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From boosting moods to mending brains

An antidepressant abandoned after Phase II trials finds new life treating neurodegenerative disease.

Health

Neurodegenerative diseases are an increasing problem in Western societies, with dementia alone affecting 10 million people in the EU. The cost of treating dementia in the EU is expected to reach over EUR 250 billion by 2030. French biotech firm SigmaThera received EU support through the NeuroPA project. They aimed to address the need for effective treatments against neurodegenerative diseases, by repurposing a drug originally trialled as a remedy for depression. If successful, SigmaThera will be able to access a market worth EUR 6.2 billion.

Early promise

Twenty-five years ago, NeuroPA project coordinator François Roman was among a team at Parke-Davis working on SIT-161, a molecule that activated a receptor in the brain known as sigma-1. This receptor is involved in a broad range of processes, including the gastrointestinal system and mood. “We investigated many areas of psychiatry, looked at anxiety and depression, and pushed this drug for treating major depression from 1997 to 2000,” he says. More than 1 000 people received the drug across nine studies in the EU and United States. The drug was well tolerated, but when Parke-Davis was acquired by Pfizer in 2000, resources were directed toward other diseases and the compound was shelved. Sixteen years later, promising results from new in vitro studies of SIT-161 against Parkinson’s and amyotrophic lateral sclerosis (ALS) have led Roman to spin out a new company. SigmaThera aims to develop the compound for use in neurodegenerative disorders.

New paradigm

This is no easy task: more than 1 000 treatments have been trialled for Alzheimer’s with no success. “In drug discovery, generally people look at one target, and then screen compounds that might interact with it, to find one novel drug,” explains Roman. “But Alzheimer’s has a very complicated pathology with many facets and the idea that attacking one of these multiple targets will be a solution is quite naïve.” SigmaThera is challenging this paradigm by developing a drug that is a potent moderator of central nervous system function as a whole. The drug can increase antioxidant activity and activate various systems of neuroprotection facilitating neuron survival. “Activation of this receptor also produces a chaperone effect,” notes Roman. “This attenuates the accumulation of misfolded proteins, a characteristic that is common across neurodegenerative disorders.” EU support through the Horizon 2020 programme allowed SigmaThera to quickly progress toward drug designation, adds Roman. Early tests in mice show SIT-161 offers better results for neurological score and survival than riluzole, the only approved treatment for ALS in Europe.

Marseille trial

Next, the company plans to carry out further preclinical studies on ALS treatment, as well as investigating the drug’s potential for treating other neurodegenerative diseases and providing the material for filing novel patents. “The aim is to design a clinical trial in Marseille; we have identified the lab and identified the clinical research organisation we want,” says Roman. “Everything is prepared, we just need the approval from authorities.”

Keywords

NeuroPA, antidepressant, psychiatry, Alzheimer’s, depression, SigmaThera, Parke-Davis, Pfizer, neurodegenerative

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