Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial

  • Ann Intern Med. 2022 Dec;175(12):1666-1674. doi: 10.7326/M22-1438.
Michael Camilleri  1 ,  Thyagarajan Subramanian  2 ,  Fernando Pagan  3 ,  Stuart Isaacson  4 ,  Ramon Gil  5 ,  Robert A Hauser  6 ,  Mary Feldman  7 ,  Mark Goldstein  8 ,  Rajeev Kumar  9 ,  Daniel Truong  10 ,  Nisha Chhabria  11 ,  Benjamin L Walter  12 ,  Jonathan Eskenazi  13 ,  Robert Riesenberg  14 ,  Daniel Burdick  15 ,  Winona Tse  16 ,  Eric Molho  17 ,  Bradley Robottom  18 ,  Perminder Bhatia  19 ,  Srinath Kadimi  20 ,  Kevin Klos  21 ,  David Shprecher  22 ,  Otto Marquez-Mendoza  23 ,  Gonzalo Hidalgo  24 ,  Stephen Grill  25 ,  George Li  26 ,  Howard Mandell  27 ,  Mary Hughes  28 ,  Sharisse Stephenson  29 ,  Joel Vandersluis  30 ,  Michael Pfeffer  31 ,  Andrew Duker  32 ,  Vikram Shivkumar  33 ,  William Kinney  34 ,  James MacDougall  35 ,  Michael Zasloff  36 ,  Denise Barbut  37
Affiliations
  • 1. Mayo Clinic, Rochester, Minnesota (M.C.).
  • 2. Penn State Hershey Medical Center, Hershey, Pennsylvania (T.S.).
  • 3. Department of Neurology, Georgetown University Hospital, Washington, DC (F.P.).
  • 4. Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, Florida (S.I.).
  • 5. Parkinson's Disease Treatment Center of SW Florida, Port Charlotte, Florida (R.G.).
  • 6. USF Parkinson's Disease and Movement Disorder Center, Tampa, Florida (R.A.H.).
  • 7. Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire (M.F.).
  • 8. JEM Headlands Research Institute, Atlantis, Florida (M.G.).
  • 9. Rocky Mountain Movement Disorder Center, Englewood, Colorado (R.K.).
  • 10. The Parkinson's and Movement Disorder Institute, Fountain Valley, California (D.T.).
  • 11. Palm Beach Neurology and Premiere Research Institute, West Palm Beach, Florida (N.C.).
  • 12. Parkinson's and Movement Disorders Center, Cleveland Clinic, Cleveland, Ohio (B.L.W.).
  • 13. SC3 Research Group, Pasadena, California (J.E.).
  • 14. Atlanta Center for Medical Research, Atlanta, Georgia (R.R.).
  • 15. Booth Gardner Parkinson's Care Center, EvergreenHealth, Kirkland, Washington (D.B.).
  • 16. Parkinson's and Movement Disorders Center, Icahn School of Medicine at Mount Sinai, New York, New York (W.T.).
  • 17. Parkinson's Disease and Movement Center, Albany Medical College, Albany, New York (E.M.).
  • 18. Raleigh Neurology Associates, Raleigh, North Carolina (B.R.).
  • 19. Neuro Pain Medical Center, Fresno, California (P.B.).
  • 20. Associated Neurologists of Southern Connecticut, Fairfield, Connecticut (S.K.).
  • 21. The Movement Disorder Clinic of Oklahoma, Tulsa, Oklahoma (K.K.).
  • 22. Banner Sun Health Research Institute, Sun City, Arizona (D.S.).
  • 23. Elias Research - Pharmax Research of South Florida, Inc., Miami, Florida (O.M.).
  • 24. The Neuromedical Clinic of Central Louisiana, Alexandria, Louisiana (G.H.).
  • 25. Parkinson's and Movement Disorders Center of Maryland, Elkridge, Maryland (S.G.).
  • 26. MEDSOL Clinical Research, Port Charlotte, Florida (G.L.).
  • 27. Metrolina Neurological Associates, Indian Land, South Carolina (H.M.).
  • 28. Premier Neurology, Greer, South Carolina (M.H.).
  • 29. BTC Network, Neurologic Associates of North Texas, Dallas, Texas (S.S.).
  • 30. Elias Research, Neurology Diagnostics, Inc., Dayton, Ohio (J.V.).
  • 31. Allied Biomedical Neurologic Research Institute, Miami, Florida (M.P.).
  • 32. University of Cincinnati, Cincinnati, Ohio (A.D.).
  • 33. University Physicians and Surgeons, Inc., Marshall Health, Huntington, West Virginia (V.S.).
  • 34. Enterin, Inc., Philadelphia, Pennsylvania (W.K.).
  • 35. MacDougall Statistical Institute, Haverhill, Massachusetts (J.M.).
  • 36. Medstar-Georgetown Transplant Institute, Washington, DC, and Enterin Research Institute and Enterin, Inc., Philadelphia, Pennsylvania (M.Z.).
  • 37. Enterin Research Institute and Enterin, Inc., Philadelphia, Pennsylvania (D.B.).
PMID: 36343348 DOI: 10.7326/M22-1438
Abstract

Background: Parkinson 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.

Objective: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation.

Design: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791).

Setting: Outpatient.

Patients: 150 patients with PD and constipation.

Intervention: ENT-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.

Measurements: The 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]).

Results: The 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).

Limitation: Longer treatment periods need to be investigated in future studies.

Conclusion: ENT-01 was safe and significantly improved constipation.

Primary funding source: Enterin, Inc.

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