### U.S. Department of Justice Drug Enforcement Administration

Schedule of Controlled Substances: Removal of Naloxegol ( alpha

- 6mPEG 7 

### - O

naloxol ) and its Salts from Schedule II

Background, Data, and Analysis: Eight Factors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537

Octo ber 20142

I. Background Naloxegol, or PEG

- naloxol, is a new molecular entity and is a polyethylene glycolyated (PEGylated) derivative of naloxone. Its chemical name s are (5  ,6  )

- 17

- allyl

- 6

- ((20

- hydroxy

3,6,9,12,15,18

- hexaoxaicos

- 1

- yl)oxy)

- 4,5

- epoxymorphinon

- 3,14

- diol or alpha

- 6m PEG 7 - O

naloxol. Naloxegol is an antagonist predominantl y of peripheral mu opioid receptors. The Food and Drug Administration (FDA) approved naloxegol for marketing on September 16, 2014 under the brand name Movantik TM . It is indicated for the treatment of opioid

- induced constipation (OIC) in adults with chronic non

- cancer pain.
In June 2010, a drug manufacturer requested a determination of the control status of naloxegol from the Drug Enforcement Administration ( DEA ) . The DEA conduc ted a scientific review of the chemical structure of mPEG

- naloxol in accordance with the definitions within the Controlled Substances Act (CSA) and its implementing regulations, and in July 2010, the DEA determined that the chemical structure of naloxegol can be derived from opium alkaloids and is therefore subject to automatic inclusion in s chedule II of the CSA pursuant to schedule II(a)(1) of 21 U.S.C. § 812(c) and in accordance with 21 CFR § 1308.12(b)(1) , which control any salt, compound, derivative, o r preparation of opium or opiate, including derivatives of noroxymorphone

. Naloxegol is related in chemical structure to naloxone, which is excluded from control, including its salts under the CSA

. 21 CFR §1308.12(b)(1). Naloxegol is not a salt of naloxone, therefore it is not included under this exclusion. The DEA determined that it can be derived from opium alkaloids and meets the requirem e nts for control in s chedule II of the CSA pursuant to 21 U.S.C. § 812 (c), Schedule II (a)(1).
In accordanc e with 21 CFR § 1308. 43,t he DEA received a petition from the drug sponsor dated March 22, 2012
, requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude naloxegol as a schedule II controlled substance. The petitioner state d that naloxegol is a mu opi oid receptor antagonist without mu opioid agonist or partial agonist properties. In accordance with 21 CFR § 1308.43(c), t he D EA accepted th e petition for filing on October 1, 2012

. Pursuant to 21 U.S.C. § 811(b), the DEA gathered the necessary data on naloxegol and forwarded the same
, the s ponsor’s petition
, and a request for scheduling recommendation o n naloxegol to the Department of Health and Human Services ( HHS ) on February 7, 2013. According to the HHS, the s ponsor s ubmitted a New Drug Application ( NDA ) for naloxegol on September 16, 2013. Based on the NDA, the HHS summarized that naloxegol is an antagonist of peripheral mu opioid receptors for the treatment of OIC. Because of its conjugation to polyethylene glycol ( PEG )
, naloxegol does not cross the blood

- brain barrier (BBB), therefore it
acts primarily as a peripheral antagonist

. On August 8, 2014 , the HHS provided to the D EA a scientific and medical evaluation entitled “Basis for the Recommendation to Decontrol Naloxegol and its Salts from Schedule II of the Controlled Substances Act” and a scheduling recommendation. Following consideration of the eight factors and findings related to the substance’s abuse potential, legitimate medical use, and dep endence liability, the HHS recommend ed that naloxegol and its salts be de controlled3

from s chedule II of the CSA. The National Institute on Drug Abuse (NIDA) concurred with the recommendation. The CSA requires the DEA to determine whether the HHS’ s scient ific and medical evaluation
, scheduling recommendation
, and all other relevant data constitute substantial evidence that a substance should be scheduled

. 21 U.S.C. § 811(b). Pursuant to 21 U.S.C. § 811(c), the Attorney General reviews the facts and all other relevant data. T he Attorney General has delegated this scheduling authority to the Administrator of the DEA. 28 CFR 0.100(b)

. This document is a summarized review of the relevant data, law enforcement information
, and determination to remove naloxegol from control under the CSA. Based on the review of the DEA eight

- factor analysis and upon the scientific and medical evaluation and recommendation of the HHS, the Deputy Administrator finds that the evidence establishes that naloxegol does not possess sufficient potential for abuse to justify its continued control in any schedule of the CSA. The information contained in this document is organized according to the eight factors as specified in 21 U.S.C. § 811(c).

