Arimoclomol Fails to Show Efficacy in Phase 3 Trial, Topline Data Show

A Phase 3 clinical trial evaluating Orphazyme’s investigational oral therapy arimoclomol for amyotrophic lateral sclerosis (ALS) has failed to meet its primary and key secondary goals.

While no safety issues were reported in the trial (NCT03491462), arimoclomol did not significantly extend patients’ lives nor delay the progression of disability among people with the disease. Topline data will be presented this week at the European Network to Cure ALS (ENCALS) meeting, to be held virtually May 12-14.

“We are disheartened by these results, as we had hoped arimoclomol might represent a viable new approach against the formidable challenge of this devastating disease,” Thomas Blaettler, MD, chief medical officer at Orphazyme, said in a press release.

“We express our sincere thanks to the investigators, patients and families for their participation and collaboration in our program,” Blaettler said.

The accumulation of toxic protein clumps is a key contributor to cell damage and death in people with ALS. These clumps are composed of abnormal proteins that fail to acquire their normal three-dimensional shape. Given that, therapies that help the misfolded proteins acquire their normal configuration are expected to slow ALS progression.

Arimoclomol is an oral therapy that increases the production of heat-shock proteins (HSPs), which stabilize misfolded proteins and help them acquire their normal shape. HSPs also direct the removal of the abnormal proteins when folding is not feasible.

Moreover, arimoclomol is able to cross the blood-brain barrier, a highly selective membrane that shields the central nervous system from the general blood circulation, and is often a roadblock for therapies that need to reach nerve cells in the brain.

The ORARIALS-01 Phase 3 trial (NCT03491462) is investigating arimoclomol in 245 adults with ALS who experienced their first sign of weakness — defined as limb weakness, swallowing/speech problems, or shortness of breath — within 18 months of enrollment.

Recruited at 29 centers across North America and Europe, participants were randomly assigned to receive either arimoclomol or a placebo, once daily for 76 weeks (about 1.5 years).

The trial’s main goal was to determine arimoclomol’s effectiveness via a combined assessment of function and survival. However, that goal was not met.

Secondary measures, also not met, included changes in lung function, changes in ability to perform daily tasks — assessed with the ALS Functional Rating Scale (ALSFRS-R) — and the time until permanent assisted ventilation.

“With over 18 months of evaluation, this trial represents one of the longest running clinical studies in this category. While unsuccessful, the data generated will contribute meaningfully to the scientific dialogue on this challenging disease,” Blaettler said.

“We will apply the invaluable insights from this and other studies to further our pipeline as we continue to pursue the full potential of the heat shock protein response,” he added.

Arimoclomol also is being investigated for the treatment of the genetic obesity disorder Niemann-Pick disease Type C, and for the metabolic condition Gaucher disease. The therapy also is being evaluated for an autoimmune disease called sporadic inclusion body myositis.

Applications seeking the therapy’s approval for Niemann-Pick disease Type C are being reviewed by both the the U.S. Food and Drug Administration and the European Medicines Agency.