Targeting neurons in the gastrointestinal tract to treat Parkinson's disease

Robert A Hauser, Dean Sutherland, Juan A Madrid, Maria Angeles Rol, Steven Frucht, Stuart Isaacson, Fernando Pagan, Brian N Maddux, George Li, Winona Tse, Benjamin L Walter, Rajeev Kumar, Daniel Kremens, Mark F Lew, Aaron Ellenbogen, Odinachi Oguh, Alberto Vasquez, William Kinney, Matt Lowery, Maria Resnick, Nicole Huff, Jerry Posner, Karla V Ballman, Brian E Harvey, Michael Camilleri, Michael Zasloff, Denise Barbut, Robert A Hauser, Dean Sutherland, Juan A Madrid, Maria Angeles Rol, Steven Frucht, Stuart Isaacson, Fernando Pagan, Brian N Maddux, George Li, Winona Tse, Benjamin L Walter, Rajeev Kumar, Daniel Kremens, Mark F Lew, Aaron Ellenbogen, Odinachi Oguh, Alberto Vasquez, William Kinney, Matt Lowery, Maria Resnick, Nicole Huff, Jerry Posner, Karla V Ballman, Brian E Harvey, Michael Camilleri, Michael Zasloff, Denise Barbut

Abstract

Background: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers.

Objective: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation.

Methods: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed.

Results: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10-7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%.

Conclusions: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

Keywords: Constipation; ENT-01; Non-motor; Parkinson's disease; Squalamine; Synuclein; Treatment.

Conflict of interest statement

Barbut, Zasloff, Kinney, Harvey, Resnick, Lowry, and Huff are employees of Enterin and hold equity. Camilleri is a member of Enterin's Scientific Advisory Board. Ballmann is a paid consultant of Enterin. Hauser has received consulting fees from Enterin.

© 2019 The Authors.

Figures

Fig. 1
Fig. 1
Phase 2a trial.
Fig. 2
Fig. 2
Prokinetic activity of ENT-01. A. In Stage 1 (single dose), cumulative prokinetic response rate was defined as the proportion of patients who had a CSBM within 24 h of dosing. Dosing started at 25 mg. In Stage 2 (daily dosing), a prokinetic response was defined as the fraction of patients who had a CSBM within 24 h of dosing on at least 2 out of 3 days at any given dose. Dosing started at 75 mg. B. Prokinetic dose of ENT-01 was significantly related to baseline constipation severity (p = 0.00055). Patients with baseline CSBM <1 required a higher dose (mean, 192 mg) of ENT-01 than patients with CSBM ≥1 (mean, 120 mg). Significance determined by t-test.

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Source: PubMed

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