Movantik for Opioid-Related Esophageal Disorders

Background MOVANTIK™ (Naloxegol) can alleviate the adverse effects associated with frequent
opiate use. The GI system is a common site for their unintended effects of opiate use, but
literature suggests that peripherally acting opioid agonist may provide relief in the
instance of GI dysfunction. (Holzer 2007) Toxicology and pharmacology summary

14 Phase I studies were completed with 439 health volunteers participating. MOVANTIK™
(Naloxegol) has been tested in a standard range of safety pharmacology studies including an
absorption, distribution, metabolism and excretion study, a QTc (corrected QT interval)
study, several PK (pharmacokinetic) studies, and a study to determine its central and
peripheral pharmacodynamics effects. MOVANTIK™ (Naloxegol) is metabolized primarily by
cytochrome P450 enzyme (CYP)-3A4 and CYP3A5 and is a substrate for a P-glycoprotein
transporter. Drug-drug interaction studies were performed for a strong and a moderate CYP3A4
inhibitor, a CYP3A5 inhibitor and P-glycoprotein transporter inhibitor.

Clinical Safety summary MOVANTIK™ (Naloxegol) was initially tested in 439 healthy volunteers
across 14 Phase I studies. Ascending-dosing studies were performed with first dose ranging
from 8-1000 mg, followed by twice daily dosing ranging from 25-250 mg, all administered
intravenously. Another ascending dose study was completed in older volunteers (age 65 and
older) in Japan to determine the effects of advanced age on PK values. Phase IIb and II
studies exposed 1497 patients to dosages ranging from 5 mg to 50 mg for periods of time
varying from 24 to 52 weeks. MOVANTIK™ (Naloxegol) has shown acceptable safety profile and
was well-tolerated at 5 mg and 25 mg. The 50 mg cohort had shown increased frequency of GI
adverse events (abdominal pain, nausea and diarrhea) when compared to the 25 mg and 5 mg
cohorts. The 25 mg dose was the maximum used across the 5 phase III studies. Two 12 week
placebo-controlled double-blind studies were completed to confirm safety and efficacy, as
well as a 12 week double-blind safety extension, a randomized 52-week open-label parallel
group, long-term safety study and a placebo-controlled, double-blind study in patients with
cancer-related pain. The efficacy studies demonstrated the therapeutic effect of MOVANTIK™
(Naloxegol) was independent of age, gender, race, body mass index, region, use of
anticholinergics, response to previous laxative use, type of opioid, or dose of opioid. Phase
III studies demonstrated that MOVANTIK™ (Naloxegol) is generally safe and well tolerated at
doses up to 25 mg once daily in patients with OIC (opioid-induced constipation) up to 52
weeks of treatment.

Acute and chronic use of opioids is associated with a variety of adverse effects on the
gastrointestinal tract. The effect of opioids on gastric, small bowel, and colonic motility
has been well characterized. The main esophageal abnormalities seen were impaired LES (lower
esophageal sphincter) relaxation. Recently a large retrospective study assessing the effect
of opioids on esophageal motility using, for the first time, HREM and the Chicago
classification of esophageal motility disorders v3.0 found that Esophageal motor dysfunction
are common in chronic opioid users whether studied on opioids and off opioids. (K raichely
2010) However, opioid use within 24 h of manometry was associated with increased EGJ (
Esophagogastric junction) outflow obstruction and other spastic esophageal motor
abnormalities. In addition, current opioid users also had significantly higher integrated
relaxation pressure and manometric patterns consistent with type III achalasia.

Benefit/risk and ethical assessment Preliminary data suggests a relationship between opioid
use and esophageal dysfunction. The decline in quality of life associated with esophageal
disorders may discourage patients from taking opioids, subjecting them to unwarranted pain.
MOVANTIK™ (Naloxegol) is an opioid antagonist specifically designed to work outside of the
central nervous system. This allows relief from undesired peripheral effects of opioids
without disrupting analgesic effects. The use of MOVANTIK™ (Naloxegol) has the potential to
mediate esophageal dysfunction while preserving vital pain relief.

