Enterin Inc., a privately held, Philadelphia-based, clinical-stage biopharmaceutical company pioneering novel treatments for neurodegenerative and metabolic diseases, announces the conclusion of a randomized, placebo-controlled, double-blind Phase 2b (KARMET) study involving 150 patients with Parkinson’s Disease (PD).
Enterin’s lead compound, ENT-01 targets alpha-synuclein, or αS, a protein known to play a key role in the pathophysiology of PD. αS accumulates in nerve cells of the gut (enteric nerves), preventing the nerve cells from functioning properly. Orally administered ENT-01 displaces αS aggregates from nerve cell membranes as well as preventing their formation. As a result, enteric nerve cell function is restored, as is communication between gut and brain.
The Phase 2b study was a randomized, placebo-controlled, double-blind study involving 150 patients with PD and constipation. Following a two-week baseline period, patients were stratified to start at high dose or low dose depending on baseline constipation severity and randomized to receive ENT-01 or placebo. Dosing was escalated every 2-3 days and “fixed” for the remainder of the 25-day treatment period. All patients were then placed on placebo for 2 weeks, followed by a 4-week wash-out.
There were no safety or tolerability concerns (n=150). There were no deaths or drug-related serious adverse events. Adverse events were largely confined to the GI tract and self-limiting. They included nausea and diarrhea.
Efficacy analyses were performed on all patients who had received at least 7 days of medication (n=136). The primary endpoint, defined as the change in complete spontaneous bowel movement (CSBM) from baseline to the end of the 3-week treatment period was significantly better in the treatment group compared to placebo (p=0.0001). The improvement persisted 2-weeks (p=0.02) and 6-weeks (p=0.05) after discontinuation of study medication. Secondary bowel endpoints were also significantly better in the treatment group compared to placebo. These included spontaneous bowel movement (SBM; p=0.001), stool consistency (p=0.0001), ease of passage (p=0.004) and laxative use (p=0.03). Exploratory endpoints included psychosis (Scale of Positive Symptoms in PD, SAPS-PD) and dementia (Mini Mental State Examination, MMSE). 13 patients had psychotic symptoms at baseline (SAPS-PD score ≥4). In the ENT-01 group (n=6), SAPS-PD score improved by 73% by the end of the 3-week treatment period and by 82% 6-weeks after treatment discontinuation. Placebo patients (n=7) showed no improvement during treatment and worsened following treatment discontinuation. Twenty-four patients had dementia at baseline (MMSE≤26). In the ENT-01 group, MMSE score improved by 2 points during the 3-week treatment period, and by 3.5 points 6 weeks beyond the treatment period. Placebo patients improved during treatment but worsened following treatment discontinuation.
In summary, both primary and secondary bowel endpoints were met, demonstrating that even a short course of ENT-01 can restore the function of enteric nerve cells. Results from small numbers of patients suggest that ENT-01 might also improve psychosis and dementia. According to Denise Barbut, MD, FRCP, Enterin’s Co-Founder, President and CMO, “The continued improvement of bowel and neurologic symptoms for weeks beyond the brief treatment period suggests a possible disease-modifying effect.”
Michael Zasloff, MD, Ph.D., Enterin’s Co-Founder and CSO, added, “Aging itself compounds the ongoing damage caused by the accumulation of alpha-synuclein. 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.”
The KARMET study was designed to replicate earlier findings of a preceding open-label RASMET study in a placebo-controlled trial. The RASMET study had established safety, tolerability and reversal of constipation following orally administered ENT-01, and signaled improvement in neurologic endpoints including memory, mood, sleep, REM-behavior disorder, psychosis, and circadian rhythm, with persistence of benefit for several weeks beyond the brief treatment period (https://doi.org/10.1016/j.prdoa.2019.06.001).
Top-line results will be presented on a conference call by Denise Barbut, MD, FRCP, Co-Founder, President and CMO of Enterin. Stuart Isaacson, MD, and Patrik Brundin, MD, Ph.D., will share their perspectives. Please join the call on Jan. 27 at 2:30 pm EST. A link to the invitation can be found on the Enterin website along with a replay of the event.