Note: Descriptions are shown in the official language in which they were submitted.
84334135
METHODS TO TREAT OPIOID USE DISORDER
[0001]
BACKGROUND
[0002] According to the Diagnostic and Statistical Manual for Mental
Disorders, 5th Edition
(DSM-5), opioid use disorder is characterized by signs and symptoms that
reflect compulsive,
prolonged self-administration of opioid substances that are used for no
legitimate medical
purpose or, if another medical condition is present that requires opioid
treatment, they are used in
doses greatly in excess of the amount needed for that medical condition. In a
2015 report from
the National Survey on Drug Use and Health, 12.4 million Americans engaged in
non-medical
use of prescription pain relievers, including opioids. Approximately 2.06
million Americans met
criteria for prescription pain reliever use disorder. The same report
suggested that 5.1 million
people aged 12 and older have used heroin at some point in their lives, with
828,000 using in the
past year and 329,000 using in the past month. There were approximately
580,000 people who
had a heroin use disorder in the past year. Perhaps most concerning, deaths
from overdose of
opioid analgesics (including opioids, methadone and other synthetic narcotics)
showed a 5.2-fold
increase from 5,528 to 28,647 deaths between 2001 and 2015. Similarly, heroin-
related overdose
fatalities showed a 5.4-fold increase during this same period, from 1,779
deaths in 2001 to
12,989 in 2015. An emerging concern contributing to recent increases in opioid
overdose deaths
were 9,580 deaths due to synthetic opioids (other than methadone) which
increased 72% in one
year (since 2014).
[0003] Opioid receptors are located in both the central nervous system (CNS)
and the
periphery. In the CNS, they are found in high concentrations in the limbic
system and the spinal
cord. The natural ligands for the opioid receptors are a group of
neuropeptides known as
endorphins. Opioid analgesics mimic the action of these natural ligands, but
have a more
prolonged action as they are not subject to rapid local metabolism. Three
major opioid receptor
subclasses have been identified: it-, lc-, and 6-. Buprenorphine is a partial
agonist at the n-opioid
receptor, an antagonist at the lc-and 8-opioid receptors and an agonist at the
nociceptin/orphanin
FQ (N(OFQ) receptor. In contrast to a full agonist at the .t-opioid receptor,
buprenorphine has
Date Recue/Date Received 2021-08-11
less maximal euphoric effect, and a ceiling on its respiratory depressant
effects. By binding to ii-
opioid receptors in the brain, buprenorphine reduces craving for opioids and
opiate withdrawal
symptoms, minimizing the need of opioid-dependent patients to use illicit
opiate drugs. For the
maintenance treatment of opioid use disorder, SUBUTEX tablets (buprenorphine;
Indivior,
Inc.), SUBOXONE tablets (buprenorphine/naloxone; Indivior, Inc.), or SUBOXONE
film
(buprenorphine/naloxone; lndivior, Inc.) may be given as a single daily dose.
10004] A major issue in the pharmacological treatment of opioid dependence is
the high rate of
non-adherence because of the need for daily intake of medication. Currently,
there is no FDA-
approved sustained-release buprenorphine injectable product indicated for the
treatment of
opioid use disorder. Such a sustained-release product would offer advantages
over existing
buprenorphine therapy by improving patient compliance and reducing diversion,
abuse, and
unintended exposure, particularly to children.
[0005] To this end, the present disclosure provides dosing regimens of
sustained-release
buprenorphine formulations that provide, among other benefits, optimal
dosages, optimal
treatment periods, therapeutic steady-state buprenorphine plasma
concentrations, and therapeutic
steady-state u-opioid receptor occupancy in the brain for the treatment of
opioid use disorder.
SUMMARY
[0006] The disclosure provides buprenorphine formulations and monthly dosing
regimens that
achieve opioid blockade (i) from the first dose of treatment and across the
entire monthly dosing
interval, (ii) at buprenorphine concentrations that are safe, therapeutic, and
well-tolerated; (iii)
that reduce the need for rescue medications. The buprenorphine formulations
and monthly
dosing regimens achieve clinically significant control of craving and
withdrawal symptoms,
prevent illicit opioid use, and limit the possibility of misuse and diversion
of buprenorphine and
enable treatment concordance.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 shows the cumulative distribution function (CDF) of the
percentage of patients
having urine samples negative for illicit opioids combined with negative self-
reports of illicit
opioid use from Weeks 5 to 24 of the study. The x-axis represents the
percentage of abstinence
and the y-axis represents the percentage of patients. With reference to Week
10, the top line is
"RBP-6000 300/100 mg +1DC," the middle line is "RBP-6000 300/300 mg + IDC,"
and the
bottom line is "Placebo + IDC."
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[0008] FIG. 2 shows the percentage of patients who had at least 80% of their
weekly urine
samples negative for illicit opioids combined with negative self-reports of
illicit opioid use from
Weeks 5 to 24 of the study.
[0009] FIG. 3 shows the mean Clinical Opiate Withdrawal Scale (COWS) score
over time for
the clinical study described in the Example. The x-axis shows time in weeks.
The y-axis shows
the COWS mean score. With reference to Week 2, the top line is "Placebo+IDC",
the middle line
is "RBP-6000 300/100 mg + 1DC," and the bottom line is "RBP-6000 300/300 mg +
IDC."
[00101 FIG. 4 shows the COWS score of a cumulative percentage of subjects in
relationship to
their buprenorphine plasma concentration levels.
[00111 FIG. 5 shows the mean opiate craving VAS over time for the clinical
study described in
the Example. The x-axis shows time in weeks. The y-axis shows the opiate
craving VAS mean
score. With reference to Week 2, the top line is "Placebo + IDC", the middle
line is "RBP-6000
300/100 mg + IDC," and the bottom line is "RBP-6000 300/300 mg + IDC."
[0012] FIG. 6 shows the cumulative percentage of subjects having an opioid
craving VAS
score of 0 with respect to the buprenorphine plasma concentration.
[0013] FIG. 7 shows the association between plasma concentrations of
buprenorphine,
predicted brain u-opioid receptor occupancy (ORO) and clinical endpoints. With
reference to
the plasma concentration value of 2 ng/mL, the top line is the percentage of
patients having an
Opioid Craving VAS score between 0 and 20 (in view of the buprenorphine plasma
concentration shown on the x-axis), the second-from-top line is the percentage
of brain u-opioid
receptor occupancy (p.ORO) (in view of the buprenorphine plasma concentration
shown on the
x-axis), the third-from-top line is the percentage of patients having urine
samples negative for
illicit opioids together with negative self-reports of illicit opioid use (in
view of the
buprenorphine plasma concentration shown on the x-axis), and the bottom line
is the percentage
of patients having an Opioid Craving VAS score of 0 (in view of the
buprenorphine plasma
concentration shown on the x-axis).
[0014] FIG. 8 shows that the EC50 for injection drug patients ("by injectable
route") was 4.3
ng/mL while the ECso for patients using opioids by non-injectable route at
baseline was 3.6 times
lower (1.2 ng/mL).
[0015] FIG. 9 shows the relationship between buprenorphine plasma
concentrations (x-axis);
drug liking VAS score (y-axis on left hand side of figure), and predicted
whole brain .t-opioid
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receptor occupancy (y-axis on right hand side of figure). With reference to
the 2 ng/mL data
point on the x-axis, the upper line refers to the [i-opioid receptor occupancy
and the bottom line
refers to the VAS score.
[0016] FIGS. 10A-C show the model predictions versus observations for dropout
per treatment
arm and age category. FIG. 10A shows the treatment arm of Formulation D at a
dose of 300 mg
for two months and 100 mg for 4 months. FIG. 10B shows the treatment arm of
Formulation D
at a dose of 300 mg for 6 months. FIG. 10C shows the placebo arm. The solid
lines are the
Kaplan Meier curves for observations, while the dashed line are the Kaplan
Meier curves for
model predictions. In each figure, the upper line represents the age group of
51-64; the next
lower line represents the age group of 41-50; the next lower line represents
the age group of 31-
40; and the lowest line represents the age group of 19-30.
[0017] FIG. 11 shows the relationship between the percent of subjects
abstinent and the
buprenorphine plasma concentration. The solid line represents the pooled
active arms.
100181 FIG. 12 provides a summary of the covariate effects on abstinence. In
particular, FIG.
12 provides information on the reference standard, employed subjects, and
black or African
American subjects.
100191 FIG. 13 provide a summary of the covariate effects on abstinence. In
particular, FIG. 13
provides information on the reference standard, injectable route users,
subjects with the OPRD I
TC genotype, and subjects with the OPRD I IT genotype. OPRD1 refers to
rs678849.
100201 FIGS. 14A-C provide a visual predictive check for the number of
subjects of each
opioid craving VAS score category. In each figure, the upper line represents
all patients, the next
lower low represents patients have a craving VAS score less than or equal to
20, the next lower
line represents patients having a craving VAS score less than or equal to 5,
and the bottom line
represents patients having a craving VAS score of 0. FIG. 14A shows the
treatment arm of
Formulation D at a dose of 300 mg for two months and 100 mg for 4 months. FIG.
14B shows
the treatment arm of Formulation D at a dose of 300 mg for 6 months. FIG. 14C
shows the
placebo arm.
[0021] FIGS. 15A-C show the model predictions versus observations for dropout
per treatment
arm based on race, particularly comparing black/African-American patients to
other races. FIG.
15A shows the treatment arm of Formulation D at a dose of 300 mg for two
months and 100 mg
for 4 months. FIG. 15B shows the treatment arm of Formulation D at a dose of
300 mg for 6
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months. FIG. 15C shows the placebo arm. The solid lines are the Kaplan Meier
curves for
observations, while the dashed line are the Kaplan Meier curves for model
predictions. In each
figure, the upper line represents black/African-American patients and the
lower line represents
all other races combined (primarily Caucasian patients). The data shows that
race was a
significant predictor in all treatment arms, with dropout rates reduced by
about 40% in
black/African American patients compared to Caucasian/other patients.
[0022] FIGS. 16A-C show the model predictions versus observations for dropout
per treatment
arm based on CG1-S score. FIG. 16A shows the treatment arm of Formulation D at
a dose of 300
mg for two months and 100 mg for 4 months. FIG. 16B shows the treatment arm of
Formulation
D at a dose of 300 mg for 6 months. FIG. 16C shows the placebo arm. The solid
lines are the
Kaplan Meier curves for observations, while the dashed line are the Kaplan
Meier curves for
model predictions. A higher dropout rate (the lower line in FIG. 16C) was only
seen in the
placebo group when the CGI-S score was less 1-3 (normal to mildly ill).
[0023] FIG. 17 shows the model predictions versus observations for dropout per
treatment
arm. Treatment was a significant predictor of dropout, with completion rates
two times higher in
the treatment arms (300/300mg at 64%; 300/100mg at 62%) compared to placebo
(34%). The
solid lines are the Kaplan Meier curves for observations, while the dashed
line are the Kaplan
Meier curves for model predictions.
[0024] FIGS. 18A-B show the effect of opioid craving on the dropout rat. FIG.
18A shows that
patients in the treatment groups who had a craving score greater than 20 at a
drop out rate that
was three times higher than those patients who had a craving score of 1-5.
FIG. 18B shows that
patients in the placebo group who had a craving score greater than 20 at a
drop out rate that was
3.6 times higher than those patients who had a craving score of 1-5.
[0025] FIGS. 19A-B show the pharmaeokinetie results (FIG. 19A) and
pharmacodynamic
results (FIG. 19B) for the two dosing regimens (300/300 vs. 300/100)
administered to injection
drug patients. In FIGS. 19A-B, "Injecting Users" refers to injection drug
patients. With reference
to week 24 in FIGS. 19A and 19B, the upper line represents injection drug
patients administered
the 300/300 mg dosing regimen, and the lower line represents injection drug
patients
administered the 300/100 mg dosing regimen.
DETAILED DESCRIPTION
[00261 "Buprenorphine" refers to buprenorphine free base and buprenorphine
CA 2995923 2018-02-21
pharmaceutically acceptable salts (e.g., buprenorphine hydrochloride).
Buprenorphine free base
is a semisynthetic derivative of thebaine, and is mixed partial agonist opioid
receptor modulator.
Buprenorphine free base has a chemical formula C29H41N04, and a chemical name
21-
cyclopropy1-7a-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-
tetrahydrooropavine.
[0027] "Sustained-release buprenorphine formulation," "composition,"
"formulation" or
"buprenorphine formulation" refer to any formulation comprising buprenorphine
that can
provide therapeutic plasma concentration levels of buprenorphine for at least
1 month. In
aspects, the sustained-release buprenorphine formulation is an injectable
formulation. In aspects,
the sustained-release buprenorphine formulation is a subcutaneous injectable
formulation. In
aspects, the sustained-release buprenorphine formulation is an intramuscular
injectable
formulation.
[0028] "Therapeutic levels" of buprenorphine refers to buprenorphine plasma
concentrations
that are effective: (a) in the treatment of opioid use disorder; (b) in
suppressing opioid
withdrawal symptoms; (c) in eliminating opioid withdrawal symptoms; (d) in
reducing opioid
craving; (e) in eliminating opioid craving; (f) in reducing illicit opioid
use; (g) in preventing
illicit opioid use; or (e) a combination of one or more of the foregoing.
"Therapeutic levels" can
also be described in terms of steady-state minimum buprenorphine plasma
concentration levels,
steady-state average buprenorphine plasma concentration levels, and steady-
state maximum
buprenorphine plasma concentration levels, all of which are described in more
detail herein.