Patients for whom MOVANTIK™ (Naloxegol) is contraindicated will be excluded as well as those
taking strong CYP3A4 inhibitors or strong CYP3A4 inducers and other opioid antagonists. In
the Phase III studies, adverse events of abdominal pain (21% v 7%), diarrhea (9% v 5%),
nausea (8% v 5%), flatulence (6% v 3%), vomiting (5% v 4%), headache (4% v 3%), and
hyperhidrosis (3% v <1%) were observed at greater rates among the 25 mg cohort when compared
to placebo.. The current study is designed to explore the potential benefit or effect of
Naloxegol on upper GI motility and clinical symptoms inpatients receiving opioid

Study design This is a single center, randomized, placebo-controlled, double-blind study to
determine the effect of MOVANTIK™ (Naloxegol) on opioid-related esophageal motility
disorders.

This study consists of 2 week screening period, a 4 week treatment period and a 2 week
follow-up period. Eligible patients will be placed in either a study group or a control
group, with 15 patients in each study arm. Patients will receive a High Resonance Esophageal
Manometry (HREM) at Visits 2 and 3.

Visit one (Day -14) Patients will be seen and informed consent will be obtained. Inclusion
and exclusion criteria will be review to determine eligibility.

At visit 1 the following procedures will be performed:

- Obtain demographic, endoscopic, clinical, and prior manometric data to determine
eligibility

- Review medication history

- Physical Examination

- Obtain Weight and Height

- Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

- Collect blood sample for Serum Pregnancy Test1

- Patients complete the following questionnaires

o Patient Assessment of GI Symptoms (PAGI-SYM)

- Patients will be given a daily diary to complete throughout the next two weeks.

Visit two (Day 0 ± 3 days) Patients will return to clinic after fasting2, except for
medications with water in the morning, and will undergo a HREM. Review the daily diary,
manometric and the inclusion/exclusion criteria to determine eligibility. The following
procedures will occur before the patient receives study drug. After the procedure, patients
will be started on the study drug (Movantik 25 mg) or Placebo daily on a random double blind
basis.

At visit 2 the following procedures will be performed:

- Review and record adverse event which have occurred from the signing of the ICF
(informed consent form) to Visit 2

- Review concomitant medications and Daily diary

- Obtain Weight and Height

- Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

- Patients complete the following questionnaires

- Patient Assessment of GI Symptoms (PAGI-SYM)

- Lower GI symptoms questionnaire

- McGill Pain inventory

- SF-36

- Chest pain symptom questionnaire

- GERD (gastroesophageal reflux disease) symptom check list

- Patients will undergo a HREM

- Obtain study number, randomize patients and dispense investigational product.

Visit Three (Day 2± 3 days) Patients will receive a phone call to assess their initial
response to treatment two days after they start the study drug and better assess the safety
of the drug.

During Visit 3the following procedures will be performed:

- Review and record adverse event which have occurred from the signing of the ICF to Visit
3

- Review concomitant medications

Visit four (Day 28 ± 3 days)

- Review and record adverse event which have occurred from Visit 3 to Visit 4

- Review concomitant medications and Daily diary

- Obtain Weight and Height

- Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

- Patients complete the following questionnaires

- Patient Assessment of GI Symptoms (PAGI-SYM)

- Lower GI symptoms questionnaire

- McGill Pain inventory

- SF-36

- Chest pain symptom questionnaire

- GERD symptom check list

- Patients will undergo a HREM2 (High Resonance Esophageal Manometry)

- Perform investigational product accountability.