II. Eight Factors Determinative of Control
Factor 1. The Substance’s Actual or Relative Potential for Abuse Naloxegol is a conjugation of polyethylene glycol (PEG) to naloxone. PEGylation of naloxone decreases the capacity of the substance to cross the blood

- brain barrier , limiting the availability of naloxegol to peripheral opioid receptors (Diego et al., 2011 ; HHS review ). Due to naloxegol being an antagonist at the three opioid receptor s , mu , delta , and kappa
, the HHS asse rts that naloxegol does not have opioid agonist properties.
In vitro studies Receptor Binding Studies Naloxegol competitively inhibited binding of [ 3 H]

- naloxone, an opioid receptor antagonist, to mu and kappa opioid receptors and [ 3 H]

- DPDPE , a delta opioid receptor ligand, to delta opioid receptors. According to the HHS, naloxegol binds with a high affinity to the mu opioid receptors, moderate

- to

- high affinity to the kappa opioid receptors, and moderate affinity to the delta opioid receptors. Receptor Activation Studies
Acc ording to the HHS, naloxegol did not exhibit full agonistic activity in a [ 35 S]GTP  S functional assay at the mu, delta, and kappa opioid receptors. Naloxegol acted as an antagonist
at the three opioid receptors. Naloxegol also acted as a slight partial a gonist at the kappa opioid receptor.4

In viv o studies Drug Discrimination Studies There is a strong correspondence between the discriminative stimulus effects of a given drug in animals and its subjective effects in humans. Thus, drug discrimination is widely used to determine whether or not a drug or substance is pharmacologically similar to a known drug of abuse.
The HHS summarize d the drug discrimination studies done in morphine

- trained rats. The se studies evaluated whether naloxegol produced morphin e

- like discriminative effects in morphine

- trained animals. Naloxegol did not produce morphine

- like responding at the tested doses, producing less than 20% of the morphine responses. The lack of morphine

- like discriminative effects is indicative of the l ack of mu opioid receptor activation. Naloxegol (3

- 300 mg/kg) was also administered orally to morphine

- trained rats prior to administration of several doses of morphine (0.96

- 9.6 mg/kg) . The purpose of these studies was to determine if naloxegol could r everse the discriminative effects of morphine. Naloxegol did dose

- dependently antagonize morphine responding, but the antagonism was limited by increasing doses of morphine. The HHS states that naloxegol can antagonize centrally

- mediated effects of morph ine, but only at high doses. Self

- administration studies It has been demonstrated that drugs that are self

- administered by animals also have abuse potential in humans (Weerts et al., 1999; Ator and Griffith, 2003). The HHS summarized two self

- administra tion studies done in rats trained to self

- administer morphine. The rats were allowed to self

- administer different doses of naloxegol ( 1

- 30 mg/kg/infusion) and morphine (0.03

- 1 mg/kg/infusion). None of the doses of naloxegol infusions induced self

- adminis tration infusions different from the vehicle

- alone
, thereby indicating that naloxegol lacks rewarding properties

. Morphine self

- administration studies showed a dose

- response pattern that is typical of mu opioid agonists.
Human Clinical Studies
Abuse

- related Adverse Effects According to the HHS, the abuse

- related pharmacology of naloxegol in humans was assessed from adverse effects (AEs) reported in the Phase I and Phase 2/3 clinical trials. Twelve Phase I studies are conducted in healthy volunteers (n=474). The HHS states that the doses of naloxegol tested in the Phase I trials represent doses which are one

- third up to 80

- fold the proposed therapeutic doses of naloxegol ( 12.5 and 25 mg/day ) in patients taking opioids for analgesia. In the se 12 naloxegol clinical trials, naloxegol did not p roduce any euphoria or abuse

- related adverse events (AEs). In the Phase 2/3 clinical studies, the patients were taking opioids for pain management. They were administered naloxegol to determine the effect of naloxegol in preventing OIC. As with the Phas e I studies, there were no reports of any euphoria or abuse

