Background
Arimoclomol is an oral capsule drug that enhances a mechanism known as the heat shock response. When a cell of the body is exposed to stress or damage, the proteins required for the cell’s normal functions can change their shape or “fold” and either lose their ability to do their job or become toxic. Cells protect themselves from this misfolding of proteins by stimulating production of heat shock proteins (Hsps) that are designed to manage the proper protein refolding.
Misfolded and clumped proteins have long been a hallmark of ALS/MND and it is believed that these may contribute to multiple disease processes. Unlike other cells, neurons, and particularly motor neurons, have an impaired ability to produce an effective heat shock response. Therefore, drugs that can enhance the production of Hsps may have therapeutic value in ALS/MND.
Arimoclomol was first published to have an effect on elevating Hsps and delaying disease progression in an ALS/MND mouse model in 2004. In 2008, it was tested for safety, tolerability and pharmacokinetics in 84 people living with ALS/MND by the Northeast ALS Consortium (NEALS), indicating it could be dosed safely up to three times daily at 100 mg per dose and that it effectively crossed the blood-brain barrier. A follow up academic (non pharma, investigator-initiated) clinical trial led by Dr. Michael Benatar, examined arimoclomol in a double-blind, placebo-controlled study of 38 people with fast-progressing ALS caused by SOD1 mutations at 200 mg/day over 12 months. Again, arimoclomol was deemed safe and tolerable but the indication that the drug may slow down disease progression and prolong survival was not statistically significant, and conclusions could not be drawn about its efficacy in ALS/MND. Arimoclomol was considered safe and well-tolerated, with only one person stopping treatment due to skin rash.
Orphazyme was founded in Denmark in 2009 based on work demonstrating that Hsps could also correct an abnormality in a cellular structure called the lysosome, implicated in diseases called lysosomal storage diseases. In advancing arimoclomol as an Hsp-inducing drug for these diseases, the company also initiated an ALS program, using the substantial groundwork to initiate a phase 3 clinical trial.
The multicenter, randomized, double-blind, placebo-controlled study was started in 2018, enrolling 245 people living with ALS, with a 2:1 treatment to placebo ratio and studied over 76 weeks. A measure called the Combined Assessment of Function and Survival (CAFS) was used as the primary means of determining if arimoclomol is effective in ALS, while other common measures like ALSFRS-R, survival and slow vital capacity (SVC) were also evaluated. Arimoclomol is an oral capsule that was taken three times daily for the duration of the study.
Trial Design & Results
On May 7, 2021, an Orphazyme press release stated that the “pivotal trial did not meet primary and secondary endpoints evaluating impact on function and survival”. This indicates that arimoclomol will not be further pursued as a treatment for ALS/MND. In May 2024, a publication on Lancet Neurology confirmed what stated in the press release, with further data suggesting an increase of adverse reactions in the treated compared to the placebo group.
Summary
Given the available data, it is the opinion of the SAC that there is enough evidence to conclude that at the studied dosage, Arimoclomol did not show overall benefit in individuals living with ALS/MND.
International Alliance of ALS/MND Associations
October 2024
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