Oral ENT-01 improves constipation in patients with Parkinson’s disease

Oral ENT-01 treatment was safe and associated with improvements in constipation among patients with Parkinson’s disease, a study in Annals of Internal Medicine found.

“In large part due to the underlying functional disruption of the [enteric nervous system (ENS)],” constipation affects about 60% of patients with Parkinson’s disease (PD), Michael Camilleri, MD, a consultant in the division of gastroenterology and hepatology at the Mayo Clinic, and colleagues wrote.

“Constipation significantly affects the quality of life of persons with PD, contributing to social isolation and depression,” they added.

Referencing previous studies, the researchers pointed to ENT-01 as a potential treatment. It displaces alpha-synuclein bound to nerve cell membranes and potentially restores function of enteric neurons, neuron signaling and bowel function.

The study consisted of 150 participants with PD, with 93 randomly assigned to ENT-01 and 57 randomly assigned to placebo.

In addition to requiring a PD diagnosis, participants also needed to have constipation — identified as fewer than three complete spontaneous bowel movements (CSBM) per week — that was not attributed to another disease.

Of all participants, 58.7% (n = 88) were men and 92.7% (n = 139) were white, while the mean age was 68 years. The mean duration of constipation was 12.7 years, while mean treatment duration for the ENT-01 group was 20.8 days, compared to 21.8 days for the placebo group.

The researchers assigned patients to one of two starting doses based on constipation severity. Those with 0.9 CSBM per week or fewer received a 150 mg dose of ENT-01 daily or six placebo pills, while those with one to 2.9 CSBMs per week received 75 mg of ENT-01 daily or three placebo pills.

In both groups, dosing was escalated by 25 mg (or one placebo pill) every 3 days “to a dose that produced a CSBM within 24 hours of administration on at least 2 of 3 days (the ‘prokinetic’ dose), to the maximum dose of 250 mg (or 10 placebo pills), or to the tolerability limit,” Camilleri and colleagues wrote.

“Dosing was fixed for the remainder of the 25 days,” they wrote. “After the ‘fixed-dose period,’ all patients were switched to placebo (with participants blinded) for 2 weeks, followed by a 4-week washout.”

At baseline, the mean weekly CBSM rate was 0.7. This rose to 3.2 for the ENT-01 group during the fixed-dose period, while the placebo group saw an increased rate of 1.2 (rate ratio = 2.78; 95% CI, 1.61-4.81).

Two weeks after treatment, mean weekly CBSM rates were 2.2 and 1.2 for the ENT-01 and placebo groups, respectively (rate ratio = 1.65; 95% CI, 0.93-2.93).

The researchers noted that the ENT-01 dose needed for functional bowel movements varied between 75 mg to 250 mg, with only 49.3% of those with 1 to 2.9 CBSMs per week on at least 200 mg. However, 250 mg of ENT-01 was associated with a greater responder rate (56.6%) than 75 mg (7.2%).

Overall, ENT-01 was safe, “with no deaths or drug-related serious adverse events,” according to Camilleri and colleagues. Adverse events mainly occurred in the GI tract, with nausea (n = 32) and diarrhea (n = 18) the most common.

“In future studies, starting at lower doses, escalating more slowly, and administering an antiemetic with antiserotonergic effects (such as ondansetron) at treatment initiation may reduce the frequency of both symptoms and reduce dropout,” they wrote.

Neurological symptoms were also examined through the Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis (SAPS-PD).

Hallucinations were present in 11 patients at baseline. For ENT-01 participants (n = 5), the mean SAPS-PD score was:

• 6.5 at baseline;
• 1.8 at the end of treatment; and
• 1.7 after 2 weeks of treatment discontinuation.

“This improvement was maintained 6 weeks after the end of treatment,” Camilleri and colleagues wrote.

For placebo participants (n = 6), the mean SAPS-PD was:

• 6.3 at baseline;
• 3.4 at the end of treatment;
• 4 after 2 weeks of treatment discontinuation; and
• 4.4 after 6 weeks of treatment discontinuation.

Dementia, present in 28 patients at baseline, also improved in the ENT-01 group, according to Mini Mental State Examination (MSSE) scores. Lower MSSE scores indicated greater severity of dementia.

Mean MSSE scores rose from 24.1 at baseline to 27.5 after 6 weeks of treatment discontinuation for ENT-01 participants (n = 14). Placebo patients (n = 14), meanwhile, saw a 2-point rise from their 24.8 mean MSSE baseline score 6 weeks after treatment.

“Differences in MMSE score between ENT-01 and placebo for the entire cohort (n = 135) were significant 6 weeks after treatment discontinuation,” the researchers wrote.

There were several limitations to the study, including ENT-01’s proposed cellular mechanism of action not being validated, the limited number of patients with dementia or psychosis and the short duration of the treatment period, Camilleri and colleagues noted.

The researchers concluded that ENT-01 “leads to an improvement in bowel function and possibly neurologic symptoms,” while results suggest that the ENS “is not irreversibly damaged in PD, even though the long-term constipation might suggest otherwise.”

“Future studies will focus on the effect of longer treatment periods on PD-related constipation and neurologic symptoms and on our understanding of the compound's mechanism of action in the human GI tract,” they wrote.

References:

• Camilleri M, et al. Ann Intern Med. 2022;doi:10.7326/M22-1438.
• Oral ENT-01 safe, significantly improves constipation in persons with Parkinson disease. https://www.eurekalert.org/news-releases/969999. Published Nov. 7, 2022. Accessed Nov. 9, 2022.