- related adverse events (AEs)

.5

According to the HHS, naloxegol has not been marketed in the United States or in any other country, so there is no available information on the actual abuse of nalo xegol. Summary Naloxegol has been demonstrated to be a mu opioid receptor antagonist. In animal abuse liability studies (drug discrimination and self

- administration )
, naloxegol did not produce responses seen with morphine administration. In clinical studies, there have been no reports that naloxegol dose

- dependently produced AEs associated with abuse potential. Therefore, naloxegol does not demonstrate a potential f or abuse.
Factor 2. Scientific Evidence of Its Pharmacological Effects Gastrointestinal AEs effects are commonly experienced by chronic users of opioid analgesics. Opioids delay gastric emptying and intestinal transport, which over time leads to debilit ating constipation. OIC is caused by activation of the mu opioid receptor in the GI tract (Asai and Power, 1999; Camilleri, 2011; Diego et al., 2011).
In vitro studies
The HHS adds that the binding studies show that naloxegol does not bind significantly (> 50% inhibition) to other molecular central nervous system ( CNS ) receptors, including dopamine, serotonin, glutamate, 

- aminobutyric acid (GABA), sigma, acetylcholine, norepinephrine, cannabinoid, histamine, and monoamine transporters.
In vi v o behavioral studies Toxicological Studies
General Behavioral Observations
The HHS summarized toxicological studies on oral naloxegol (25

- 500 mg/kg) that were done in rats (28 days) and beagles (14 and 28 days). These studies did not produce behavioral sign s of abuse potential, e.g. increased or decreased motor behavior, decreased body weight, or food intake. A t supratherapeutic doses (doses above those comparable to proposed human therapeutic doses) , nalo xegol occasionally produced signs of endogenous opio id system antagonism such as diarrhea, soft stool, excessive salivation, retching and emesis.
Irwin Screen
The Irwin screen is used to assess acute toxicity of a new substance in rodents. It also shows the dose range for chemical

- induced CNS responses and the primary effects of the test substance on behavior and physiological functions. The animals are observed over a period ranging from several hours to the following day after administration. The behaviors being assessed are related to neurotoxicity, such as convulsions and tremor and behaviors related to either CNS stimulation or depression. Autonomic function responses are also assessed (Roux et al., 2004; Moser, 2011).6

According to the HHS, in a standard Irwin screen test, rats were administered naloxegol (100

- 1000 mg/kg) orally. Naloxegol did not induce any of the behaviors in the battery of tests for the Irwin screen. The HHS asserts that an opioid antagonist without abuse potential would not induce the behaviors assessed in the Irwin screen, especially those related to predictors of abuse potential such as changes in motor activity, body weight, or food intake. Analgesia Studies According to the HHS, there were two analgesia models in which naloxegol was tested in rodents, hotplate test and grid stimulation. Naloxegol was administered orally (10

– 1000 mg/kg). In both models naloxegol did not produce any analgesic effects, demonstrating the lack of mu opioid receptor activatio n. Naloxegol was also tested in both analgesia models for its potency in reversing morphine

- induced (s.c. or i.v. 1

- 32 mg/kg) analgesia. Naloxegol did not fully reverse the analgesia produced by morphine

. Human clinical trials Withdrawal effects of Nalox egol According to the HHS, oral naloxegol (12.5 and 25 mg/day) did precipitate opioid withdrawal in patients receiving opioids for pain management in the Phase 2/3 clinical trials. The incidence of withdrawal was low, th e symptoms of opioid withdrawal oc curred in patients taking naloxegol (2%) compared to placebo (< 1%). It occurred with a higher incidence in patients receiving naloxegol (3%) at the higher dose (25 mg/day) than those receiving the 12.5 mg/day dose (1%). The HHS asserts that the withdraw al symptoms reported did not always meet the criteria of a clinically meaningful opioid withdrawal syndrome. Though the incidence of opioid withdrawal was low, these data show that there may be some involvement of central mediated antagonism of mu opioid receptors by naloxegol.
Factor 3

. The State of Current Scientific Knowledge Regarding the Drug or Other Substances According to the HHS, n aloxegol is a conjugate of the opioid antagonist alpha

