Arimoclomol for amyotrophic lateral sclerosis

Last updated Aug. 1, 2023, by Teresa Carvalho, MS
Fact-checked by Inês Martins, PhD

What is arimoclomol for ALS?

Arimoclomol is an oral therapy that has been tested in clinical trials for the treatment of amyotrophic lateral sclerosis (ALS), but its development has been discontinued for this indication.

The therapy received fast track designation in the U.S., as well as orphan drug status in both the U.S. and European Union, given to aid and accelerate its development and review for ALS.

However, Orphazyme, the company developing this medication, discontinued its ALS clinical program following unsatisfactory results in a Phase 3 trial. The rights to arimoclomol have since been acquired by Zevra Therapeutics, which is developing it to possibly treat Niemann-Pick type C disease, a rare genetic condition.

Therapy Snapshot

How does arimoclomol work in ALS?

ALS is a neurodegenerative disease characterized by the death of motor neurons, the nerve cells that control voluntary muscle movements, leading to the progressive loss of muscle control.

The exact mechanisms leading to nerve cell loss in ALS are not fully understood, but the accumulation of toxic protein clumps is known to be a key contributor to neuronal damage.

These clumps may occur due to genetic mutations, such as those in the SOD1 gene that result in the accumulation of an abnormal SOD1 protein. But they also can develop without any association to specific mutations. For example, while mutations in the gene that codes for the TDP-43 protein affect only a small percentage of patients, TDP-43 protein aggregates are found in about 97% of all ALS patients.

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

The therapy can cross the blood-brain barrier — a semipermeable membrane that controls which substances reach the brain and spinal cord — and was designed to be able to correct misfolded proteins and prevent the formation of toxic protein clumps in nerve cells.

One of the HSPs whose production increased with arimoclomol treatment was able to bind and correct the faulty SOD1 protein found in some patients. The therapy also reduced the amount of TDP-43 clumps.

How was arimoclomol administered in ALS?

Arimoclomol has been tested in ALS in the form of oral capsules, taken orally three times daily. Clinical trials have evaluated daily doses ranging from 75 mg to 600 mg.

Arimoclomol in ALS clinical trials

After showing the ability to slow disease progression and extend survival in a mouse model of SOD1-ALS, arimoclomol was tested in a Phase 2 clinical trial (NCT00244244) involving 84 patients with familial disease or sporadic ALS.

Phase 2 trial

The Phase 2 clinical trial tested multiple doses of arimoclomol (25 mg, 50 mg, and 100 mg) versus a placebo, administered orally three times a day for 12 weeks. Participants then could join an open-label extension, in which all were treated at the 100 mg dose three times daily for six months.

Arimoclomol was deemed safe and well tolerated at all doses tested, with no particular side effect being more common with the active treatment than with a placebo. A preliminary efficacy analysis also showed patients initially given arimoclomol in the main trial progressed at a significantly slower rate than those who first received a placebo and started on arimoclomol only in the study’s extension.

Phase 2/3 trial

Arimoclomol next was tested in a Phase 2/3 clinical trial (NCT00706147), whose 36 patients with familial ALS carried SOD1 mutations linked with rapid disease progression. Participants were randomly assigned to receive a 200 mg dose of arimoclomol or a placebo, three times a day for up to one year.

Its main goal was to measure changes in the rate of disease progression, as assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). Secondary measures included lung function decline and the time to death or to needing ventilatory support in the form of permanent assisted ventilation or a tracheostomy.

Trial results overall favored arimoclomol. Compared with patients given a placebo, those on arimoclomol experienced a slower decline on their ALSFRS-R scores (3 vs. 2.5 points per month), lived 33% longer without requiring permanent ventilatory support, and had a slower rate of lung function decline. However, the differences between arimoclomol and a placebo failed to reach statistical significance across all measures.

Phase 3 trial

To confirm these findings in a larger population, Orphazyme launched a Phase 3 clinical trial, called ORARIALS-01 (NCT03491462), enrolling 245 patients with ALS in the U.S., Canada, and Europe.

Participants whose symptoms had started within the last 18 months were randomly assigned to receive arimoclomol at 248 mg three times daily or a placebo for up to 76 weeks (about 1.5 years).

The trial’s main goal was changes in a combined assessment of function and survival, a measure that considers survival, the need for ventilatory support, and disease progression on the ALSFRS-R scale. Secondary measures included lung function decline, disease progression, and the time to needing permanent assisted ventilation or a tracheostomy, or death.

While full data has not been disclosed, the trial failed at its primary and secondary goals, implying that arimoclomol does not slow disease progression or extend survival in people with ALS.

Common side effects of arimoclomol

Arimoclomol, overall, was well tolerated in ALS patients, and no specific adverse event were more commonly reported with the active drug than with a placebo. Still, the most common side effects reported in ALS patients given arimoclomol in ALS clinical trials were:

• skin rash
• increases in creatinine, indicating kidney problems
• pulmonary embolism, or blood clots in the lungs
• dry mouth
• insomnia
• swelling in the arms and legs.

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