.

Particularly, a total of 30% of patients in the 64 mg and 32 mg groups withdrew from the trial, compared with 6% in the placebo group.

The number of serious adverse events did not significantly differ between groups.

Adverse events experienced by guanabenz-treated patients, such as low blood pressure, fatigue, and drowsiness, were consistent with those commonly reported with high doses of guanabenz and its main activity on alpha-2 adrenergic receptor, a protein involved in blood pressure regulation.

“In summary, there is strong evidence to suggest that ER stress may play a critical role in the [development] of ALS through an altered regulation of [protein balance] and that molecules acting on the functional control of the UPR pathway may be of benefit in slowing the progression of the disease,” the researchers wrote.

“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,” the team concluded.