Daily treatment with tablets of ENT-01, an investigational therapy for Parkinson’s disease, is safe and may restore patients’ bowel movements, according to results from Enterin‘s Phase 2a RASMET study.
ENT-01 seems to locally stimulate a network of nerve cells that directs bowel function, suggesting that part of the nervous system is not irreversibly damaged in Parkinson’s patients.
The trial has been completed and results are reported in the study, “Targeting neurons in the gastrointestinal tract to treat Parkinson’s disease,” published in the journal Clinical Parkinsonism & Related Disorders.
In Parkinson’s disease toxic aggregates of alpha-synuclein protein accumulate in the enteric nervous system (ENS), as they do in the brain. The ENS is a network of nerve cells that regulates the function of the gastrointestinal (GI) tract independently of the central nervous system (CNS) — the brain and spinal cord.
Several studies have noted that accumulation of alpha-synuclein in the ENS may be the reason why some Parkinson’s patients are affected by dysmotility (lack of normal bowel movements) and constipation.
To find a treatment for this medical problem, Enterin is investigating ENT-01 (or kenterin), a lab-made version of squalamine expected to act locally on enteric nerve cells, altering gut-to-brain signaling and stimulating gut motility.
Squalamine is an antimicrobial compound found in the dogfish shark, that is able to enter cells and displace certain protein-membrane aggregates, preventing the build-up of alpha-synuclein into toxic clumps.
RASMET was a Phase 2a multicenter, dose-escalating trial (NCT03047629) to evaluate the safety, tolerability and effectiveness of oral ENT-01 to relieve symptoms of constipation in people with Parkinson’s disease.
The trial, which ran over a period of nine months, enrolled 50 Parkinson’s patients who had been constipated for more than six months; they were recruited at 15 sites in the U.S.
In the first phase of the trial, 10 patients received a single escalating dose (from 25 to 200 mg a day or a maximum tolerated dose) every three to seven days, which was followed by a two-week washout period.
During the second phase of the trial, 34 patients received daily, escalating doses from 75 to a maximum of 250 mg a day to identify ENT-01’s prokinetic dose (the dose needed to stimulate bowel motility). Patients were then randomized to receive a fixed prokinetic dose of ENT-01, or a placebo, over one week, followed by a washout period of two weeks.
The results showed that 80% of the patients reached the primary efficacy goal — an increase of at least one complete spontaneous bowel movement (CSBM) per week relative to study start, or three per week during the fixed-dose period. Efficacy criteria was defined according to FDA’s guidelines for prokinetic (promotility) agents.
Researchers also observed that the higher the ENT-01 dose, the more severe was the patient’s constipation at the beginning of the study, which is in line with the idea that the more alpha-synuclein accumulates in the ENS, the greater are its consequences for bowel motility.
This means that the dose of ENT-01 required to restore nerve cell activity is proportional to alpha-synuclein’s burden.
No safety issues were reported and adverse side effects were limited mostly to the GI tract. The most common were nausea (40% and 50% in stage 1 and 2) and loose stools (40% and 44%). The only other noteworthy side effect was dizziness (18%), researchers reported.
“We demonstrate in this study that ENT-01 can restore gastrointestinal motility in patients with PD, suggesting that a major division of the nervous system and the largest sensory organ in the body (the GI tract) is not irreversibly damaged in patients with PD, despite the long-standing constipation that might suggest otherwise,” Denise Barbut, MD, said in a press release. Barbut is the study’s senior author and Enterin’s co-founder, president and chief medical officer.
“We believe that this is the first demonstration of the reversal of a neurodegenerative process in humans,” she added.
The study also indicates potential benefits of ENT-01 for parkinsonism, cognition, hallucinations, and sleep problems.
“While these results are intriguing, this was an open label trial and placebo effects cannot be excluded. These findings must undergo rigorous evaluation in future place-controlled trials,” said the study’s lead author, Robert Hauser, MD, professor and director of the Parkinson’s Disease and Movement Disorders Center at the University of South Florida in Tampa.
Enterin is currently running a larger, placebo-controlled trial, KARMET (NCT03781791), to confirm and further explore ENT-01’s effects. That trial is ongoing, but no longer recruiting participants.