FDA OKs ENT-01 for patient with multiple system atrophy

The FDA agrees a man can be treated with ENT-01, Enterin’s investigational therapy

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The U.S. Food and Drug Administration (FDA) has agreed that a 42-year-old man with prodromal, or early stage, multiple system atrophy (MSA) , a form of atypical parkinsonism, be treated with ENT-01, Enterin’s investigational therapy for reducing the accumulation of toxic alpha-synuclein in gut nerve cells.

Treatment will be maintained indefinitely and halted only if significant adverse events require its discontinuation.

“We hope that ENT-01 will be helpful in preventing progression of MSA in this individual and that this work will help promote personalized medicine for neurodegenerative diseases,” Robert Hauser, MD, said in a press release. Hauser is the physician treating the patient and the director of the Parkinson’s Disease and Movement Disorders Center at the University of South Florida, in Tampa.

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MSA and Parkinson’s belong to a class of neurodegenerative disorders called synucleinopathies that are characterized by the accumulation of misfolded alpha-synuclein protein.

These protein aggregates have been shown to first accumulate in the enteric nervous system — the network of nerves that innervate the gastrointestinal tract — and can lead to symptoms such as constipation. The clumps then spread to the central nervous system (the brain and spinal cord), where they progressively destroy brain cells, leading to symptoms such as slowness of movement, bowel and bladder control problems, cognitive dysfunction, and rapid eye movement (REM)-behavior disorder — a sleep disorder in which people act out their dreams.

ENT-01 is an oral lab-made compound derived from squalamine, a substance originally discovered in the liver and gall bladder of the dogfish shark. Preclinical data support the efficacy of ENT-01 in clearing the toxic alpha-synuclein clumps and prevent their formation within gut nerve cells,  improving cells’ normal signaling.

Restoring the gut-brain axis

According to Enterin, inhibiting the buildup of toxic alpha-synuclein in the enteric nervous system could restore a healthy connection between the gut and the brain, commonly referred to as the gut-brain axis, which may slow the progression of  synucleinopathies like MSA.

The patient has a mutation in the ATP13A2 gene, which has been linked with a potential higher risk for developing Parkinson’s and MSA. The gene plays a role in regulating the activity of lysosomes — small cell compartments that digest and recycle different types of molecules. As a result, patients may be more prone to accumulate toxic clumps of misfolded proteins, such as alpha-synuclein.

The patient has a two-year clinical history that includes constipation, urinary symptoms, erectile dysfunction, dysfunctional circadian rhythm (the body’s internal clock that controls the sleep-wake cycle), and sleep disturbances suggestive of REM-behavior disorder. He was found to have deposits of alpha-synuclein in enteric neurons located in the duodenum, the first part of the small intestine. Based on these symptoms, he was diagnosed with prodromal MSA.

In lab tests using the patient’s own cells, ENT-01 showed a protective effect  against oxidative stress induced by rotenone, a highly toxic agent used to induce some motor and biochemical changes in animals that mimic those caused by Parkinson’s in humans. Oxidative stress is a type of cellular damage that is partly driven by the resulting products of mitochondria, the cell’s powerhouses, which can promote nerve cell damage.

“This is the first time that any compound is being used to prevent the progression of MSA and a milestone in the development of ENT-01 for both treatment and prevention of other neurodegenerative disorders,” said Denise Barbut, MD, co-founder, president and chief medical officer of Enterin.

ENT-01 in clinical trials

ENT-01 is being tested in a Phase 2 study to treat Parkinson’s disease-associated dementia. Data from a previous Phase 2b trial (NCT03781791), called KARMET, showed that ENT-01 eased constipation significantly better than a placebo in people with Parkinson’s and constipation. Improvements in bowel movement were maintained for up to six weeks after the treatment stopped.

An exploratory analysis suggested that ENT-01 might also ease disease-related psychosis, which are the hallucinations and delusions associated with Parkinson’s.

According to the company, ENT-01’s effectiveness in easing Parkinson’s disease-related constipation will be tested in future Phase 3 trials. More Phase 2 studies in Parkinson’s disease-related psychosis and dementia are being planned.