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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. 

About Enterin Inc.

Enterin Inc. is the first company to develop novel compounds that repair the dysfunctional gut-brain axis in patients with neurodegenerative diseases. Enterin Inc. is pioneering the medical community's understanding of the link between infections, dysfunction of the enteric nervous system (ENS) and the onset and progression of neurodegenerative disease. Enterin's lead compound, ENT-01, displaces membrane-bound alpha-synuclein (αS) aggregates from nerve cells in the ENS and improves neural signaling between the gut and the brain. Enterin Inc. is now progressing ENT-01 through Phase 2 clinical trials in an attempt to reverse the neurologic symptoms of Parkinson's disease. The second compound, ENT-03, increases insulin sensitivity by acting at the level of the brain and acutely normalizes blood sugar in diabetic mice. ENT-03 is being developed for the treatment of diabetes, obesity and Alzheimer's disease. Studies in humans will begin in 2022. 

For more information, please visit www.enterininc.com.

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Enterin Inc.
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