Evaluation of Safety and Tolerability of ENT-01 for the Treatment of Parkinson's Disease Related Constipation

Phase 1 will enroll 10 patients to assess the safety, tolerability, and pharmacokinetics of
single escalating doses over a 30-60 day period. The dose-escalation period will be preceded
by a 2-week run in period and followed by a 2-week wash-out period.

Phase 2 follow the safe completion of Phase 1. It will enroll 40 patients and is composed of
4 periods of study: 1) a 2-week run-in period, 2) a 3-5 week escalating dose period to
identify a prokinetic dose in the initial set of 10 patients, 3) a 1-week period of
randomized dosing (placebo versus the previously identified pro-kinetic dose), and 4) a
2-week wash-out period. Pharmacodynamics will be assessed along with safety and tolerability.
Relative outcomes will be compared within each patient and across groups for the randomized
dosing period.

Frequency of bowel movements and other non-motor symptoms of Parkinson's Disease will be
collected over the course of both phases.

Inclusion Criteria:

1. Parkinson's disease diagnosis confirmed by a neurologist specializing in movement
disorders

2. Insufficient criteria for a diagnosis of Irritable Bowel Syndrome

3. Constipation for over 6 months, unresponsive to Milk of Magnesia, and requiring at
least weekly treatment using an oral laxative, stool softener, bulking agent, and/or a
suppository, and dissatisfaction with current treatment.

4. Body Mass Index is 18-40 kg/m2

5. At least 2 of the Rome IV functional constipation criteria are met

6. Loose stools are rarely present without the use of laxatives

7. Patient is willing and able to sign informed consent and comply with all study
procedures

8. Patients must be able to read, understand, and accurately record data into the diary
to guarantee full participation in the study

Females only:

9. Must have negative serum or urine pregnancy tests and must not be lactating

10. If of child-bearing age: Must agree to using a hormonal (i.e., oral, implantable, or
injectable) and either single- or double-barrier method of birth control throughout
the study period. A vasectomized partner will be allowed as one in conjunction with
another single-barrier method.

11. If unable to have children: Must have this documented in the case report form (i.e.,
ubal ligation, hysterectomy, or post-menopausal [defined as a minimum of one year
since last menstrual period]). Post-menopausal status will be confirmed by follicle
stimulating hormone in women less than 60 years of age.

Exclusion Criteria:

1. Unable or unwilling to provide informed consent or to comply with study procedures

2. Diagnosis of secondary constipation beyond that of PD

3. Structural or metabolic diseases that affect the GI system

4. Functional GI disorder

5. Unable or unwilling to withdraw from taking the following medications 2 weeks prior to
the dose-escalation period and throughout the study: Laxatives, opiates, sedatives,
hypnotics, anti-histamines, protein pump inhibitors or any medications which may cause
constipation

6. History of recent major surgery (within 60 days of screening)

7. Any clinically significant abnormalities on screening laboratories or physical
examination as determined by the Investigator

8. Neurological disorder other than PD

9. On treatment with intra-jejunal dopamine

10. Treatment with COMT inhibitors for fewer than 4 weeks (entacapone, tolcapone, Stalevo)

11. Unable to maintain a stable diet regimen

12. Patients with a cognitive impairment that preclude them from understanding the
informed consent

13. Patients placed under legal guardianship

14. Acute GI illness within 48 hours of the baseline period

15. History of major GI surgery (e.g. previous abdominal surgery, including
cholecystectomy), except that patients with uncomplicated appendectomy are allowed

16. ALT or AST > 1.5 X upper limit of normal (ULN) during screening

17. Females who are pregnant or breastfeeding

18. History of excessive alcohol use or substance abuse

19. Patient or caregiver unable to administer daily oral dosing

20. Participation in an investigational clinical study within the 6 months prior to dosing
in the present study

21. Any other reason, which in the opinion of the Investigator would confound proper
interpretation of the study