[0029] "One month" means 28 days to 31 days. In one embodiment, one month is
28 days. In
one embodiment, one month is 29 days. In one embodiment, one month is 30 days.
In one
embodiment, one month is 31 days.
[0030] "Patient" or "subject" refers to a human. In aspects, the "patient" is
an injection drug
patient. In aspects, the patient is black or African-American. In aspects, the
patient is a black or
African-American injection drug patient. In aspects, the patient has an OPRDI
TT genotype. In
aspects, the patient has an OPRD1 TC genotype. In aspects, the patient is an
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is an injection
drug patient with an
OPRDI TC genotype. In aspects, the patient is black or African-American with
an OPRDI TT
genotype. In aspects, the patient is black or African-American with an OPRD1
TC genotype. In
aspects, the patient is a black or African-American injection drug patient
with an OPRDI TT
genotype. In aspects, the patient is a black or African-American injection
drug patient with an
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84334135
OPRD1 TC genotype.
[0031] "Injection drug patient" refers to a patient who used illicit opioids
by an injectable route
at baseline (e.g., upon entry into the treatment program described herein).
"Injection drug
patient" can be used interchangeably with "patient injecting illicit opioids"
and "patient using
illicit opioids by injectable route." In aspects, the injectable route is
intravenous. In aspects, the
injectable route is intramuscular. In aspects, the injectable route is
subcutaneous. In aspects, the
"injection drug patient" is an intravenous injection drug patient, i.e., the
patient intravenously
injects illicit opioids. In aspects, the "injection drug patient" is an
intramuscular injection drug
patient, i.e., the patient intramuscularly injects illicit opioids. In
aspects, the "injection drug
patient" is a subcutaneous injection drug patient, i.e., the patient
subcutaneously injects illicit
opioids.
[0032] "Illicit opioid" refers to any opioid that is abused or misused by a
patient. The illicit
opioid can be a street drug (e.g., heroin) or a prescription drug (e.g.,
fentanyl, oxycodone,
hydrocodone, hydromorphone, oxymorphone, meperidine, morphine, codeine,
methadone). In
aspects, the illicit opioids are abused by an injectable route. In aspects,
the illicit opioids are
abused by a non-injectable route, such as pulmonary route (e.g., smoking),
oral route (e.g.,
swallowing), nasal route (e.g., snorting), or rectal route (e.g.,
suppository).
[0033] "Black" or "African-American" refers to a patient who self-identifies
their race as black
or African-American.
[0034] "OPRD1" refers to the opioid receptor delta 1 gene having the UniProtKB
Accession
Number P41143.
[0035] An "OPRD1 TC genotype" refers to patients having the intronic SNP
rs678849 and the
TC genotype in the opioid receptor delta 1 gene.
[0036] An "OPRD1 TT genotype" refers to patients the intronic SNP rs678849 and
the TT
genotype in the opioid receptor delta I gene.
[0037] With reference to the Diagnostic and Statistical Manual for Mental
Disorders, 5th
Edition, American Psychiatric Association, 2013 (also referred to herein as
DSM5), "opioid use
disorder" is characterized by signs and symptoms that reflect compulsive,
prolonged
self-administration of opioid substances that are used for no legitimate
medical purpose or, if
another medical
7
Date Recue/Date Received 2021-08-11
condition is present that requires opioid treatment, they are used in doses
greatly in excess of the
amount needed for that medical condition. In aspects, the opioid use disorder
is moderate opioid
use disorder. "Moderate opioid use disorder" is defined by reference to the
DSM5 Opioid Use
Disorder Checklist (ICD-9-CM code 304.00 or ICD-10-CM code F11.20) as having
the presence
of 4 or 5 symptoms indicated in the DSM5 Opioid Use Disorder Checklist. In
aspects, the
opioid use disorder is severe opioid use disorder. "Severe opioid use
disorder" is defined by
reference to the DSM5 Opioid Use Disorder Checklist (ICD-9-CM code 304.00 or
ICD-10-CM
code F11.20) as having the presence of 6 or more symptoms indicated in the
DSM5 Opioid Use
Disorder Checklist. In aspects, the opioid use disorder is moderate-to-severe
opioid use disorder.
Moderate-to-severe opioid use disorder refers to the presence of 4 or more
symptoms indicated
in the DSM5 Opioid Use Disorder Checklist. In aspects, the opioid use disorder
is mild opioid
use disorder. "Mild opioid use disorder" is defined by reference to the DSM5
Opioid Use
Disorder Checklist (ICD-9-CM code 305.50 or ICD-I 0-CM code F11.10) as having
the presence
of 2 or 3 symptoms indicated in the DSM5 Opioid Use Disorder Checklist. In
aspects, the opioid
use disorder is mild-to-moderate opioid use disorder. Mild-to-moderate opioid
use disorder
refers to the presence of 2 to 5 symptoms indicated in the DSM5 Opioid Use
Disorder Checklist.
As used herein, the term "opioid use disorder" is synonymous with "opioid
dependence," "opioid
addiction," and "opioid abuse." In aspects, "treating opioid use disorder"
encompasses one or
more of reducing opioid withdrawal symptoms, eliminating opioid withdrawal
symptoms,
reducing opioid craving, eliminating opioid craving, and reducing or
eliminating the use of illicit
opioid use.
[0038] "Opioid withdrawal symptoms" includes one or more symptoms associated
with
withdrawal from illicit opioids. Such symptoms can include one or more of the
following:
agitation, anxiety, muscle aches, increased tearing, insomnia, runny nose,
sweating, yawning,
abdominal cramping, diarrhea, dilated pupils, goose bumps, nausea, and
vomiting. Opioid
withdrawal symptoms can begin to occur within a few hours to a few days after
the last intake of
an opioid. Opiate withdrawal symptoms can be measured by the Clinical Opiate
Withdrawal
Scale (COWS).
[0039] "Reducing opioid withdrawal symptoms" refers to a patient who has fewer
or milder
illicit opioid withdrawal symptoms when compared to the withdrawal symptoms at
a baseline
time point. In aspects, the method of reducing opioid withdrawal symptoms
refers to a patient
who has a lower score on the COWS when compared to a baseline time point.
8
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[0040] "Eliminating opioid withdrawal symptoms" refers to a patient who does
not have any
withdrawal symptoms. In aspects, the method of eliminating illicit opioid
withdrawal symptoms
refers to a patient who has a score of 0 to 4 on the COWS.
[0041] "Craving" refers to a desire of a patient to take an illicit opioid,
and may have physical,
behavioral, or cognitive underpinnings. Craving can be measured, for example,
the by Opioid
Craving Visual Analog Scale (VAS), which is a self-report by patients of the
intensity of their
illicit opioid craving on a 0 to 100 mm scale. In aspects, craving is a
symptom of opioid use
disorder where the patient is actively taking illicit opioids or where the
patient has stopped taking
illicit opioids.
[0042] "Reducing opioid craving" refers to a patient who has less or milder
craving for illicit
opioids when compared to the craving at a baseline time point. In aspects, the
method of
reducing plaid craving refers to a patient who achieves a lower score on the
Opioid Craving
VAS when compared to a baseline time point.
[0043] "Eliminating opioid craving" refers to a patient who does not have any
craving for an
illicit opioid. In embodiments, the methods of eliminating opioid craving
refers to a patient who
has a score of 0 on the Opioid Craving VAS.
[0044] "Reducing illicit opioid use" and "reducing opioid use" refer to a
patient who consumes
(e.g., injectable/non-injectable routes) less illicit opioids when compared to
a baseline time point.
[0045] "Preventing illicit opioid use" and "preventing opioid use" refer to a
patient who no
longer consumes (e.g., injectable/non-injectable routes) illicit opioids.
"Preventing illicit opioid
use" results in "opioid abstinence."
[0046] "Opioid abstinence" refers to a patient who has stopped taking illicit
opioids. In
aspects, opioid abstinence is identified by negative urine drug screens for
illicit opioids
combined with negative self-reports for illicit opioid use. In aspects, the
methods described
herein allow for a patient to maintain opioid abstinence over a period of
time.
[0047] "RBP-6000" refers to Formulation D, described herein. RBP-6000, also
known as
SUBLOCADETM (lndivior, Richmond, VA) was approved by the US Food and Drug
Administration on November 30, 2017. In aspects, RBP-6000 contains about 300
mg
buprenorphine free base. In aspects, RBP-6000 contains about 100 mg
buprenorphine free base.
[0048] "300/100 mg," "300/100," and "300mg/100mg" refer to a treatment program
where
Formulation D containing 300 mg buprenorphine was administered to a patient
for 2 months, and
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84334135
then Formulation D containing 100 mg buprenorphine was administered to a
patient for at least 4
months.
[0049] "300/300 mg," "300/300," or "300mg/300mg" refer to a treatment program
where
Formulation D containing 300 mg buprenorphine was administered to a patient
for at least 6
months.
[0050] "IDC" refers to individual drug counseling.
[0051] "Administering" means parenteral administration of the formulations
described herein
to the patient or the implantation of a slow-release device, such as a mini-
osmotic pump, in the
patient. Parenteral administration includes, for example, intravenous,
intramuscular, intra-
arteriole, intradermal, intrathecal, subcutaneous, intraperitoneal,
intraventricular, and
intracranial. In aspects, "administering" refers to subcutaneous injection of
the formulations
described herein.
[0052] "Pharmaceutically acceptable salt" refers to acid or base salts of
buprenorphine.
Examples of pharmaceutically acceptable salts include mineral acid
(hydrochloric acid,
hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic
acid, propionic acid,
glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl
iodide, ethyl iodide,
and the like) salts, and the like.
[0053] "EC50" is the buprenorphine plasma concentration yielding half of the
maximal effect
in the maximal effect (Emax) model used for logistic regression modeling of
abstinence data
[0054] "Equation 1" refers to the maximal effect (En...) model that is used to
describe the
relationship between buprenorphine plasma concentrations and -opioid receptor
occupancy
( 0R0) as follows:
p,ORO = E. = Cp
ECõ + Cp
where Cp is buprenorphine plasma concentration and ECso is buprenorphine
plasma
concentration expected to achieve 50% of the maximal ORO (E.). This model was
developed
assuming a direct relationship between plasma concentration and ORO without
equilibration
delay. This model assumes that the metabolite norbuprenorphine has negligible
activity with
respect to brain ORO. Equation 1 is further described in WO 2016/071767.
Date Recue/Date Received 2021-08-11
[0055] "Steady-state Cmm" and "steady-state minimum buprenorphine plasma
concentration"
refer to the lowest steady-state concentration of buprenorphine present in the
patient's plasma
over the dosing interval. In aspects, the steady-state Cmia is achieved after
about 5 months of
treatment with the buprenorphine formulations described herein. In aspects,
the steady-state Cmin
is achieved after about 6 months of treatment with the buprenorphine
formulations described
herein. Six months of treatment refers to the once-monthly administration of
six doses of the
buprenorphine formulations described herein. In aspects, the minimum
buprenorphine plasma
concentration is the average of individual values for the minimum
buprenorphine plasma
concentrations for a group of patients in a study or a group of patients
taking the formulations
described herein. In aspects, the minimum buprenorphine plasma concentration
is that for a
single patient.
[0056] "Steady-state Cmax" and "steady-state maximum buprenorphine plasma
concentration"
refer to the highest steady-state concentration of buprenorphine present in
the patient's plasma.
The steady-state Cmax is generally reached within the first day (e.g., about
18-36 hours; or about
20-24 hours) after administration of the buprenorphine formulations described
herein. In
aspects, the steady-state Cmax is achieved after about 5 months of treatment
with the
buprenorphine formulations described herein. In aspects, the steady-state Cmax
is achieved after
about 6 months of treatment with the buprenorphine formulations described
herein. Six months
of treatment refers to the once-monthly administration of six doses of the
buprenorphine
formulations described herein. In aspects, the maximum buprenorphine plasma
concentration is
the average of individual values for the maximum buprenorphine plasma
concentrations for a
group of patients in a study or a group of patients taking the formulations
described herein. In
aspects, the maximum buprenorphine plasma concentration is that for a single
patient.
[0057] "Steady-state Cavg," "steady-state average buprenorphine
concentration," and "mean
steady-state buprenorphine concentration" refer to the steady-state average
concentration of
buprenorphine that is present in the patient's plasma. In aspects, the steady-
state Cavg is achieved
after about 5 months of treatment with the buprenorphine formulations
described herein. In
aspects, the steady-state Cavg is achieved after about 6 months of treatment
with the
buprenorphine formulations described herein. Six months of treatment refers to
the once-
monthly administration of six doses of the buprenorphine formulations
described herein. In
aspects, the average buprenorphine plasma concentration is the average of
individual values for
the average buprenorphine plasma concentrations for a group of patients in a
study or a group of
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84334135
patients taking the formulations described herein. In aspects, the average
buprenorphine plasma
concentration is that for a single patient.
[0058] In embodiments, the sustained-release buprenorphine formulation is a
formulation
described in US Patent No. 8,921,387, US Patent No. 8,975,270, US Patent No.
9,272,044, US
Patent No. 9,498,432, and US Publication No. 2013/210853. In aspects, the
sustained-release
buprenorphine formulation is a formulation described in US Patent No.
8,236,292, US Patent
No. 8,236,755, US Patent No. 8,545,832, and US Patent No. 9,526,788.
