• Michael Camilleri, Thyagarajan Subramanian, Fernando Pagan, Stuart Isaacson, Ramon Gil, Robert A Hauser, Mary Feldman, Mark Goldstein, Rajeev Kumar, Daniel Truong, Nisha Chhabria, Benjamin L Walter, Jonathan Eskenazi, Robert Riesenberg, Daniel Burdick, Winona Tse, Eric Molho, Bradley Robottom, Perminder Bhatia, Srinath Kadimi, Kevin Klos, David Shprecher, Otto Marquez-Mendoza, Gonzalo Hidalgo, Stephen Grill, George Li, Howard Mandell, Mary Hughes, Sharisse Stephenson, Joel Vandersluis, Michael Pfeffer, Andrew Duker, Vikram Shivkumar, William Kinney, James MacDougall, Michael Zasloff, and Denise Barbut.
• Mayo Clinic, Rochester, Minnesota (M.C.).
• Ann. Intern. Med. 2022 Dec 1; 175 (12): 166616741666-1674.

BackgroundParkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD.ObjectiveTo evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation.DesignRandomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791).SettingOutpatient.Patients150 patients with PD and constipation.InterventionENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period.MeasurementsThe primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]).ResultsThe weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016).LimitationLonger treatment periods need to be investigated in future studies.ConclusionENT-01 was safe and significantly improved constipation.Primary Funding SourceEnterin, Inc.

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