- naloxo l to the polymer polyethylene glycol (PEG). PEGylating naloxone substantially decreases the ability the substance from crossing the BBB, thereby containing the drug in peripheral circulation. Chemistry According to the HHS, naloxegol is known as (5  ,6  )

- 17

- allyl

- 6

- ((20

- hydroxy

3,6,9,12,15,18

- hexa oxaicos

- 1

- yl)oxy)

- 4,5

- epoxymorphinon

- 3,14

- diol alpha

- 6mPEG 7 - O

- naloxol

. The CAS number is 854601

- 70

- 0. The molecular formula of naloxegol is C 34 H 53 NO 11 and the molecular weight is 651.8 g/mol. It is a white to off

- white powder and is soluble in aqueous solvents over a pH range of 1 to 7.5. Naloxegol is synthesized in a five

- step process from naloxone hydrochloride, an opioid antagonist derived from thebaine.
The HHS states that though the patients in the Phase 3 trials were given a tablet of naloxego l as a free base, the s ponsor will market naloxegol as an oxalate salt.7

Pharmacokinetics According to the HHS, naloxegol (25 mg/day) is rapidly absorbed following oral administration in healthy volunteers. Maximum plasma concentra tions were reached in 1.5

– 2 h

. The plasma half

- life (t 1⁄2 ) is 7

– 9 h , with a maximal plasma concentration (C max ) of 45 ng/ml. In a human distribution study with radiolabeled naloxegol
, the highest levels of radioactivity were in the liver and kidneys. The el i mination t 1⁄2 of naloxegol is rapid, with the majority being eliminated within 24

- hours post

- dose.
Factor 4 . Its history and current pattern of abuse According to the HHS, t here has been no evidence of abuse

- related signals from the human clinical trials. Naloxegol is a mu opioid antagonist, which as a class does not have abuse potential.

Factor 5. The scope, duration, and significance of abuse There have been no reports of abuse of naloxegol. According to the National Forensic Laboratory Information System (NFLIS ) and the System to Retrieve Information from Drug Evidence (STRIDE), there have been no reports of naloxegol seizures from 2010

– present. Once naloxegol is marketed, the HHS asserts that it is unlikely that it will be abused.

Factor 6. What, if any, risk there is to the public health According to the HHS, n aloxegol is well

- tolerated and safe at the therapeutic doses of 12.5 mg and 25 mg. Preclinical and clinical studies showed no evidence of potential for abuse of naloxegol and thus there is little public health risk from naloxegol.

Factor 7. Its psychic or physiological dependence liability The HHS summarized a physical dependence liability study of naloxegol in rats. The rats were orally administered naloxegol (0 (vehicle), 50, 150 or 500 mg/kg) for 15 days . The rats were observed for behavior on the Irwin screen, both during the drug administration period and 10 days following drug discontinuation. No symptoms of physical dependence were observed for naloxegol during either p eriod. The HHS also mentioned that the lack of naloxegol self

administration by animals is consistent with a lack of psychic dependence liability.

Factor 8. Whether the substance is an immediate precursor of a substance already controlled Naloxegol is n ot considered an immediate precursor of any substance controlled under the CSA.8

References

1. Asai T and Power I. (1999). Anesthesia and Analgesia
, 88 , 204

- 208. 2. Ator NA and Griffiths PR. (2003). Drug and Alcohol Dependence
, 70 : S55

- 72 3. Department of Health and Human Services, FDA Review (201 3 ). Basis for the Recommendation to Decontrol Naloxegol and its Salts from Schedule II of the Controlled Substances Act. 4. Camilleri M. (2011). American Jou r nal of Gastroenterology
, 106 , 835

- 842. 5. Diego, L, Atayee, R, Helmons, P, Hsi ao G and von Gunten, CF. (2011). Expert Opinions on Investigational Drugs
, 20 , 1047

- 1056. 6. Moser VC (2011)

. Functional assays for neurotoxicity testing. Toxicologic Pathology
, 39 : 36

- 45. 7. Roux S, Sablé E, and Porsolt RD (2004). Current Protocols in Pharmacology , Chapter 10: Unit 10.10.
8. Weerts EM, Ator NA, and Griffiths RR

. (1999). Drug and Alcohol Dependence
, 57 : 51

- 60.