[0059] In one embodiment, the sustained-release buprenorphine formulation is
Formulation D.
"Formulation D" is a composition that comprises, consists essentially of, or
consists of: (i) about
18 wt% buprenorphine free base; (ii) about 32 wt% of a 50:50 poly(DL-lactide-
co-glycolide)
copolymer having a carboxy terminal group and having an average molecular
weight of about
9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt% of N-methyl-2-
pyrrolidone.
"Formulation Dl" refers to Formulation D containing about 300 mg of
buprenorphine free base.
"Formulation D2" refers to Formulation D containing about 100 mg of
buprenorphine free base.
In aspects, Formulation D consists of (i), (ii), and (iii).
[0060] In one embodiment, the sustained-release buprenorphine formulation is
Formulation C.
"Formulation C" is a composition that comprises, consists essentially of, or
consists of: (i) about
14 wt% to about 22 wt% buprenorphine in the form of the free base; (ii) about
22 wt% to about
42 wt% of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having an
average
molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii)
about 40 wt% to
about 60 wt% of N-methyl-2-pyrrolidone.
[0061] In one embodiment, the sustained-release buprenorphine formulation is
Formulation B.
"Formulation B" is a composition that comprises, consists essentially of, or
consists of: (i) about
wt% to about 30 wt% buprenorphine in the form of the free base or a
pharmaceutically
acceptable salt; (ii) about 10 wt% to about 60 wt% of a 50:50 to 95:5 poly(DL-
lactide-co-
glycolide) copolymer having an average molecular weight of about 5,000 Daltons
to about
40,000 Daltons; and (iii) about 30 wt% to about 70 wt% of N-methyl-2-
pyrrolidone. In aspects
of Formulation B, the buprenorphine is in the form of the free base.
[00621 In one embodiment, the sustained-release buprenorphine formulation is
Formulation A.
12
Date Recue/Date Received 2021-08-11
"Formulation A" is a composition that comprises, consists essentially of, or
consists of: (i) at
least one biodegradable polymer; (ii) at least one organic solvent which
comprises an amide, an
ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination
thereof; and (iii)
about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or
pharmaceutically
acceptable salt. In one embodiment, the buprenorphine is in the form of a free
base. In other
aspects, the buprenorphine is present in an amount from about 10 wt % to about
25 wt %; or in
an amount from about 15 wt % to about 20 wt %. In other aspects, the organic
solvent is present
in an amount of about 30 wt% to about 70 wt%; or in an amount of about 40 wt%
to about 60
wt%. In one embodiment, the organic solvent is N-methyl-2-pyrrolidone, 2-
pyrrolidone,
propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl
alcohol, dimethyl
isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate,
monomethyl succinate acid,
monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol,
2,2-dimethy1-1,3-
dioxolone-4-methanol, dimethylforrnamide, dimethylacetamide, N,N-
dimethylformamide,
propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-
caprolactone,
butyrolactone, caprolactam, and a mixture of two or more thereof. In other
aspects, the organic
solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide,
dimethyl sulfoxide,
propylene carbonate, caprolactam, polyethylene glycol, ethanol, or a mixture
of two or more
thereof. In other aspects, the organic solvent is N-methyl-2-pyrrolidone. The
term
"biodegradable polymer" refers to any polymer that can degrade in vivo and be
eliminated from
a patient's body. In other aspects, the biodegradable polymer is present in an
amount of about 10
wt% to about 60 wt%; or in an amount of about 20 wt% to about 40 wt%. In one
embodiment,
the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer
thereof, a
terpolymer thereof, any combination thereof, or a mixture of two or more
thereof. In one
embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer. The
polymer, such as
the poly(DL-lactide-co-glycolide) copolymer, can have an average molecular
weight of about
1,000 Daltons to about 50,000 Daltons; or from about 5,000 Daltons to about
40,000 Daltons; or
from about 5,000 Daltons to about 30,000 Daltons; or from about 5,000 Daltons
to about 20,000
Daltons; or from about 10,000 Daltons to about 20,000 Daltons. The poly(DL-
lactide-co-
glycolide) copolymer can be a 50:50 to 95:5 poly(DL-lactide-co-glycolide)
copolymer; or a
50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer; or a 50:50 poly(DL-
lactide-co-
glycolide) copolymer.
100631 The phrase "average molecular weight" refers to the weight average
molecular weight
of a polymer as determined by gel permeation chromatography (also known as GPC
or size
13
CA 2995923 2018-02-21
exclusion chromatography) using tetrahydrofuran as the solvent and using a
molecular weight
calibration curve using polystyrene standards.
[0064] In one embodiment, the buprenorphine formulations comprise from about
295 mg to
about 305 mg of buprenorphine, or about 300 mg of buprenorphine. In aspects,
the
buprenorphine formulation is Formulation D comprising from about 295 mg to
about 305 mg of
buprenorphine free base; or from about 296 mg to about 304 mg of buprenorphine
free base; or
from about 297 mg to about 303 mg of buprenorphine free base; or from about
298 mg to about
302 mg of buprenorphine free base; or about 299 mg to about 301 mg of
buprenorphine free
base. In aspects, the buprenorphine formulations comprise about 300 mg
buprenorphine free
base.
100651 The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by (a) administering a composition of Formulation A, Formulation B,
Formulation C, or
Formulation D to the patient once per month for at least six months; where the
composition
comprises from about 295 mg to about 305 mg of buprenorphine; or from about
296 mg to
about 304 mg of buprenorphine; or from about 297 mg to about 303 mg of
buprenorphine; or
about 298 mg to about 302 mg of buprenorphine; or from about 299 mg to about
301 mg of
buprenorphine; or about 300 mg of buprenorphine. In one embodiment, the
composition is
Formulation A. In one embodiment, the composition is Formulation B. In one
embodiment, the
composition is Formulation C. In one embodiment, the composition is
Formulation D. In one
embodiment, the composition of Formulation A, Formulation B, Formulation C, or
Formulation
D contains about 300 mg buprenorphine. In one embodiment, the buprenorphine is
buprenorphine free base. In one embodiment, the injection is a subcutaneous
injection. In
aspects, the patient is black or African-American. In aspects, the patient is
a black or African-
American injection drug patient. In aspects, the patient has an OPRDI TT
genotype. In aspects,
the patient has an OPRD1 TC genotype. In aspects, the patient is an injection
drug patient with
an OPRDI TT genotype. In aspects, the patient is an injection drug patient
with an OPRDI TC
genotype. In aspects, the patient is black or African-American with an OPRDI
TT genotype. In
aspects, the patient is black or African-American with an OPRD1 TC genotype.
In aspects, the
patient is a black or African-American injection drug patient with an OPRDI TT
genotype. In
aspects, the patient is a black or African-American injection drug patient
with an OPRDI TC
14
CA 2995923 2018-02-21
genotype.
[0066] The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation A, Formulation B, Formulation C, or
Formulation D
comprising from about 295 mg to about 305 mg of buprenorphine (e.g., 300 mg
buprenorphine
free base) for at least six months to provide a steady-state average
buprenorphine plasma
concentration from about 5.1 ng/mL to about 10 ng/mL; or from 5.1 ng/mL to
about 10 ng/mL;
or from about 5.2 ng/mL to about 9 ng/mL; or from 5.2 ng/mL to about 9 ng/mL;
or from about
5.3 ng/mL to about 8 ng/mL; or from 5.3 ng/mL to about 8 ng/mL; or from about
5.4 ng/mL to
about 7.5 ng/mL; or from 5.4 ng/mL to about 7.5 ng/mL; or from about 5.5 ng/mL
to about 7.5
ng/mL; or from 5.5 ng/mL to about 7.5 ng/mL; or from about 5.5 ng/mL to about
7 ng/mL; or
from 5.5 ng/mL to about 7 ng/mL; or from about 5.8 ng/mL to about 7.2 ng/mL;
or from 5.8
ng/mL to about 7.2 ng/mL; or from about 5.9 ng/mL to about 7.0 ng/mL; or from
5.9 ng/mL to
7.0 ng/mL; or from about 6.0 ng/mL to about 7.0 ng/mL; or from 6.0 ng/mL to
about 7.0 ng/mL;
or from 6.1 ng/mL to 7.0 ng/mL; or from 6.2 ng/mL to 7.0 ng/mL; or from 6.3
ng/mL to 7.0
ng/mL; or about 6.0 ng/mL to about 6.8 ng/mL; or 6.0 ng/mL to about 6.8 ng/mL;
or 6.1 ng/mL
to about 6.8 ng/mL; or 6.2 ng/mL to about 6.8 ng/mL; or 6.3 ng/mL to about 6.8
ng/mL; or from
about 6.1 ng/mL to about 6.5 ng/mL; or from 6.1 ng/mL to about 6.5 ng/mL; or
from about 6.2
ng/mL to about 6.4 ng/mL; or from 6.2 ng/mL to about 6.4 ng/mL; or from about
6.3 ng/mL to
about 6.4 ng/mL; or from 6.3 ng/mL to about 6.4 ng/mL; or about 6.3 ng/mL. In
aspects, the
patient is an injection drug patient. In aspects, the patient is black or
African-American. In
aspects, the patient is a black or African-American injection drug patient. In
aspects, the patient
has an OPRDI TT genotype. In aspects, the patient has an OPRD1 TC genotype. In
aspects, the
patient is an injection drug patient with an OPRDI Fl genotype. In aspects,
the patient is an
injection drug patient with an OPRDI TC genotype. In aspects, the patient is
black or African-
American with an OPRDI TT genotype. In aspects, the patient is black or
African-American
with an OPRDI TC genotype. In aspects, the patient is a black or African-
American injection
drug patient with an OPRD1 TT genotype. In aspects, the patient is a black or
African-American
injection drug patient with an OPRD I TC genotype.
[0067] The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
CA 2995923 2018-02-21
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation D comprising about 300 mg buprenorphine
free base for at
least six months to provide a steady-state average buprenorphine plasma
concentration from
about 6.2 ng/mL to about 6.4 ng/mL; or from about 6.3 ng/mL to about 6.4
ng/mL; or about 6.3
ng/mL. In aspects, the patient is an injection drug patient. In aspects, the
patient is black or
African-American. In aspects, the patient is a black or African-American
injection drug patient.
In aspects, the patient has an OPRDI IT genotype. In aspects, the patient has
an OPRD1 TC
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TT genotype. In
aspects, the patient is an injection drug patient with an OPRD1 TC genotype.
In aspects, the
patient is black or African-American with an OPRDI TT genotype. In aspects,
the patient is
black or African-American with an OPRDI TC genotype. In aspects, the patient
is a black or
African-American injection drug patient with an OPRDI TT genotype. In aspects,
the patient is
a black or African-American injection drug patient with an OPRD1 TC genotype.
[00681 The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation A, Formulation B, Formulation C, or
Formulation D
comprising from about 295 mg to about 305 mg of buprenorphine (e.g., 300 mg
buprenorphine
free base) for at least six months to provide a steady-state minimum
buprenorphine plasma
concentration (Cmin) from about 5.0 ng/mL to a steady-state maximum
buprenorphine plasma
concentration (Cmax) of about 11 ng/mL; or from about 5.0 ng/mL to about 10
ng/mL,
respectively; or from about 5.0 ng/mL to about 9 ng/mL, respectively; or from
5.0 ng/mL to
about 11 ng/mL, respectively; or from 5.0 ng/mL to about 10 ng/mL,
respectively; or from 5.0
ng/mL to about 9 ng/mL, respectively; or from about 5.1 ng/mL to about 11
ng/mL
respectively; or from about 5.1 ng/mL to about 10 ng/mL, respectively; or from
about 5.1 ng/mL
to about 9 ng/mL, respectively; or from 5.1 ng/mL to about 11 ng/mL,
respectively; or from 5.1
ng/mL to about 10 ng/mL, respectively; or from 5.1 ng/mL to about 9 ng/mL,
respectively. In
aspects, the patient is an injection drug patient. In aspects, the patient is
black or African-
American. In aspects, the patient is a black or African-American injection
drug patient. In
aspects, the patient has an OPRDI IT genotype. In aspects, the patient has an
OPRD1 TC
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TT genotype. In
aspects, the patient is an injection drug patient with an OPRDI TC genotype.
In aspects, the
patient is black or African-American with an OPRDI IT genotype. In aspects,
the patient is
16
CA 2995923 2018-02-21
black or African-American with an OPRD1 TC genotype. In aspects, the patient
is a black or
African-American injection drug patient with an OPRDI TT genotype. In aspects,
the patient is
a black or African-American injection drug patient with an OPRD1 TC genotype.
[0069] The disclosure provides methods for treating opioid dependence, methods
for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation D comprising about 300 mg buprenorphine
free base for at
least six months to provide a steady-state minimum buprenorphine plasma
concentration (Cmin)
from about 5.1 ng/mL to a steady-state maximum buprenorphine plasma
concentration (Cmax) of
about 9 ng/mL. In aspects, the patient is an injection drug patient. In
aspects, the patient is black
or African-American. In aspects, the patient is a black or African-American
injection drug
patient. In aspects, the patient has an OPRDI IT genotype. In aspects, the
patient has an
OPRD1 TC genotype. In aspects, the patient is an injection drug patient with
an OPRDI TT
genotype. In aspects, the patient is an injection drug patient with an OPRD1
TC genotype. In
aspects, the patient is black or African-American with an OPRDI TT genotype.
