In addition to improving constipation in patients with Parkinson disease, ENT-01 also helped improve Mini-Mental State Examination scores, an exploratory measure of cognition.
Newly published data from the phase 2b KARMET study (NCT03781791) showed that ENT-01 (Enterin), an investigational agent that targets α-synuclein, met both its primary and secondary bowel end points, and restored the function of enteric nerve cells in patients with Parkinson disease (PD) and constipation. Results from small subgroups of patients suggested that ENT-01 might also improve psychosis and dementia.1
ENT-01, an orally administered medication, displaces α-synuclein aggregates from nerve cell membranes as well as prevents their formulation. Following the results, Denise Barbut, MD, FRCP, cofounder, president, and chief medical officer, Enterin, said in a statement that, “the continued improvement in bowel and neurologic symptoms for weeks beyond the brief treatment period suggests a possible disease-modifying effect."
KARMET was a randomized, placebo-controlled, double-blind study that evaluated 150 patients with PD and constipation, starting with a 2-week baseline period. There, patients were stratified to either the low or high dose based on constipation severity and randomized to receive study drug (n = 75) or placebo (n = 75). The treatment period was 25 days, with dosing escalated every 2-3 days. All patients were then placed on placebo for 2 weeks, followed by a 4-week washout period.
A total of 136 patients who received at least 7 days of medication were included in the efficacy analysis. From baseline to the end of the 3-week treatment period, treatment with ENT-01 resulted in a significant change in the primary end point, or complete spontaneous bowel movement (CSBM), compared with those on placebo (P = .0001). The improvements were observed continued 2 weeks (P = .02) and 6 weeks (P = .05) after discontinuing study drug.
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ENT-01 was also found to be safe and well-tolerated among patients, with no reported deaths or drug-related serious adverse events (AE). Most AEs were self-limiting and confined to the gastrointestinal tract. They included nausea and diarrhea. The study drug demonstrated improvements over placebo on several different secondary end points, including spontaneous bowel movement (SBM; P = .001), stool consistency (P = .0001), ease of passage (P = .004), and laxative use (P = .03).
An exploratory analysis included 13 patients who had psychotic symptoms at baseline, each of which had scores of at least 4 on Scale of Positive Symptoms in PD (SAPS-PD). Among the 6 individuals treated with ENT-01, SAPS-PD scores improved by 73% by the end of the 3-week treatment period, and by 82% 6-weeks after treatment discontinuation, whereas no improvement was observed for the 7 individuals on placebo.
Dementia, another exploratory end point, was evaluated using the Mini-Mental State Examination (MMSE). At baseline, 24 individuals had baseline, indicated by scores of 26 or less on MMSE. Of those treated with ENT-01, MMSE scores improved by 2 points during the 3-week treatment period, and by 3.5 points 6 weeks beyond the treatment period, Notably, improvements were also seen in the placebo group during the treatment period but worsened after treatment discontinuation.
"Aging itself compounds the ongoing damage caused by the accumulation of alpha-synuclein,” Michael Zasloff, MD, PhD, cofounder and chief strategy officer, Enterin, said in a statement. “Our preclinical studies suggest that the persistence of benefit observed with ENT-01 are a consequence of the reversal of certain aspects of the aging process."1
These findings were intended to follow up on the previously completed open-label RASMET study (NCT03047629), which established the safety, tolerability, and reversal of constipation with treatment of ENT-01. The primary efficacy end point, defined as an increase of 1 CSBM/week or 3 CSBM/week over the baseline period, was achieved in more than 80% of patients. The mean number of CSBM/week increased from 1.2 at baseline to 3.6 during fixed dosing (P = 1.2 x 10-7).2