Researchers from the Marcia Dunn and Jonathan Sobel Department of Neurology at Hospital for Special Surgery (HSS) in New York City have announced the opening of recruitment for a phase 3 international multicenter clinical trial aimed to see if an experimental drug can slow or stop the progression of progressive weakness experienced by patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

The drug, arimoclomol, is made by Orphazyme, a Danish biotechnology company that focuses on developing drugs for rare disorders. Orphazyme purchased the rights to arimoclomol (then BRX-220) from CytRx Corp., of Los Angeles, in 2011.

An estimated 30,000 people in the United States are living with ALS, which has a five-year survival rate of only 20 percent. The cause of the disease is largely unknown except for those with the inherited form (10% of all patients with ALS). However, the signature finding in all patients that leads to cell death is the progressive accumulation of large misfolded proteins that form aggregates in affected cells, said Dale J. Lange, MD, Chairman of Neurology at HSS, Professor of Neurology at Weill Cornell Medicine and Director of the ALSA and MDA sponsored clinics devoted to the care of patients with ALS and other neuromuscular diseases.

"Once the diagnosis is made, the progression is relentless," said Dr. Lange, who is leading the new trial. "It varies in terms of speed but progression is the defining feature of the illness. But the clinical syndrome of ALS is pretty much the same across all causes. If we can impact disease progression in one form we should be able to extrapolate our findings to the others."

In earlier research, arimoclomol appeared to be better than placebo at reducing progression of in a very rapidly progressive form of ALS caused by a mutation in the SOD1 gene. Those results and phase I and basic science models prompted the new phase 3 trial, which, if successful, will form the basis of a drug application to the U.S. Food and Drug Administration, Dr. Lange said.

Although the exact mechanism of action of arimoclomol is not fully understood, it is known to enhance the action of heat shock proteins. These substances—also called "molecular chaperones"—act as quality control agents in cells by repairing damage to other proteins from excessive heat, radiation, malnutrition and other stressors. Problems with heat shock proteins have been implicated in a variety of neurologic disorders, including ALS and Parkinson’s, as well as cardiovascular disease and even autoimmune conditions.

Heat-shock proteins play a dual role. They repair and refold proteins that are damaged or misfolded, and, if that doesn’t work, they help cells break down and eliminate the errant molecules.

But cells in patients with ALS are unable to rid themselves of protein debris. "The thought is that the aggregates result from the inability of the cell to clear them, and that their presence results in disruption of cell function and ultimately cell death," Dr. Lange said.

In theory, drugs like arimoclomol that can stimulate the housekeeping function of cells could slow or stop the degenerative course of ALS even if they do not cure the disease.

"This trial is particularly exciting because arimoclomal is a targeted treatment against intracellular aggregates that are strongly implicated in being a cause of ALS. We think that across all forms of ALS, if we can cause the proteins to be better handled, especially early in the course of the disease, then the therapeutic effect should be seen in all patients regardless of the triggering factor," Dr. Lange said.

For the new trial, Dr. Lange and his colleagues will be administering arimoclomol to women and men with newly-diagnosed ALS. "The goal is to begin treatment early in the disease (less than 18 months after the first appearance of weakness) when there is little or no disease burden and stop it. That would be ideal. If we could slow it down, that would be great, too,” he said. “But the primary objective is to show that people using this medication relative to placebo have a significantly lower accumulating disease burden and a slower rate of progression over time."

To qualify for the trial, patients must have been diagnosed with ALS within the past 18 months. The 18-month study is relatively long, Dr. Lange added, "because we think there may be an additive effect over time. Data suggests that the longer you take it, the greater the impact it will have on disease progression."

Interim results from the study are expected in H2 2020 and full analysis in H1 2021. Interested patients should contact Dr. Lange’s office and research staff at (646) 797-8917.