In aspects, the
patient is black or African-American with an OPRDI TC genotype. In aspects,
the patient is a
black or African-American injection drug patient with an OPRDI TT genotype. In
aspects, the
patient is a black or African-American injection drug patient with an OPRD1 TC
genotype.
[0070] The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation A, Formulation B, Formulation C, or
Formulation D
comprising from about 295 mg to about 305 mg of buprenorphine (e.g., 300 mg
buprenorphine
free base) for at least six months produce a steady-state minimum
buprenorphine plasma
concentration (Cmin) from about 5.0 ng/mL to about 5.2 ng/mL; a steady-state
average
buprenorphine plasma concentration (Can) from about 6.2 ng/mL to about 6.4
ng/mL; and a
steady-state maximum plasma buprenorphine concentration (Cmax) from about 8
ng/mL to about
9 ng/mL in the patient. In aspects, the methods described herein provide a
steady-state minimum
buprenorphine plasma concentration (Cm.) of about 5.1 ng/mL; a steady-state
average
buprenorphine plasma concentration (Cavg) of about 6.3 ng/mL; and a steady-
state maximum
buprenorphine plasma concentration (Cmax) of about 9 ng/mL. In aspects, the
methods described
herein provide a steady-state minimum buprenorphine plasma concentration
(Cmin) of about 5.1
17
CA 2995923 2018-02-21
84334135
ng/mL; a steady-state average buprenorphine plasma concentration (Cavg) of
about 6.3 ng/mL;
and a steady-state maximum buprenorphine plasma concentration (Cm) of about
8.7 ng/mL. In
aspects, the patient is an injection drug patient. In aspects, the patient is
black or African-
American. In aspects, the patient is a black or African-American injection
drug patient. In
aspects, the patient has an OPRDI TT genotype. In aspects, the patient has an
OPRDI TC
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TT genotype. In
aspects, the patient is an injection drug patient with an OPRDI TC genotype.
In aspects, the
patient is black or African-American with an OPRDI TT genotype. In aspects,
the patient is
black or African-American with an OPRDI TC genotype. In aspects, the patient
is a black or
African-American injection drug patient with an OPRDI TT genotype. In aspects,
the patient is
a black or African-American injection drug patient with an OPRD1 TC genotype.
[00711 The disclosure provides methods for treating opioid use disorder,
methods for reducing
and/or eliminating opioid craving, methods for reducing and/or eliminating
opioid withdrawal
symptoms, and methods for reducing and/or eliminating illicit opioid use in a
patient in need
thereof by administering Formulation A, Formulation B, Formulation C, or
Formulation D
comprising from about 295 mg to about 305 mg of buprenorphine (e.g., 300 mg
buprenorphine
free base) for at least six months provide a steady-state -opioid receptor
occupancy in the brain,
as predicted by the maximal effect model of Equation 1, of at least 80% in the
patient. In
aspects, the methods provide a steady-state }t-opioid receptor occupancy (as
predicted by
Equation 1) of at least 81% alternatively at least 82%, alternatively at least
83%, alternatively at
least 85%, alternatively at least 90%, alternatively at least 95%,
alternatively at least about 98%,
alternatively at least 80% to about 90% or about 95% or about 98%,
alternatively at least about
81% to about 90% or about 95% or about 98%, alternatively at least about 82%
to about 90% or
about 95% or about 98%, alternatively at least about 83% to about 90% or about
95% or about
98% or to 100%. In one aspect, the }t-opioid receptor occupancy (as predicted
by a maximal
effect model of Equation 1) is 100%. Of note, Equation I has a maximal effect
of 91.4%, but
when variability is added, individual measurements as predicted by the model
can go up to
100%. In another embodiment, the receptor occupancy is sustained for at least
one month after
dosing. In another aspect, the receptor occupancy period is at least two
months, alternatively at
least three months, alternatively at least four months, alternatively at least
five months. In
aspects, the brain mu-opioid receptor occupancy can be measured by
[11c1carfentanil PET (see
Greenwald et al, Biological Psychiatry, 61:101-110 (2007)). In aspects, p.-
opioid receptor
occupancy is the average of
18
Date Recue/Date Received 2021-08-11
individual predicted values for }1-opioid receptor occupancy. In aspects, -
opioid receptor
occupancy is the predicted value for an average plasma concentration. In
aspects, yt-opioid
receptor occupancy is the predicted or observed value for a single patient. In
aspects, the patient
is an injection drug patient. In aspects, the patient is black or African-
American. In aspects, the
patient is a black or African-American injection drug patient. In aspects, the
patient has an
OPRDI TT genotype. In aspects, the patient has an OPRD1 TC genotype. In
aspects, the patient
is an injection drug patient with an OPRDI TT genotype. In aspects, the
patient is an injection
drug patient with an OPRDI TC genotype. In aspects, the patient is black or
African-American
with an OPRDI TT genotype. In aspects, the patient is black or African-
American with an
OPRDI TC genotype. In aspects, the patient is a black or African-American
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is a black or
African-American
injection drug patient with an OPRD1 TC genotype.
100721 The disclosure provides methods of treating opioid use disorder in an
injection drug
patient in need thereof by administering Formulation D to the injection drug
patient once per
month to treat the opioid use disorder; wherein Formulation D comprises about
300 mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the opioid use disorder is mild opioid use
disorder, moderate
opioid use disorder, severe opioid use disorder, or moderate-to-severe opioid
use disorder. In
aspects, the injection drug patient is black or African-American. In aspects,
the injection drug
patient has an OPRDI TT genotype. In aspects, the injection drug patient has
an OPRDI TC
genotype. In aspects, the injection drug patient is black or African-American
with an OPRDI IT
genotype. In aspects, the injection drug patient is black or African-American
with an OPRDI TC
genotype.
[0073] The disclosure provides methods of reducing and/or eliminating opioid
craving in an
injection drug patient in need thereof by administering Formulation D to the
injection drug
patient once per month to reduce or eliminate the opioid craving; wherein
Formulation D
comprises about 300 mg buprenorphine free base. In aspects, Formulation D is
administered to
the injection drug patient once per month for at least six months. In aspects,
Formulation D is
administered by subcutaneous injection. In aspects, the methods are for
reducing opioid craving.
In aspects, the methods are for eliminating opioid craving. In aspects, the
injection drug patient
is black or African-American. In aspects, the injection drug patient has an
OPRDI TT genotype.
19
CA 2995923 2018-02-21
In aspects, the injection drug patient has an OPRDI TC genotype. In aspects,
the injection drug
patient is black or African-American with an OPRDI TT genotype. In aspects,
the injection drug
patient is black or African-American with an OPRDI TC genotype.
00741 The disclosure provides methods of reducing and/or eliminating opioid
withdrawal
symptoms in an injection drug patient in need thereof by administering
Formulation D to the
injection drug patient once per month to reduce or eliminate the opioid
withdrawal symptoms;
wherein Formulation D comprises about 300 mg buprenorphine free base. In
aspects,
Formulation D is administered to the injection drug patient once per month for
at least six
months. In aspects, Formulation D is administered by subcutaneous injection.
In aspects, the
methods are for reducing opioid withdrawal symptoms. In aspects, the methods
are for
eliminating opioid withdrawal symptoms. In aspects, the injection drug patient
is black or
African-American. In aspects, the injection drug patient has an OPRDI IT
genotype. In aspects,
the injection drug patient has an OPRDI TC genotype. In aspects, the injection
drug patient is
black or African-American with an OPRDI TT genotype. In aspects, the injection
drug patient is
black or African-American with an OPRDI TC genotype.
100751 The disclosure provides methods of reducing illicit opioid use in an
injection drug
patient in need thereof by administering Formulation D to the injection drug
patient once per
month to induce opioid abstinence; wherein Formulation D comprises about 300
mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the injection drug patient is black or African-
American. In aspects, the
injection drug patient has an OPRDI TT genotype. In aspects, the injection
drug patient has an
OPRD1 TC genotype. In aspects, the injection drug patient is black or African-
American with
an OPRDI TT genotype. In aspects, the injection drug patient is black or
African-American with
an OPRDI TC genotype.
100761 The disclosure provides methods of eliminating illicit opioid use in an
injection drug
patient in need thereof by administering Formulation D to the injection drug
patient once per
month to induce opioid abstinence; wherein Formulation D comprises about 300
mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
CA 2995923 2018-02-21
abstinence. In aspects, the injection drug patient is black or African-
American. In aspects, the
injection drug patient has an OPRDI TT genotype. In aspects, the injection
drug patient has an
OPRDI TC genotype. In aspects, the injection drug patient is black or African-
American with
an OPRDI TT genotype. In aspects, the injection drug patient is black or
African-American with
an OPRDI TC genotype.
[0077] The disclosure provides methods of inducing opioid abstinence in an
injection drug
patient in need thereof by administering Formulation D to the injection drug
patient once per
month to induce opioid abstinence; wherein Formulation D comprises about 300
mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the injection drug patient is black or
African-American. In
aspects, the injection drug patient has an OPRDI TT genotype. In aspects, the
injection drug
patient has an OPRDI TC genotype. In aspects, the injection drug patient is
black or African-
American with an OPRDI TT genotype. In aspects, the injection drug patient is
black or
African-American with an OPRDI TC genotype.
[0078] The disclosure provides methods of maintaining opioid abstinence in an
injection drug
patient in need thereof by administering Formulation D to the injection drug
patient once per
month to maintain opioid abstinence; wherein Formulation D comprises about 300
mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the injection drug patient is black or
African-American. In
aspects, the injection drug patient has an OPRDI TT genotype. In aspects, the
injection drug
patient has an OPRD1 TC genotype. In aspects, the injection drug patient is
black or African-
American with an OPRDI TT genotype. In aspects, the injection drug patient is
black or
African-American with an OPRDI TC genotype.
[0079] The disclosure provides methods of treating opioid use disorder in an
injection drug
patient in need thereof by administering Formulation A, Formulation B,
Formulation C, or
Formulation D to the injection drug patient once per month to treat the opioid
use disorder;
wherein Formulation A, Formulation B, Formulation C, or Formulation D
comprises from about
295 mg to about 305 mg buprenorphine; or from about 296 mg to about 304 mg
buprenorphine;
or from about 297 mg to about 303 mg buprenorphine; or from about 298 mg to
about 302 mg
buprenorphine; or from about 299 mg to about 301 mg buprenorphine; or about
300 mg
21
CA 2995923 2018-02-21
buprenorphine. In aspects, the buprenorphine is buprenorphine free base. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
Formulation C is administered. In aspects, Formulation D is administered. In
aspects, the opioid
use disorder is mild opioid use disorder, moderate opioid use disorder, severe
opioid use
disorder, or moderate-to-severe opioid use disorder. In aspects, the injection
drug patient is black
or African-American. In aspects, the injection drug patient has an OPRDI TT
genotype. In
aspects, the injection drug patient has an OPRD1 TC genotype. In aspects, the
injection drug
patient is black or African-American with an OPRDI TT genotype. In aspects,
the injection drug
patient is black or African-American with an OPRDI TC genotype.
10080] The disclosure provides methods of reducing and/or eliminating opioid
craving in an
injection drug patient in need thereof by administering Formulation A,
Formulation B,
Formulation C, or Formulation D to the injection drug patient once per month
to reduce and/or
eliminate the opioid craving; wherein Formulation A, Formulation B,
Formulation C, or
Formulation D comprises from about 295 mg to about 305 mg buprenorphine; or
from about 296
mg to about 304 mg buprenorphine; or from about 297 mg to about 303 mg
buprenorphine; or
from about 298 mg to about 302 mg buprenorphine; or from about 299 mg to about
301 mg
buprenorphine; or about 300 mg buprenorphine. In aspects, the buprenorphine is
buprenorphine
free base. In aspects, Formulation A, Formulation B, Formulation C, or
Formulation D is
administered to the injection drug patient once per month for at least six
months. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, Formulation A is administered. In aspects,
Formulation B is
administered. In aspects, Formulation C is administered. In aspects,
Formulation D is
administered. In aspects, the methods are for reducing opioid craving. In
aspects, the methods
are for eliminating opioid craving. In aspects, the methods are for reducing
opioid craving and
for eliminating opioid craving. In aspects, the injection drug patient is
black or African-
American. In aspects, the injection drug patient has an OPRDI TT genotype. In
aspects, the
injection drug patient has an OPRDI TC genotype. In aspects, the injection
drug patient is black
or African-American with an OPRDI TT genotype. In aspects, the injection drug
patient is black
or African-American with an OPRDI TC genotype.
22
CA 2995923 2018-02-21
[00811 The disclosure provides methods of reducing and/or eliminating opioid
withdrawal
symptoms in an injection drug patient in need thereof by administering
Formulation A,
Formulation B, Formulation C, or Formulation D to the injection drug patient
once per month to
reduce and/or eliminate the opioid withdrawal symptoms; wherein Formulation A,
Formulation
B, Formulation C, or Formulation D comprises from about 295 mg to about 305 mg
buprenorphine; or from about 296 mg to about 304 mg buprenorphine; or from
about 297 mg to
about 303 mg buprenorphine; or from about 298 mg to about 302 mg
buprenorphine; or from
about 299 mg to about 301 mg buprenorphine; or about 300 mg buprenorphine. In
aspects, the
buprenorphine is buprenorphine free base. In aspects, Formulation A,
Formulation B,
Formulation C, or Formulation D is administered to the injection drug patient
once per month for
at least six months. In aspects. Formulation A, Formulation B, Formulation C,
or Formulation D
is administered by subcutaneous injection. In aspects, Formulation A is
administered. In
aspects, Formulation B is administered. In aspects, Formulation C is
administered. In aspects,
Formulation D is administered. In aspects, the methods are for reducing opioid
withdrawal
symptoms. In aspects, the methods are for eliminating opioid withdrawal
symptoms. In aspects,
the methods are for reducing opioid withdrawal symptoms, and for eliminating
opioid
withdrawal symptoms. In aspects, the injection drug patient is black or
African-American. In
aspects, the injection drug patient has an OPRDI TT genotype. In aspects, the
injection drug
patient has an OPRDI TC genotype. In aspects, the injection drug patient is
black or African-
American with an OPRDI TT genotype. In aspects, the injection drug patient is
black or
African-American with an OPRDI TC genotype.