Visit five (Day 42 ± 7 days) Patients will be seen to ensure collection of the daily diaries
and for a final safety assessment

- Review and record adverse event which have occurred from Visit 4 to Visit 5 and further
detail any adverse event that have occurred throughout the study

- Review concomitant medications and return daily diary

- Obtain Weight and Height

- Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

Early Withdrawal/Early Termination

Patients who withdraw early will be encouraged to complete their Visit 3 requirements:

- Review and record adverse event which have occurred from Visit 2 to withdrawal
(termination) date

- Review concomitant medications and Daily diary

- Obtain Weight and Height

- Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

- Patients complete the following questionnaires

- Patient Assessment of GI Symptoms (PAGI-SYM)

- Lower GI symptoms questionnaire

- McGill Pain inventory

- SF-36

- Chest pain symptom questionnaire

- GERD symptom check list

- Perform investigational product accountability

Rationale for study design, doses and control groups This study seeks to determine the
effectiveness of MOVANTIK™ (Naloxegol) in treating patients with opioid-induced esophageal
disorders. MOVANTIK™ (Naloxegol) has already been shown to be effective in other opioid
induced gastric disorders. To the Investigator's knowledge there has been no double-blind
randomized control trial evaluating the effects of MOVANTIK™ (Naloxegol) on opioid
induced-esophageal disorders. The same dosage that has been proven effective in other patient
populations will be used. The use of a control group eliminates potential bias in the
patient-reported outcome endpoints. The enrollment goal is 50 patients for this study. A
recent study showed all 15 enrolled patients showed signs of opioid-induced motility
abnormalities on HREM. (Kraichely 2010) Relatively large effects can be expected in this
sample size. Using G* power 3 will ensure that that a sample size of 42 patients will give
provide a 95% chance of detecting a large effect size (defined as 0.80 population s.d.
between groups) between the two groups as significant at the 5% level (two tailed) using t
-test between means. Enrolling 50 patients ensures an adequate amount of patients complete
the course of treatment.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures

2. Age 18-85, Males and Females

3. On a stable daily opioid dose for various indications for at least 4 weeks prior to
the HREM (High Resonance Esophageal Manometry

4. Symptoms of odynophagia, dysphagia, or chest pain based on symptoms recorded on the
PAGI-SYM

Exclusion Criteria:

1. Renal impairment (cct<60) or severe Hepatic impairment as defined by the Child-Pugh
Classification (Appendix J)

2. Concomitant use of strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers,
NSAIDS, Plavix/Clopidogrel and other opioid antagonists

3. History of GI obstruction, bowel perforation, or with potential for either based on
investigator's clinical judgment

4. Subjects with known Barrett's esophagus or peptic stricture on endoscopy

5. Subjects with previous upper gastrointestinal surgery

6. Pregnant, plan to be pregnant, or are breastfeeding

7. Women of childbearing potential who are unwilling to use contraceptives throughout the
course of treatment

8. Subjects with serious co-morbidities (Cardiovascular, respiratory, renal, hepatic,
hematologic, endocrine, neurologic) which may prevent the patient to participate in
the study based on PI's clinical judgment or malignancy

9. Patients with an increased risk of gastrointestinal perforation due to conditions that
may be associated with localized or diffuse reduction of structural integrity in the
wall of the gastrointestinal tract (e.g. peptic ulcer disease, Ogilvie's syndrome,
diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal
metastases).

10. Subjects with upper airway symptoms (such as hoarseness, wheezing or laryngospasm)

11. Patients taking baclofen or sucralfate and those unwilling to discontinue prohibited
medications.

12. Known history of substance abuse

13. Subject unable to consent or is unwilling to provide informed consent

14. History of major comorbid psychiatric conditions including mania and schizophrenia or
severe current depression

15. At-risk populations, including prisoners and mentally challenged. Any condition or is
in a situation which may put him/her at significant risk, may confound the study
results, or may interfere significantly with the subject's participation in the study
(e.g., difficulty hearing, cognitive impairment)

16. Known allergy to MOVANTIK™ (Naloxegol)

17. Patients with a history of cancer within past 5 years prior to the screening visit

18. Patients with a medical condition which may disrupt the blood-brain barrier