New Research Suggests FDA-Approved Anti-Inflammatory Might Help Slow ALS

Earlier this week, the U.S. Food and Drug Administration (FDA) approved Aquestive Therapeutics’ Exservan for amyotrophic lateral sclerosis (ALS). Today, new research was published in Scientific Reports, showing that cromolyn sodium, an anti-inflammatory, delayed the onset of ALS in a mouse model.

ALS, sometimes known as Lou Gehrig’s disease, is a progressive neurodegenerative illness that affects nerve cells in the brain and spinal cord. The degeneration of the motor neurons eventually kills them. When motor neurons die, the brain can’t initiate and control muscle movement.

The new research was conducted by investigators at the Massachusetts General Hospital (MGH) and led by Ghazaleh Sadri-Vakili, director of the NeuroEpigenetics Laboratory at the Sean M. Healey & AMG Center for ALS and the MassGeneral Institute for Neurodegenerative Diseases. They injected cromolyn sodium into mice who had a genetic mutation that results in ALS. Cromolyn sodium is an anti-inflammatory used to treat mastocytosis.

Sadri-Vakili and his team found that the treatment delayed the development of ALS symptoms in the mice with the ALS mutations. Further analysis showed that it protected neurons from degeneration and assisted in keeping the connections between nerves and muscles. It also decreased inflammation surrounding muscles by targeting mast cells, specific types of immune cells. It also decreased pro-inflammatory markers in the spinal cord and blood.

“Our study supports the notion that inflammation has a significant role in the progression of ALS and therefore exploring anti-inflammatory treatments may be of great value for developing an effective treatment,” Sadri-Vakili said. “Our findings demonstrate that cromolyn treatment provides neuroprotection in a mouse model of ALS.”

He went on to say, “It remains to be seen whether these effects will translate to people living with the disease. Therefore, we will continue to explore inflammation’s role in disease development and progression in hopes of translating this research into potential ALS treatments.”

Aquestive’s Exservan is a riluzole oral film (ROF). It is a new formulation of riluzole, which is an adjunctive treatment of ALS. Riluzole is sold under the brand name Rilutek and was the first ALS therapy approved by the FDA in 1995. Rilutek is sold in the U.S. by Covis Pharma and Sanofi holds the rights outside the U.S.

In clinical studies, Aquestive’s Exservan demonstrated pharmacokinetic bioequivalence to Rilutek.

In 2018, Mitsubishi Tanabe and its new subsidiary, MT Pharma America, received approval for Radicava, the first ALS drug approved in 22 years. Radicava is not a cure but slows decline of daily function of ALS patients.

In September, scientists at Oregon State University identified a key factor in why some motor neurons in the spinal cord die and others don’t. The research was published in the journal Experimental Biology and Medicine.

The research focuses on a protein called heat shock protein 90 (Hsp90). Heat shock protein 90 is especially sensitive to inhibition in motor neurons by “trophic factors,” which are small proteins that are called “helper molecules.” Trophic factors seem to have the ability to save dying neurons.

In the nervous system, neurons are cells that carry information to muscles, glands and other nervous. Motor neurons are large neurons found in the spine and brain stem. They have long axons that spread outside the nervous system in order to make contact with muscles and control their movements.

“It is well known that there are some motor neuron subpopulations resistant to degeneration in ALS, and other subpopulations that are highly susceptible to degeneration,” said Alvaro Estevez, associate professor of biochemistry and biophysics at OSU and corresponding author of the study. “Understanding the mechanisms involved in these different predispositions could provide new insight into how ALS progresses and open new alternatives for the development of novel treatments for the disease.”

In their research, Estevez and Maria Clara Franco, assistant professor of biochemistry and biophysics, found that Hsp90 repressed the activation of a key cellular receptor that was critical to neuron survival. When Hsp90 was inhibited, motor neuron death resulted.

They utilized a Hsp90 inhibitor called geldanamycin, which is an antibiotic used in chemotherapy. One of the unintended effects, this study suggests, is that decreasing motor neurons’ trophic pathways puts the nerve cells at risk.

“The inhibition of Hsp90 as a therapeutic approach may require the development of inhibitors that are more selective, so the cancer cells are targeted and healthy motor neurons are not,” said Franco.

It is possible that this research will lead to new approaches to treating ALS and similar neurodegenerative disorders.