[00821 The disclosure provides methods of reducing illicit opioid use in an
injection drug
patient in need thereof by parenterally administering Formulation A,
Formulation B, Formulation
C, or Formulation D to the injection drug patient once per month to induce
opioid abstinence;
wherein Formulation A, Formulation B, Formulation C, or Formulation D
comprises from about
295 mg to about 305 mg buprenorphine; or from about 296 mg to about 304 mg
buprenorphine;
or from about 297 mg to about 303 mg buprenorphine; or from about 298 mg to
about 302 mg
buprenorphine; or from about 299 mg to about 301 mg buprenorphine; or about
300 mg
buprenorphine. In aspects, the buprenorphine is buprenorphine free base. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
23
CA 2995923 2018-02-21
Formulation C is administered. In aspects, Formulation D is administered. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the injection drug patient is black or African-
American. In aspects, the
injection drug patient has an OPRDI TT genotype. In aspects, the injection
drug patient has an
OPRD1 TC genotype. In aspects, the injection drug patient is black or African-
American with
an OPRDI TT genotype. In aspects, the injection drug patient is black or
African-American with
an OPRDI TC genotype.
100831 The disclosure provides methods of eliminating illicit opioid use in an
injection drug
patient in need thereof by parenterally administering Formulation A,
Formulation B, Formulation
C, or Formulation D to the injection drug patient once per month to induce
opioid abstinence;
wherein Formulation A, Formulation B, Formulation C, or Formulation D
comprises from about
295 mg to about 305 mg buprenorphine; or from about 296 mg to about 304 mg
buprenorphine;
or from about 297 mg to about 303 mg buprenorphine; or from about 298 mg to
about 302 mg
buprenorphine; or from about 299 mg to about 301 mg buprenorphine; or about
300 mg
buprenorphine. In aspects, the buprenorphine is buprenorphine free base. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
Formulation C is administered. In aspects, Formulation D is administered. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the injection drug patient is black or African-
American. In aspects, the
injection drug patient has an OPRDI TT genotype. In aspects, the injection
drug patient has an
OPRDI TC genotype. In aspects, the injection drug patient is black or African-
American with
an OPRDI TT genotype. In aspects, the injection drug patient is black or
African-American with
an OPRDI TC genotype.
10084] The disclosure provides methods for maintaining opioid abstinence in an
injection drug
patient in need thereof by parenterally administering Formulation A,
Formulation B, Formulation
C, or Formulation D to the injection drug patient once per month to for
maintaining opioid
abstinence; wherein Formulation A, Formulation B, Formulation C, or
Formulation D comprises
24
CA 2995923 2018-02-21
from about 295 mg to about 305 mg buprenorphine; or from about 296 mg to about
304 mg
buprenorphine; or from about 297 mg to about 303 mg buprenorphine; or from
about 298 mg to
about 302 mg buprenorphine; or from about 299 mg to about 301 mg
buprenorphine; or about
300 mg buprenorphine. In aspects, the buprenorphine is buprenorphine free
base. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
one aspect,
Formulation A is administered. In another aspect, Formulation B is
administered. In other
aspects, Formulation C is administered. In yet other aspects, Formulation D is
administered. In
aspects, the injection drug patient is black or African-American. In aspects,
the injection drug
patient has an OPRDI TT genotype. In aspects, the injection drug patient has
an OPRDI TC
genotype. In aspects, the injection drug patient is black or African-American
with an OPRDI TT
genotype. In aspects, the injection drug patient is black or African-American
with an OPRDI TC
genotype.
100851 The disclosure provides methods of treating opioid use disorder in a
black or African-
American patient in need thereof by administering Formulation D to the
injection drug patient
once per month to treat the opioid use disorder; wherein Formulation D
comprises about 300 mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the opioid use disorder is mild opioid use
disorder, moderate
opioid use disorder, severe opioid use disorder, or moderate-to-severe opioid
use disorder. In
aspects, the patient has an OPRDI TT genotype. In aspects, the patient has an
OPRDI TC
genotype. In aspects, the patent is an injection drug patient with an OPRDI IT
genotype. In
aspects, the patient is an injection drug patient with an OPRDI TC genotype.
In aspects, the
patient is an injection drug patient.
[0086] The disclosure provides methods of reducing and/or eliminating opioid
craving in a
black or African-American patient in need thereof by administering Formulation
D to the
injection drug patient once per month to reduce or eliminate the opioid
craving; wherein
Formulation D comprises about 300 mg buprenorphine free base. In aspects,
Formulation D is
administered to the injection drug patient once per month for at least six
months. In aspects,
Formulation D is administered by subcutaneous injection. In aspects, the
methods are for
reducing opioid craving. In aspects, the methods are for eliminating opioid
craving. In aspects,
CA 2995923 2018-02-21
the patient has an OPRDI TT genotype. In aspects, the patient has an OPRDI TC
genotype. In
aspects, the patent is an injection drug patient with an OPRDI TT genotype. In
aspects, the
patient is an injection drug patient with an OPRDI TC genotype. In aspects,
the patient is an
injection drug patient.
[0087] The disclosure provides methods of reducing and/or eliminating opioid
withdrawal
symptoms in a black or African-American patient in need thereof by
administering Formulation
D to the injection drug patient once per month to reduce or eliminate the
opioid withdrawal
symptoms; wherein Formulation D comprises about 300 mg buprenorphine free
base. In aspects,
Formulation D is administered to the injection drug patient once per month for
at least six
months. In aspects, Formulation D is administered by subcutaneous injection.
In aspects, the
methods are for reducing opioid withdrawal symptoms. In aspects, the methods
are for
eliminating opioid withdrawal symptoms. In aspects, the patient has an OPRDI
TT genotype. In
aspects, the patient has an OPRDI TC genotype. In aspects, the patent is an
injection drug
patient with an OPRDI IT genotype. In aspects, the patient is an injection
drug patient with an
OPRDI TC genotype. In aspects, the patient is an injection drug patient.
[0088] The disclosure provides methods of reducing illicit opioid use in a
black or African-
American patient in need thereof by administering Formulation D to the
injection drug patient
once per month to induce opioid abstinence; wherein Formulation D comprises
about 300 mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the patient has an OPRDI TT genotype. In aspects, the
patient has an
OPRD1 TC genotype. In aspects, the patent is an injection drug patient with an
OPRDI TT
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TC genotype. In
aspects, the patient is an injection drug patient.
[0089] The disclosure provides methods of eliminating illicit opioid use in a
black or African-
American patient in need thereof by administering Formulation D to the
injection drug patient
once per month to induce opioid abstinence; wherein Formulation D comprises
about 300 mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the patient has an OPRDI TT genotype. In aspects, the
patient has an
26
CA 2995923 2018-02-21
OPRD1 TC genotype. In aspects, the patent is an injection drug patient with an
OPRDI TT
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TC genotype. In
aspects, the patient is an injection drug patient.
[0090] The disclosure provides methods of inducing opioid abstinence in a
black or African-
American patient in need thereof by administering Formulation D to the
injection drug patient
once per month to induce opioid abstinence; wherein Formulation D comprises
about 300 mg
buprenorphine free base. In aspects, Formulation D is administered to the
injection drug patient
once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the patient has an OPRDI TT genotype. En
aspects, the
patient has an OPRDI TC genotype. In aspects, the patent is an injection drug
patient with an
OPRDI TT genotype. In aspects, the patient is an injection drug patient with
an OPRDI TC
genotype. In aspects, the patient is an injection drug patient.
[0091] The disclosure provides methods of maintaining opioid abstinence in a
black or
African-American patient in need thereof by administering Formulation D to the
injection drug
patient once per month to maintain opioid abstinence; wherein Formulation D
comprises about
300 mg buprenorphine free base. In aspects, Formulation D is administered to
the injection drug
patient once per month for at least six months. In aspects, Formulation D is
administered by
subcutaneous injection. In aspects, the patient has an OPRDI TT genotype. In
aspects, the
patient has an OPRDI TC genotype. In aspects, the patent is an injection drug
patient with an
OPRDI TT genotype. In aspects, the patient is an injection drug patient with
an OPRDI TC
genotype. In aspects, the patient is an injection drug patient.
[0092] The disclosure provides methods of treating opioid use disorder in a
black or African-
American patient in need thereof by administering Formulation A, Formulation
B, Formulation
C, or Formulation D to the injection drug patient once per month to treat the
opioid use disorder;
wherein Formulation A, Formulation B, Formulation C, or Formulation D
comprises from about
295 mg to about 305 mg buprenorphine; or from about 296 mg to about 304 mg
buprenorphine;
or from about 297 mg to about 303 mg buprenorphine; or from about 298 mg to
about 302 mg
buprenorphine; or from about 299 mg to about 301 mg buprenorphine; or about
300 mg
buprenorphine. In aspects, the buprenorphine is buprenorphine free base. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
27
CA 2995923 2018-02-21
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
Formulation C is administered. In aspects, Formulation D is administered. In
aspects, the opioid
use disorder is mild opioid use disorder, moderate opioid use disorder, severe
opioid use
disorder, or moderate-to-severe opioid use disorder. In aspects, the patient
has an OPRDI TT
genotype. In aspects, the patient has an OPRD I TC genotype. In aspects, the
patent is an
injection drug patient with an OPRDI TT genotype. In aspects, the patient is
an injection drug
patient with an OPRDI TC genotype. In aspects, the patient is an injection
drug patient.
[0093] The disclosure provides methods of reducing and/or eliminating opioid
craving in a
black or African-American patient in need thereof by administering Formulation
A, Formulation
B, Formulation C, or Formulation D to the injection drug patient once per
month to reduce
and/or eliminate the opioid craving; wherein Formulation A, Formulation B,
Formulation C, or
Formulation D comprises from about 295 mg to about 305 mg buprenorphine; or
from about 296
mg to about 304 mg buprenorphine; or from about 297 mg to about 303 mg
buprenorphine; or
from about 298 mg to about 302 mg buprenorphine; or from about 299 mg to about
301 mg
buprenorphine; or about 300 mg buprenorphine. In aspects, the buprenorphine is
buprenorphine
free base. In aspects, Formulation A, Formulation B, Formulation C, or
Formulation D is
administered to the injection drug patient once per month for at least six
months. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, Formulation A is administered. In aspects,
Formulation B is
administered. In aspects, Formulation C is administered. In aspects,
Formulation D is
administered. In aspects, the methods are for reducing opioid craving. In
aspects, the methods
are for eliminating opioid craving. In aspects, the methods are for reducing
opioid craving and
for eliminating opioid craving. In aspects, the patient has an OPRDI TT
genotype. In aspects,
the patient has an PRIM TC genotype. in aspects, the patent is an injection
drug patient with
an OPRDI TT genotype. In aspects, the patient is an injection drug patient
with an OPRDI TC
genotype. In aspects, the patient is an injection drug patient.
[0094] The disclosure provides methods of reducing and/or eliminating opioid
withdrawal
symptoms in a black or African-American patient in need thereof by
administering Formulation
A, Formulation B, Formulation C, or Formulation D to the injection drug
patient once per month
to reduce and/or eliminate the opioid withdrawal symptoms; wherein Formulation
A,
Formulation B, Formulation C, or Formulation D comprises from about 295 mg to
about 305 mg
buprenorphine; or from about 296 mg to about 304 mg buprenorphine; or from
about 297 mg to
28
CA 2995923 2018-02-21
about 303 mg buprenorphine; or from about 298 mg to about 302 mg
buprenorphine; or from
about 299 mg to about 301 mg buprenorphine; or about 300 mg buprenorphine. In
aspects, the
buprenorphine is buprenorphine free base. In aspects, Formulation A,
Formulation B,
Formulation C, or Formulation D is administered to the injection drug patient
once per month for
at least six months. In aspects, Formulation A, Formulation B, Formulation C,
or Formulation D
is administered by subcutaneous injection. In aspects, Formulation A is
administered. In
aspects, Formulation B is administered. In aspects, Formulation C is
administered. In aspects,
Formulation D is administered. In aspects, the methods are for reducing opioid
withdrawal
symptoms. In aspects, the methods are for eliminating opioid withdrawal
symptoms. In aspects,
the methods are for reducing opioid withdrawal symptoms, and for eliminating
opioid
withdrawal symptoms. In aspects, the patient has an OPRDI TT genotype. In
aspects, the patient
has an OPRDI TC genotype. In aspects, the patent is an injection drug patient
with an OPRDI
TT genotype. In aspects, the patient is an injection drug patient with an
OPRDI TC genotype. In
aspects, the patient is an injection drug patient.
