Arimoclomol Fails to Show Efficacy in ALS


The investigational drug, previously granted fast-track designation, did not meet primary or secondary end points in the ORARIALAS-01 trial.

Thomas Blaettler, MD, chief medical officer, Orphazyme

Thomas Blaettler, MD

Data from the ORARIALS-01 trial (NCT03491462) of arimoclomol for the treatment of amyotrophic lateral sclerosis (ALS) revealed that the Orphazyme agent did not meet its primary or secondary end points of impact on function or survival.1

“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. We express our sincere thanks to the investigators, patients and families for their participation and collaboration in our program,” said Thomas Blaettler, MD, chief medical officer, Orphazyme, in a statement.

The randomized, placebo-controlled phase 3 trial enrolled 245 patients at 29 sites in 12 countries across North America and Europe. Participants were randomized 2:1 to receive either 248 mg of arimoclomol 3 times daily and administered orally, or placebo for up to 76 weeks. The primary end point of the trial was efficacy compared to placebo as assessed by the combined assessment of function and survival (CAFS). This end point would reveal the overall treatment effect based on survival and change in ALS Functional Rating Scale-Revised (ALSFRS-R) score. Secondary end points included survival, change in ALSFRS-R, and slow vital capacity (SVC).

The trial reported no significant safety signal information. Topline data will be presented at the upcoming virtual European Network to Cure ALS (ENCALS) annual meeting, May 12-14, with final results to be published later this year.

READ MORE: The Impact of Big Data on ALS Care: Matthew B. Harms, MD

“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. 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,” Blaettler added.

The investigational drug candidate works by amplifying the production of heat shock proteins (HSPs), which can rescue defective misfolded protein, clear protein aggregates, and improve lysosome function. The treatment has been studied in 10 phase 1, 4 phase 2, and 3 pivotal phase 2/3 trials.

Arimoclomol was previously granted fast-track designation for ALS in 2020, after a phase 2/3 clinical trial (NCT00706147) demonstrated safety and well-tolerance in participants with superoxide dismutase 1 (SOD1)-related ALS. This trial enrolled 36 patients who received either arimoclomol 200 mg TID or placebo 3 times a day for up to 12 months.2,3

The data from that trial suggested efficacy of arimoclomol, as after adjusting for riluzole exposure and baseline ALSFRS-R score, survival favored arimoclomol with a hazard ratio (HR) of 0.77 (95% CI, 0.32—1.80). The researchers also found that ALSFRS-R score and predicted forced expiratory volume in 6 seconds (FEV6) declined more slowly in the arimoclomol group, with treatment differences of 0.5 points per month (95% CI, –0.63 to 1.63) and 1.24% predicted FEV6 per month (95% CI, –2.77 to 5.25), respectively. CAFS data similarly favored arimoclomol.

Despite this setback in ALS, arimoclomol remains in development for Niemann-Pick disease (NPC) and Gaucher disease, receiving orphan drug designation, fast-track designation, breakthrough therapy designation, and rare-pediatric disease designation by the FDA for NPC. The PDUFA date for NPC is June 17, 2021.

“Data from the randomized, controlled, clinical trial of arimoclomol for NPC support the positive effect of this agent in stabilizing neurologic progression of the disease, specifically in subgroups of patients over 4 years of age, and in those also taking miglustat,” said Marc Patterson, MD, professor, neurology, pediatrics, and medical genetics, Mayo Clinic Children’s Center, in an earlier statement.4 “The data show clear evidence of target engagement, specifically an elevation of Heat-Shock Protein levels, with encouraging changes in biomarkers of excess lipid storage. These data support the role of enhanced HSP 70 expression in NPC and may have applications in other lysosomal disorders.”

1. Orphazyme announces topline data from pivotal trial of arimoclomol in Amyotrophic Lateral Sclerosis (ALS). News release. Orphazyme. Published online May 7, 2021.
2. Orphazyme’s arimoclomol receives US fast track designation in Amyotrophic Lateral Sclerosis. News release. Orphazyme. Published May 22, 2020.
3. Benatar M, Wuu J, Anderson PM, et al. Randomized, double blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018 Feb 13:90(7):e565—e574. doi: 10.1212/WNL.0000000000004960
4. Orphazyme completes rolling submission of New Drug Application to U.S. FDA for arimoclomol for Niemann-Pick disease Type C. News release. Orphazyme. Published July 20, 2020.
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