100951 The disclosure provides methods of reducing illicit opioid use in a
black or African-
American patient in need thereof by parenterally administering Formulation A,
Formulation B,
Formulation C, or Formulation D to the injection drug patient once per month
to induce opioid
abstinence; wherein Formulation A, Formulation B, Formulation C, or
Formulation D comprises
from about 295 mg to about 305 mg buprenorphine; or from about 296 mg to about
304 mg
buprenorphine; or from about 297 mg to about 303 mg buprenorphine; or from
about 298 mg to
about 302 mg buprenorphine; or from about 299 mg to about 301 mg
buprenorphine; or about
300 mg buprenorphine. In aspects, the buprenorphine is buprenorphine free
base. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
Formulation C is administered. In aspects, Formulation D is administered. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. I In aspects, the patient has an OPRD1 TT genotype. In aspects,
the patient has an
OPRD1 TC genotype. In aspects, the patent is an injection drug patient with an
OPRDI TT
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TC genotype. In
aspects, the patient is an injection drug patient.
29
CA 2995923 2018-02-21
[00961 The disclosure provides methods of eliminating illicit opioid use in a
black or African-
American patient in need thereof by parenterally administering Formulation A,
Formulation B,
Formulation C, or Formulation D to the injection drug patient once per month
to induce opioid
abstinence; wherein Formulation A, Formulation B, Formulation C, or
Formulation D comprises
from about 295 mg to about 305 mg buprenorphine; or from about 296 mg to about
304 mg
buprenorphine; or from about 297 mg to about 303 mg buprenorphine; or from
about 298 mg to
about 302 mg buprenorphine; or from about 299 mg to about 301 mg
buprenorphine; or about
300 mg buprenorphine. In aspects, the buprenorphine is buprenorphine free
base. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
to the injection
drug patient once per month for at least six months. In aspects, Formulation
A, Formulation B,
Formulation C, or Formulation D is administered by subcutaneous injection. In
aspects,
Formulation A is administered. In aspects, Formulation B is administered. In
aspects,
Formulation C is administered. In aspects, Formulation D is administered. In
aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In aspects, the methods further comprising maintaining
opioid
abstinence. In aspects, the patient has an OPRDI TT genotype. In aspects, the
patient has an
OPRD1 TC genotype. In aspects, the patent is an injection drug patient with an
OPRDI TT
genotype. In aspects, the patient is an injection drug patient with an OPRDI
TC genotype. In
aspects, the patient is an injection drug patient.
[0097] The disclosure provides methods for maintaining opioid abstinence in a
black or
African-American patient in need thereof by parenterally administering
Formulation A,
Formulation B, Formulation C, or Formulation D to the injection drug patient
once per month to
for maintaining opioid abstinence; wherein Formulation A, Formulation B,
Formulation C, or
Formulation D comprises from about 295 mg to about 305 mg buprenorphine; or
from about 296
mg to about 304 mg buprenorphine; or from about 297 mg to about 303 mg
buprenorphine; or
from about 298 mg to about 302 mg buprenorphine; or from about 299 mg to about
301 mg
buprenorphine; or about 300 mg buprenorphine. In aspects, the buprenorphine is
buprenorphine
free base. In aspects, Formulation A, Formulation B, Formulation C, or
Formulation D is
administered to the injection drug patient once per month for at least six
months. In aspects,
Formulation A, Formulation B, Formulation C, or Formulation D is administered
by
subcutaneous injection. In one aspect, Formulation A is administered. In
another aspect,
Formulation B is administered. In other aspects, Formulation C is
administered. In yet other
aspects, Formulation D is administered. In aspects, the patient has an OPRDI
TT genotype. In
CA 2995923 2018-02-21
aspects, the patient has an OPRD1 TC genotype. In aspects, the patent is an
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is an injection
drug patient with an
OPRDI TC genotype. In aspects, the patient is an injection drug patient.
[00981 In aspects of the methods described herein, the sustained-release
buprenorphine
formulation comprises from about 95 mg to about 105 mg buprenorphine, or about
100 mg
buprenorphine. In aspects, the buprenorphine formulation is Formulation D
comprising from
about 95 mg to about 105 mg of buprenorphine free base; alternatively from
about 96 mg to
about 104 mg, alternatively from about 97 mg to about 103 mg, alternatively
from about 98 mg
to about 102 mg, alternatively from about 99 mg to about 101 mg, alternatively
about 100 mg of
buprenorphine free base.
[0099] The disclosure provides methods for treating opioid dependence,
reducing and/or
eliminating opioid craving, reducing and/or eliminating opioid withdrawal
symptoms, reducing
and/or eliminating illicit opioid use, or a combination of two or more
thereof, in a patient in need
thereof by (a) administering a first composition of Formulation A, Formulation
B, Formulation
C, or Formulation D comprising buprenorphine to the patient once per month by
injection for
two months; and thereafter (b) administering a second composition of
Formulation A,
Formulation B. Formulation C, or Formulation D comprising buprenorphine to the
patient once
per month by injection beginning with the third month of administration and
for each month
thereafter for at least four months (such that step (a) is for 2 months, and
step (b) is for at least
for 4 months to provide a treatment period of at least 6 months); wherein the
amount of
buprenorphine in the first composition is from about 295 mg to about 305 mg
and the amount of
buprenorphine in the second composition is from about 95 mg to about 105 mg.
In some
aspects, the amount of buprenorphine in the first composition is from about
296 mg to about 304
mg, alternatively from about 297 mg to about 303 mg, alternatively from about
298 mg to about
302 mg, alternatively from about 288 mg to about 301 and the amount of
buprenorphine in the
second composition is from about 96 mg to about 104 mg, alternatively from
about 97 mg to
about 103 mg, alternatively from about 98 mg to about 102 mg, alternatively
from about 99 mg
to about 101 mg. In one embodiment, the first composition comprises about 300
mg of
buprenorphine, and the second composition comprises about 100 mg of
buprenorphine. In one
embodiment, the first and second compositions are Formulation A. In one
embodiment, the first
and second compositions are Formulation B. In one embodiment, the first and
second
compositions are Formulation C. In one embodiment, the first and second
compositions are
31
CA 2995923 2018-02-21
Formulation D. In one embodiment, the buprenorphine is buprenorphine free
base. In aspects,
the first composition is Formulation D containing about 300 mg of
buprenorphine free base, and
the second composition is Formulation D containing about 100 mg of
buprenorphine free base.
In aspects, the injections are subcutaneous injections. In aspects, the
patient is an injection drug
patient. In aspects, the patient is black or African-American. In aspects, the
patient is a black or
African-American injection drug patient. In aspects, the patient has an OPRDI
TT genotype. In
aspects, the patient has an OPRDI TC genotype. In aspects, the patient is an
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is an injection
drug patient with an
OPRDI TC genotype. In aspects, the patient is black or African-American with
an OPRDI TT
genotype. In aspects, the patient is black or African-American with an OPRDI
TC genotype. In
aspects, the patient is a black or African-American injection drug patient
with an OPRDI TT
genotype. In aspects, the patient is a black or African-American injection
drug patient with an
OPRDI TC genotype.
[0100] The disclosure provides methods for treating opioid dependence,
reducing and/or
eliminating opioid craving, reducing and/or eliminating opioid withdrawal
symptoms reducing
and/or eliminating illicit opioid use, or a combination of two or more
thereof, in a patient by
administering a first composition of Formulation A, Formulation B, Formulation
C, or
Formulation D comprising from about 295 mg to about 305 mg of buprenorphine
(e.g., 300 mg
buprenorphine free base) for two months and thereafter administering a second
composition of
Formulation A, Formulation B, Formulation C, or Formulation D comprising from
about 95 mg
to about 105 mg of buprenorphine (e.g., 100 mg buprenorphine free base) for at
least four
months provide a steady-state average buprenorphine plasma concentration
(Cavg) from about 2.6
ng/mL to about 3.6 ng/mL; or from about 2.7 ng/mL to about 3.5 ng/mL; or from
about 2.8
ng/mL to about 3.4 ng/mL; or from about 2.9 ng/mL to about 3.3 ng/mL; or from
about 3.0
ng/mL to about 3.2 ng/mL; or about 3.1 ng/mL. In aspects, the patient is an
injection drug
patient. In aspects, the patient is black or African-American. In aspects, the
patient is a black or
African-American injection drug patient. In aspects, the patient has an OPRDI
TT genotype. In
aspects, the patient has an OPRDI TC genotype. In aspects, the patient is an
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is an injection
drug patient with an
OPRD1 TC genotype. In aspects, the patient is black or African-American with
an OPRDI TT
genotype. In aspects, the patient is black or African-American with an OPRDI
TC genotype. In
aspects, the patient is a black or African-American injection drug patient
with an OPRDI Tr
genotype. In aspects, the patient is a black or African-American injection
drug patient with an
32
CA 2995923 2018-02-21
OPRD1 TC genotype.
[0101] The disclosure provides methods for treating opioid dependence,
reducing and/or
eliminating opioid craving, reducing and/or eliminating opioid withdrawal
symptoms, reducing
and/or eliminating illicit opioid use, or a combination of two or more
thereof, in a patient by
administering a first composition of Formulation A, Formulation B, Formulation
C, or
Formulation D comprising from about 295 mg to about 305 mg of buprenorphine
(e.g., 300 mg
buprenorphine free base) for two months and thereafter administering a second
composition of
Formulation A, Formulation B, Formulation C, or Formulation D comprising from
about 95 mg
to about 105 mg of buprenorphine (e.g., 100 mg buprenorphine free base) for at
least four
months provide a steady-state minimum buprenorphine plasma concentration
(Cmin) from about
2.2 ng/mL to about 2.9 ng/mL; or from about 2.3 ng/mL to about 2.9 ng/mL; or
from about 2.4
ng/mL to about 2.9 ng/mL; or from about 2.5 ng/mL to about 2.9 ng/mL; or from
about 2.6
ng/mL to about 2.9 ng/mL; or from about 2.7 ng/mL; to about 2.9 ng/mL; or from
about 2.0
ng/mL to about 2.8 ng/mL; or from about 2.1 ng/mL to about 2.8 ng/mL; or from
about 2.2
ng/mL to about 2.8 ng/mL; or from about 2.3 ng/mL to about 2.8 ng/mL; or from
about 2.4
ng/mL to about 2.8 ng/mL; or from about 2.5 ng/mL to about 2.8 ng/mL; or from
about 2.6
ng/mL to about 2.8 ng/mL; or from about 2.7 ng/mL; to about 2.8 ng/mL; or
about 2.7 ng/mL;
or about 2.73 ng/mL; or about 2.74 ng/mL; or about 2.75 ng/mL. In aspects, the
patient is an
injection drug patient. In aspects, the patient is black or African-American.
In aspects, the
patient is a black or African-American injection drug patient. In aspects, the
patient has an
OPRDI TT genotype. In aspects, the patient has an OPRD1 TC genotype. In
aspects, the patient
is an injection drug patient with an OPRDI TT genotype. In aspects, the
patient is an injection
drug patient with an OPRD1 TC genotype. In aspects, the patient is black or
African-American
with an OPRDI TT genotype. In aspects, the patient is black or African-
American with an
OPRDI TC genotype. In aspects, the patient is a black or African-American
injection drug
patient with an OPRDI TT genotype. In aspects, the patient is a black or
African-American
injection drug patient with an OPRDI TC genotype.
[0102] The disclosure provides methods for treating opioid dependence,
reducing and/or
eliminating opioid craving, reducing and/or eliminating opioid withdrawal
symptoms, reducing
and/or eliminating illicit opioid use, or a combination of two or more
thereof, in a patient by
administering a first composition of Formulation A, Formulation B, Formulation
C, or
Formulation D comprising from about 295 mg to about 305 mg of buprenorphine
(e.g., 300 mg
33
CA 2995923 2018-02-21
84334135
buprenorphine free base) for two months and thereafter administering a second
composition of
Formulation A, Formulation B, Formulation C, or Formulation D comprising from
about 95 mg
to about 105 mg of buprenorphine (e.g., 100 mg buprenorphine free base) for at
least four
months provide a steady-state maximum buprenorphine plasma concentration
(Cmax) about 3.6
ng/mL to about 4.6 ng/mL; about 3.7 ng/mL to about 4.5 ng/mL; about 3.8 ng/mL
to about 4.4
ng/mL; about 3.9 ng/mL to about 4.3 ng/mL; from about 4.0 ng/mL to about 4.2
ng/mL; or about
4.1 ng/mL; or about 4.11 ng/mL; or about 4.12 ng/mL. In aspects, the patient
is an injection drug
patient. In aspects, the patient is black or African-American. In aspects, the
patient is a black or
African-American injection drug patient. In aspects, the patient has an OPRDI
IT genotype. In
aspects, the patient has an OPRD1 TC genotype. In aspects, the patient is an
injection drug
patient with an OPRDI IT genotype. In aspects, the patient is an injection
drug patient with an
OPRDI TC genotype. In aspects, the patient is black or African-American with
an OPRDI TT
genotype. In aspects, the patient is black or African-American with an OPRDI
TC genotype. In
aspects, the patient is a black or African-American injection drug patient
with an OPRDI TT
genotype. In aspects, the patient is a black or African-American injection
drug patient with an
OPRDI TC genotype.
[0103] Methods for making the sustained-release buprenorphine formulations
described herein
are known in the art and described, for exatnple, in US Patent No. 8,921,387,
US Patent No.
8,975,270, US Patent No. 9,272,044, US Patent No. 9,498,432, and US
Publication No.
2013/210853.
EXAMPLES
[0104] The following examples are for illustrative purposes and are not
intended to limit the
scope of the claims or the disclosure.
[0105] Example 1
[0106] A 6 month, double-blind, placebo-controlled, Phase 3 clinical study
(NCT02357901)
was conducted to test two different dosage regimens of Formulation D on
patients seeking
treatment for opioid use disorder. Formulation D1 (Formulation D containing
300 mg
buprenorphine free base) and Formulation D2 (Formulation D containing 100 mg
buprenorphine
free base) were used. After screening, all patients went through a 3 day
induction phase using
SUBOXONE film, followed by a 4-11 day stabilization phase using SUBOXONE
film.
After the induction and stabilization phases, patients were randomized to
three groups.
34
Date Recue/Date Received 2021-08-11
[0107] Patient Group 1 (n=194 patients) was administered Formulation D1 on
Month 1 (Day
1) and Month 2 (Day 29), and was subsequently administered Formulation D2 on
Month 3 (Day
57), Month 4 (Day 85), Month 5 (Day 113), and Month 6 (Day 141). Formulation
D1 contained
about 300 mg buprenorphine free base, and Formulation D2 contained about 100
mg
buprenorphine free base. This dosing regimen is also referred to as
300mg/100mg (i.e., 300 mg
for the first two months, and 100 mg for the subsequent four months).
[0108] Patient Group 2 (n=196 patients) was administered Formulation D1 on
Month 1 (Day
1), Month 2 (Day 29), Month 3 (Day 57), Month 4 (Day 85), Month 5 (Day 113),
and Month 6
(Day 141). Formulation DI contained about 300 mg buprenorphine free base. This
dosing
regimen is also referred to as 300mg/300mg (i.e., 300 mg for the first two
months, and 300 mg
for the subsequent four months).
[0109] Patient Group 3 (n=99) was administered a placebo on Month 1 (Day 1),
Month 2 (Day
29), Month 3 (Day 57), Month 4 (Day 85), Month 5 (Day 113), and Month 6 (Day
141).
[0110] Each Patient Group received individual drug counseling (IDC) during the
course of the
study. Through the course of the study, each Patient Group provided a weekly
urine sample for
opioid testing. The primary measure of efficacy was assessed by centrally
tested urine drug
screening (UDS) results and self-reported illicit opioid use. Additionally,
scores for Opioid
Craving VAS, COWS and SOWS were assessed.
[0111] Urine drug screens and self-reports were assessed at screening, and
then on a weekly
basis following each subcutaneous injection of Formulation D or placebo (Days
1, 8, 15, 22, 29,
36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148,
155, 162 and 169), as
well as at a safety follow-up visit (Day 197). Urine drug screens were also
assessed on the day
after each subcutaneous injection at 24 hours post-dose (Days 2. 30, 58, 86,
114 and 142).
[0112] The results of the urine drug screens and self-reports are shown in
FIG. 1 and FIG. 2.
FIG. 2 shows that about 28.4% of the patients in Group 1 and 29.1% of the
patients in Group 2
had negative urine samples for illicit opioids combined with negative self-
reports of illicit opioid
use at least 80% of the time over the course of the study. In contrast, only
about 2% of the
patients in the placebo group had negative urine samples for illicit opioids
combined with
negative self-reports of illicit opioid use at least 80% of the time over the
course of the study.
[0113] Scores for Opioid Craving VAS, COWS and SOWS were measured at the same
times
as the urine drug samples (with the exception of the follow-up visit on Day
197). Opioid craving
CA 2995923 2018-02-21
was additionally measured during the dose-adjustment period with SUBOXONE
film. The
COWS and SOWS scores were measured during both induction and dose adjustment
with
SUBOXONE film (Days -14, -13, -12, -11, -8, -4 and/or -1).
[0114] The COWS were used to quantify withdrawal symptoms, and the results of
the study
are shown in Table 1 and FIG. 3. The COWS scores ranged from 0 to 48 and were
categorized as
no withdrawal (0 - 4), mild (5 - 12), moderate (13 - 24), moderately severe
(25 - 36) and severe
withdrawal (> 36). Following SUBOXONE film run-in and treatment with
Formulation D,
withdrawal symptoms were controlled in more than 99% of the patients (scores <
12), with the
majority of patients having scores < 4. In the placebo group, COWS scores were
also < 12 in
97% of the patients; however, this result is not surprising because over 90%
of the subjects in the
placebo group were using illicit opioids throughout the study, thus
controlling their cravings and
withdrawal symptoms with the illicit opioids. Only 2 patients from the placebo
group were not
using opioids at the end of the study. No patients showed severe withdrawal
(COWS score
> 36). About 50% of the cumulative percentage of subjects had a COWS score of
0 when the
buprenorphine plasma concentration was about 3.5 ng/mL to about 4 ng/mL, as
shown in FIG. 4.
Similar results were observed for SOWS scores, as shown in Table 2.
[0115] Table 1
Clinical Opiate Withdrawal Scale Group 1 Group 2
(COWS) (300mg/100mg) (300mg/300mg)
Difference in LS means (SE) -0.4 (0.38) -1.0 (0.38)
95% CI -1.13, -4.30 -1.72, -0.23
p-value 0.3143 0.0101
[0116] Table 2
Subjective Opiate Withdrawal Scale Group 1 Group 2
(SOWS) (300mg/100mg) (300mg/300mg)
Difference in LS means (SE) -1.6 (0.87) -2.6 (0.87)
95% CI -3.29, 0.14 -4.32, -0.90
p-value 0.0726 0.0028
[0117] The Opioid Craving VAS score chart is shown in Table 3. Most patients
(81-90%)
reported significant craving (> 20) at screening. Opioid craving was also
assessed during the
induction and dose stabilization period with SUBOXONE film. Following the
first
subcutaneous injection of Formulation D. the number of patients with zero
craving increased
rapidly to reach a plateau on Day 2. On average, 54-61% of patients in Group 1
and Group 2
36
CA 2995923 2018-02-21
reported zero craving between Day 2 and Day 169 (vs 27% for placebo); 81% of
patients in
Group 1 and Group 2 reported opioid craving VAS score < 5 (vs 48% for
placebo); and only 6-
7% of patients in Group 1 and Group 2 reported craving > 20 (vs 34% for
placebo). Table 4
shows the mean changes in Opioid Craving VAS scores compared to placebo. Mean
Opioid
Craving VAS scores over the course of the study are shown in FIG. 5. The
cumulative
percentage of subjects who reported an opioid craving VAS score of 0 was about
60% at
buprenorphine plasma concentration levels of about 2.5 ng/mL to 3 ng/mL, as
shown in FIG. 6.
[0118] Table 3
Opioid Craving Visual Analog Scale Score (VAS)
0 (no craving)
1-5
6-20
21-100 (significant craving)
[0119] Table 4
Opioid Craving Visual Analog Scale Score Group 1 Group 2
(VAS) (300mg/100mg) (300mg/300mg)
Difference in LS means (SE) -9.4 (2.62) -12.4 (2.61)
95% Cl -14.56, -4.30 -17.51, -7.28
p-value 0.0003 0.0101
[01201 Blood samples for PK assessment were taken during the run-in phase on
Day -1 (within
1 hour prior to dosing and 1-2 hours post-dose) and during the double-blind
treatment phase on
Days 1, 2, 8, 15, 22, 29, 30, 36, 43, 50, 57, 58, 64, 71, 78, 85, 86, 92, 99,
106, 113, 114, 120,
127, 134, 141, 142, 148, 155, 162 and 169). On Days 1, 29, 57, 85, 113 and
141, blood samples
were taken within 1 hour prior to subcutaneous injection of Formulation D and
at 4 hours ( 15
minutes) after subcutaneous injection of Formulation D.
[0121] Blood samples were collected in all subjects, including placebo, to
preserve the blind.
Plasma concentrations of buprenorphine were determined using a previously
validated LC-
MS/MS assay. The lower limit of quantification was established as 0.0500 ng/mL
for
buprenorphine (bioanalytical method ATM-1899).
[0122] The mean steady-state buprenorphine pharmacokinetic parameters for
Patient Groups 1
and 2 are shown in Table 5 below. The steady-state concentrations are based on
a 6 month
treatment period. In Table 5, the % mu-opioid receptor occupancy (nORO) is the
predicted
whole brain mu-opioid receptor occupancy corresponding to the mean steady-
state Cavg.
37
CA 2995923 2018-02-21
[0123] Table 5
Dose Group N Cmin (ng/mL) Cavg (ng/mL) Cmax (ng/mL) % u0R0
Group! 194 2.74 3.14 4.11 75
300mg/100mg
Group 2 196 5.11 6.32 8.68 83
300mg/300mg
[0124] The study compared the opioid abstinence rates of patients in Patient
Groups 1-3 and
the results are shown in Tables 6 and 7 below. 61% of the patients in Group 1
and 64% of the
patients in Group 2 completed the therapy, while only 33.3% of the patients in
the placebo group
completed the study. 47% of the patients in Group 2 were drug free in the last
4 weeks of the 6-
month study.
[0125] Table 6
% Abstinent Weeks Group 1 Group 2 Placebo
(300mg/100mg) (300mg,/300mg)
Mean (SD) 42.7% (38.50%) 41.3% (39.66%) 5.0% (16.98%)
p-value <0.0001 <0.0001
[0126] Table 7
Group 1 Group 2 Placebo
(300mg/100mg) (300mW300mg)
>80% Abstinent Weeks 28.4% 29.1% 2.0%
(Responders)
p-value <0.0001 <0.0001
[0127] The study compared the abstinence rate of Group I and Group 2 for
injection drug
patients compared to patients who had used opioids by other routes.
Unexpectedly, non-linear
mixed effect modeling of pharmacokinetic/pharmacodynamic (PK/PD) data
indicated that the
EC50 for injection drug patients was 4.3 ng/mL while the ECso for patients who
had abused
opioids by non-injectable routes was only 1.2 ng/mL. These results are shown
in FIG. 8. As
shown in Table 8 below, it was also discovered that injection drug patients in
Group 2 (who were
administered the 300 mg dose of Formulation D for 6 months) achieved an opioid
abstinence rate
of 69% at Day 169 compared to injection drug patients in Group I (who were
administered the
300 mg dose of Formulation D for 2 months, and then the 100 mg dose of
Formulation D for 4
months) who only achieved an opioid abstinence rate of 53% at Day 169. Thus,
the data
unexpectedly showed that injection drug patients would strongly benefit from
the 300 mg dose
of Formulation D over a period of 6 months due to the higher ECso value.
38
CA 2995923 2018-02-21
[0128] Table 8
Abstinence Rate (Day 169) For Injection Drug Patients
Group 1 (300mg/100mg) 53%
Group 2 (300mg/300mg) 69%
[0129] The results of this study confirmed that the dosing regimens for
patients in Group 1 and
Group 2 were efficacious and statistically superior to placebo. The
relationship between clinical
endpoints and buprenorphine plasma concentration was characterized by PK/PD
modelling. The
results of the PK/PD modelling analysis indicate similar shape of exposure-
response for brain
mu-opioid receptor occupancy and clinical endpoints investigated, consistent
with the maximal
effect (Emax) model, as shown in FIG. 7. The correlation between clinical
endpoints and mu-
opioid receptor occupancy was evaluated using the base population PK/PD models
developed for
illicit opioid use and craving. The overall probability of negative opioid use
increased within the
range of 70% to 90% mu-opioid receptor occupancy, indicating that patients
would benefit from
the 300 mg dose. The probability of zero craving also increased between 70% to
90% mu-opioid
receptor occupancy.
[0130] The treatment was generally well-tolerated. There were no serious
injection site
reactions, and there were no discontinuations from the study due to injection
site reactions. The
treatment-emergent adverse events (TEAE) are shown in Table 9 below.
[0131] Table 9
Occurrence (%) Placebo + I Formulation D
Formulation D
IDC 300mg/100mg + 300mg/300mg +
(n=100) IDC IDC
(n=203) (w=201)
Any TEAE 56.0 76.4 66.7
Serious TEAE 5.0 2.0 3.5
TEAE leading to discontinuation 2.0 3.4 5.0
from study
Any injection site TEAE 9.0 13.8 18.9
Serious injection site TEAE 0 0 0
Injection site l'EAE leading to 0 0 0.5
discontinuation from study
[0132] The study's primary efficacy endpoint was the mean percentage
abstinence (opioid-free
weeks), assessed as a cumulative distribution function (CDF) and measured by
the percentage of
urine samples negative for opioids, combined with self-reports negative for
illicit opioid use,
39
CA 2995923 2018-02-21
from Weeks 5 to Week 24. The key secondary endpoint was treatment success,
defined as any
patient with >80% of urine samples negative for opioids combined with self-
reports negative for
illicit opioid use from Weeks 5 to 24. Additional secondary measures included
the proportion of
patients who completed the study, as well as the patients' scores on both the
Opioid Craving
VAS and the COWS. The safety of Formulation D was also assessed relative to
placebo.
[0133] The results showed that Formulation D met the primary efficacy
endpoint, with both
Formulation D dosage regimens demonstrating significantly superior abstinence
rates versus
placebo (300/300 mg: 41.3%; 300/100 mg: 42.7%; placebo: 5.0%, p<0.0001). Both
Formulation
D dosing regimens also met the key secondary endpoint of treatment success
(300/300 mg:
29.1%; 300/100 mg: 28.4%; placebo: 2.0%, p<0.0001). In addition to the
efficacy findings,
PK/PD (exposure-response) analyses demonstrated a positive relationship
between
buprenorphine exposure, mu-opioid receptor occupancy and clinical endpoints of
abstinence and
opioid craving. Patients taking the 300/300 mg dosage of Formulation D
achieved
buprenorphine plasma concentrations >2 ng/mL, resulting in improvements in
abstinence and
reductions in opioid craving.
[0134] Significantly more patients in both dosing regimen Groups 1 and 2
completed the study
compared with those on placebo (300/300 mg: 64.3%; 300/100 mg: 61.3%; placebo:
33.3%,
p<0.0001). Formulation D was safe and well-tolerated relative to placebo.
Treatment-emergent
adverse events (TEAEs) were consistent with the known safety profile of
Formulation D, with no
unexpected safety findings. The most common TEAE was injection site reactions
(300/300 mg:
18.9%; 300/100 mg: 13.8%; placebo: 9.0%), but these were not treatment-
limiting. Serious
TEAEs were observed in 2.7% of patients on Formulation D (both dosage regimens
combined)
compared with 5.0% of patients on placebo.
[0135] Phase III Clinical Trial Conclusions. Both dosing regimens of
Formulation D
demonstrated compelling, persistent, and statistically significant differences
in percentage
abstinence and treatment success when compared to placebo. The treatment
benefits were
consistent across other important clinical endpoints, including control of
craving and withdrawal
symptoms. The positive results were confirmed by exposure-response analyses
demonstrating a
clear relationship between buprenorphine plasma concentration levels,
predicted whole brain
mu-opioid receptor occupancy, abstinence, and opioid craving. Benefits from
Formulation D
started with the first dose that achieved a buprenorphine plasma concentration
greater than or
equal to 2 ng/mL and predicted brain mu-opioid receptor occupancy greater than
or equal to
CA 2995923 2018-02-21
70%. The benefits of Formulation D were maintained for the one month dosing
interval and
over the entire treatment duration, reducing the risk of requiring rescue
medication. Formulation
D was safe and generally well-tolerated. The safety profile was consistent
with the known safety
profile of transmucosal buprenorphine with no unexpected safety findings.
Injection site
reactions were not treatment-limiting.
[0136] Example 2
[0137] The results of the Phase HI clinical trial described in Example 1 were
further analyzed
to characterize exposure-response relationships for Formulation D with respect
to illicit opioid
use and opioid craving, and to assess dropout patterns in the pivotal Phase
III efficacy study.
Abstinence was the primary efficacy variable defined as opioid negative urine
samples combined
with self-reports negative for illicit opioid use. Opioid craving was a
secondary efficacy variable
and was assessed on a visual analog scale (VAS) ranging from 0 (no craving) to
100 (strongest
craving). Weekly measures of abstinence and craving were obtained following
randomization.
The integrated PKJPD model for abstinence utilized two categories: (i) opioid
use = 0 when there
was a negative urine drug screen & self report; and (ii) opioid use = 1. The
craving VAS score
used four categories: (i) craving = 0; (ii) craving = 1-5; (iii) craving = 6-
20; and (iv) craving =-
21-100. For subjects who dropped out of the study, no data was utilized.
101381 A sequential PK/PD modeling approach was used where empirical Bayes
estimates
(EBEs) of PK parameters were used to derive buprenorphine concentrations at
the time of
efficacy measurements. EBEs were estimated from a population PK model
developed using
combined PK data from a multiple ascending dose study and the Phase III double-
blind efficacy
study.
[0139] Abstinence was analyzed as a binary variable using an Emax logistic
model shown in
Equation 2:
1ogit1P(Yi1 = 0)1 = a + fd + ni
x co;
fd ______________________________________
EC50 + Cnij
P(Yii = 0),-- probability of abstinence for subject i
at time tu
a = effect in absence of buprenorphine treatment
= subject-specific random effect on a
Cp buprenorphine plasma concentration
Emaz = maximum of drug effect (fd)
EC501 = Concentration at which 50% of maximum
etf fd ic
CA 2995923 2018-02-21
[0140] Craving was analyzed as an ordinal variable with 4 categories described
above using a
proportional odds model as shown in Equation 3:
logit[P(Yij 5_]= am + fd +
m= craving severity categories 1, 2, or 3
am = effect in absence of drug treatment for categories 1 (a1), 2 (a2), or 3
(a3) such that al <
a2 < a3
fd and n, are drug effect and random effect as defined for equation 1
[0141] Since dropout rates of 32-33% for the treatment arm vs. 64% for the
placebo arm were
observed (as shown in FIG. 17), dropout was modeled using time-to-event
analysis. Several
models were tested and the Gompertz model provided the best fit. Accordingly,
the probability
of staying in the trial up to time t, was given by Equation 4:
t,
Survival(ti) = exp hazard(t)dt)
hazard t x exp(¨ke x t)
= baseline instantaneous rate (hazard) of dropout, ke = rate constant of
decrease
in ha7arri
101421 Covariate analyses were conducted for Equations 2, 3, and 4, including
demographic
characteristics, baseline clinical characteristics (e.g., Beck Depression,
Pain, Clinical Global
Impression of Disease Severity [CGI-S], injectable vs. non-injectable route
for illicit opioid use),
social characteristics (e.g., employment, health insurance) as well as genetic
status for opioid
receptors (OPRM1, OPRD1, OPRK1) and dopamine D2 receptors (DRD2). For time-to-
event
analysis, observed records of opioid use and craving were evaluated as
predictors of dropout.
Model parameters were estimated using NONMEM version 7.3 and R was used for
data
preparation, exploration and post-processing of NONMEM output.
[0143] Data from 489 subjects was including in the PK/PD analyses. The
baseline
42
CA 2995923 2018-02-21
characteristics of subjects included in the PK/PD analyses are shown in Table
10, where numbers
in brackets refer to standard deviation.
[0144] Table 10
Formulation D (300mg for Formulation D (300mg for
Characteristic 2 months followed by 100 2 months
followed by 100 Placebo
mg for 4 months) mg for 4 months)
Age
Mean (SD) 40.42(11.23) 39.34 (10.96 39.19 (10.96)
Sex (N(%))
Male 128 (66) 132 (67) 64 (65)
Female 66 (34) 64 (33) 35 (35)
Race (N(%))
White 132 (68) 140 (71) 77(78)
Black or African 56 (29) 54 (28) 20 (20)
American
Others 6(3.1) 2(1.0) 2(2.0)
OPRD1 (rs678849 (N(%))
CC 66 (34) 68 (35) 33 (33)
TC 80(41) 78 (40) 47 (48)
TT 38(20) 37(19) 15(15)
not available 10 (5.2) 13(6.6) 4(4.0)
Opioid Use (Screening)(N(Y0))
non-injectable 110 (57) 116(59) 49(50)
route
Injectable route 84 (43) 80 (41) 50 (50)
Employment Status (N(%))
Unemployed 130 (67) 113 (58) 55 (56)
Employed 55 (28) 76 (39) 34 (34)
not available 9(4.6) 7(3.6) 10(10)
Mean Baseline Scores
Opiate Craving 4.6 (5.80) 4.6 (8.75 7.6 (15.88
Visual Analog
Scale
Clinical Opiate 2.22 (2.56) 2.1 (2.31) 2.3 (2.50)
Withdrawal
Scale
Subjective 4.4 (6.12) 3.6 (5.42 4.5 (5.64
Opiate
Withdrawal
Scale
[0145] Dropout. Dropout was successfully predicted from baseline subject
characteristics and
recorded measures of efficacy (craving), supporting missing at random (MAR)
mechanisms.
Craving: A score greater than 20 was associated with up to 3.0-fold and 3.6-
fold higher dropout
rates in active and placebo arms, respectively, compared to craving score of 1-
5 (FIGS. 19A-B).
Thus, opioid craving was identified as a major predictor of dropout for both
placebo and active
43
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treatment arms, indicating that craving should be closely monitored for
treatment of OUD
patients. CGI-S (baseline) (i.e., a score of disease severity): A higher
dropout rate was only seen
in the placebo group when the CGI-S score was less than or equal to 3, as
shown in FIGS. 16A-
C. As shown in FIGS. 15A-C, Black or African American subjects had a dropout
rate that was
about 40% lower in all treatment groups. As shown in FIGS. 10A-C, age had an
effect only on
subjects from the placebo group, which suggests that once treatment was
started, age made no
difference with respect to treatment retention.
[0146] Abstinence. At screening, all but one subject used opioids. During
treatment with
Formulation D, the percent abstinence increased from 37-40% on Day 1 (end of
SUBOXONE
run-in) to 64-66% at the end of the trial. As expected, the percent abstinence
in the placebo
group rapidly declined after Day 2, reaching 6% at the end of the trial.
Observations clearly
supported an exposure-response relationship consistent with an Emax model, as
shown in FIG. 11.
The plateau was reached at about 2 ng/mL. The logistic regression model
successfully described
the time course of the number and percent of subjects abstinent and non-
abstinent in all treatment
arms (data not shown).
[0147] As shown in FIGS. 12 and 13, significant covariates were identified on
Emax and EC50.
Especially, subjects who injected opioids at baseline had a 3.6-fold higher
EC50 than subjects
using opioids by non-injectable route, indicating that those subjects would
benefit from the
higher 300 mg maintenance dose (as opposed to the 100 mg maintenance dose).
[0148] Craving VAS Score. Similar to abstinence, observed measures of craving
supported an
exposure-response relationship consistent with an Etna, model, where the
plateau for maximal
response was reached at about 3 ng/mL. The proportional odds model described
the observed
data over the course of the study, as shown in FIGS. 14A, 14B, and 14C. Body
mass index was a
significant covariate on Emax, but only explained 1% of the variability.
[0149] As shown in FIG. 7, the results indicated similar shape of exposure-
response for mu-
opioid receptor occupancy, abstinence, and craving VAS score, consistent with
an Enm, model.
[0150] Example 3
[0151] The results of the Phase III clinical trial described in Example 1 were
further analyzed
to compare injection drug patients to non-injection drug patients (i.e.,
patients who used illicit
opioids by a non-injectable route). The subgroup analysis found that injection
drug patients
achieved additional benefit from the higher dose regimen of RBP-6000 (300 mg
buprenorphine
44
CA 2995923 2018-02-21
once monthly for six months). Among injection drug patients, the mean (median)
percentage
abstinence was higher in the group administered 300 mg once monthly for six
months (45%
[40%]) than in the group administered 300 mg once monthly for two months
followed by 100
mg once monthly for four months (36% [20%]). Among non-injection drug
patients, the mean
(median) percentage abstinence was higher in the group administered 300 mg
once monthly for
two months followed by 100 mg once monthly for four months (48% [48%]) than in
the group
administered 300 mg buprenorphine once monthly for six months (39% [25%]).
These data were
supported by an exposure-response analysis indicating maximal response for
abstinence at higher
buprenorphine concentrations (-6 ng/mL) for injection drug patients, compared
with non-
injection drug patients. Buprenorphine plasma level of 6 ng/mL corresponds to
the average
plasma concentration delivered by the 300-mg maintenance dose at steady-state.
[01521 A consistent relationship was observed for the PK and PD results
between the 2 dosing
regimens (300/300 vs. 300/100) for injection drug patients as shown in FIGS.
19A-B. Mean
levels start to diverge after the first maintenance dose (Week 8) and the
difference in
concentrations is greatest after the sixth injection. The right-hand panel of
FIGS. 19A-B shows
the percentage of injection drug patients who were abstinent over the course
of the study, using
the same pre-specified imputation method as the primary efficacy endpoint. The
abstinence rates
started to diverge after the administration of the first maintenance dose
(Week 8), consistent with
the divergence in the plasma concentrations. By the end of the study, the
abstinence rate among
injection drug patients was 54% with the 300/300 dosing regimen compared to
32% with the
300/100 dosing regimen.. Based on the relative risk, subjects who received the
higher
maintenance dose were 1.7 times, or 70% more likely to be abstinent at 6
months than subjects
who received the lower maintenance dose. This demonstrates that the 300/300
dosing regimen
gives injection drug patients the best chance of success.
[0153] While various embodiments and aspects are shown and described herein,
it will be clear
to the skilled artisan that such embodiments and aspects are provided by way
of example.
Variations, changes, and substitutions will occur to the skilled artisan. It
will be understood that
various alternatives to the embodiments described herein can be used.
[0154] References: Gerstein et al, New England Journal of Medicine, 323:844-
848 (1990);
Hser et al, Addiction, 109:79-87 (2014); Crist et al, Neuropsychopharmacology,
38:2003-2010
(2013); Wiens et al, Stat Biopharm, 5:383-393 (2013); Ling et al, JAMA,
304:1576-1583 (2010);
Rosenthal eta!, Addiction, 108:2141-2149 (2013); Bickel et al, Experimental
and Clinical
CA 2995923 2018-02-21
Psychopharmacology, 3:477-489 (1995); Greenwald eta!, Drug Alcohol Depend,
144:1-11
(2014); Greenwald et al, Neuropsychopharmacology, 28:2000-2009 (2003);
Greenwald et al,
Biol Psychiatry, 61:101-110 (2007); Hillhouse et al, The American Journal of
Drug and Alcohol
Abuse, 37:453-459 (2011); Tkacz et al, Am J Addict, 21:55-62 (2012); Laffont
et al, J Clin
Pharmacol, 56:806-815 (2016): Nasser et at, Clin Pharmacokinet, 53:813-824
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Amass eta!, Addiction, 107:142-151 (2012).
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