CA2995923C - Methods to treat opioid use disorder - Google Patents

Abstract

The disclosure provides buprenorphine formulations that produce therapeutic plasma concentration levels of buprenorphine in patients to treat opioid use disorder, to reduce or eliminate opioid withdrawal symptoms, to reduce or eliminate opioid craving, and to induce and maintain opioid abstinence.

Description

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."

[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 CA 2995923 2018-02-21 _ 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

4 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 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 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 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 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 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.

[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 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 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.

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 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

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 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 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 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 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 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.

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 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 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.

[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, 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 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, 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 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, 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 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.

[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 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 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 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 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.

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 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 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) 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.

[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.

[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, 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 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 [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 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 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 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 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 (2014); Bickel, Exp Clin Psychopharmacol, 3:477-489 (1995); Fudala et al. N. Engl J Med, 949-958 (2003);
Amass eta!, Addiction, 107:142-151 (2012).

Claims (36)

CLAIMS:

1. A buprenorphine composition for use in treating moderate-to-severe opioid use disorder in an injection drug patient in need thereof, the use comprising subcutaneous administration of the buprenorphine composition once per month for at least six months in the injection drug patient, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at 18 wt%; (ii) about 32 wt% of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt% of N-methy1-2-pyrrolidone.

2. A buprenorphine composition for use in treating opioid use disorder in an injection drug patient in need thereof, the use comprising subcutaneous administration of the buprenorphine composition once per month for at least six months in the injection drug patient, wherein the buprenorphine composition comprises about 300 mg buprenorphine free base, a poly(lactide-co-glycolide) copolymer, and N-methy1-2-pyrrolidone.

3. A buprenorphine composition for use according to claim 2, wherein the opioid use disorder is: moderate-to-severe opioid use disorder, moderate opioid use disorder, or severe opioid use disorder.

4. A buprenorphine composition for use according to claim 2, for reducing opioid craving; eliminating opioid craving; reducing opioid withdrawal symptoms eliminating opioid withdrawal symptoms; reducing illicit opioid use;
preventing illicit opioid use; or a combination of two or more thereof.

5. A buprenorphine composition for use according to any one of claims 2 to 4, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at about 10 wt% to about 30 wt%; (ii) about 10 wt% to about 60 wt% of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt% to about 70 wt% of N-methy1-2-pyrrolidone.

6. A buprenorphine composition for use according to any one of claims 2 to 4, wherein the buprenorphine composition comprises: (i) about 300 mg Date Recue/Date Received 2022-03-02 buprenorphine free base at about 14 wt% to about 22 wt%; (ii) about 22 wt% to about 42 wt% of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt% to about 60 wt% of N-methy1-2-pyrrolidone.

7. A buprenorphine composition for use according to any one of claims 2 to 4, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at 18 wt%; (ii) about 32 wt% of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt%
of N-methy1-2-pyrrolidone.

8. The buprenorphine composition for use according to any one of claims 1 to 7, wherein the use comprises subcutaneous administration of the buprenorphine composition once per month for at least twelve months.

9. The buprenorphine composition for use according to any one of claims 1 to 8, wherein the use produces opioid abstinence in the injection drug user.

10. The buprenorphine composition for use according to any one of claims 1 to 9, wherein the injection drug patient is: an intravenous injection drug patient;
an intramuscular injection drug patient, a subcutaneous injection drug patient, or a combination of two or more thereof.

11. A buprenorphine composition for use in treating opioid use disorder in an injection drug patient in need thereof, the use comprising subcutaneous administration of the buprenorphine composition once per month in the injection drug patient; wherein the buprenorphine composition comprises about 300 mg buprenorphine free base, a poly(lactide-co-glycolide) copolymer, and N-methy1-2-pyrrolidone.

12. A buprenorphine composition for use according to claim 11, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at about 10 wt% to about 30 wt%; (ii) about 10 wt% to about 60 wt% of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having a weight 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.

Date Recue/Date Received 2022-03-02

13. A buprenorphine composition for use according to claim 11, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at about 14 wt% to about 22 wt%; (ii) about 22 wt% to about 42 wt% of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt% to about 60 wt% of N-methy1-2-pyrrolidone.

14. A buprenorphine composition for use according to claim 11, wherein the buprenorphine composition comprises: (i) about 300 mg buprenorphine free base at about 18 wt%; (ii) about 32 wt% of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt% of N-methy1-2-pyrrolidone.

15. A buprenorphine composition for use according to any one of claims 11 to 14, wherein the opioid use disorder is: moderate-to-severe opioid use disorder, moderate opioid use disorder, or severe opioid use disorder.

16. A buprenorphine composition for use according to any one of claims 11 to 15, for reducing opioid craving, eliminating opioid craving, reducing opioid withdrawal symptoms, eliminating opioid withdrawal symptoms, reducing illicit opioid use, eliminating illicit opioid use, or a combination of two or more thereof.

17. A buprenorphine composition for use according to any one of claims 11 to 16, wherein the use produces opioid abstinence in the injection drug user.

18. A buprenorphine composition for use according to any one of claims 11 to 17, wherein the injection drug patient is: an intravenous injection drug patient, an intramuscular injection drug patient, a subcutaneous injection drug patient, or a combination of two or more thereof.

19. Buprenorphine for use in the manufacture of a medicament for treating moderate-to-severe opioid use disorder in an injection drug patient in need thereof, wherein the medicament is for use subcutaneously once per month for at least six months in the injection drug patient, and wherein the medicament comprises: (i) about 300 mg buprenorphine free base at 18 wt%; (ii) about 32 wt% of a 50:50 poly(DL-lactide-co-Date Recue/Date Received 2022-03-02 glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt%
of N-methy1-2-pyrrolidone.

20. Buprenorphine for use in the manufacture of a medicament for treating opioid use disorder in an injection drug patient in need thereof, wherein the medicament is for use subcutaneously once per month for at least six months in the injection drug patient, and wherein the medicament comprises about 300 mg buprenorphine free base, a poly(lactide-co-glycolide) copolymer, and N-methy1-pyrrolidone.

21. Buprenorphine for use according to claim 20, wherein the opioid use disorder is: moderate-to-severe opioid use disorder, moderate opioid use disorder, or severe opioid use disorder.

22. Buprenorphine for use according to claim 20, wherein the medicament is for use in reducing opioid craving; eliminating opioid craving;
reducing opioid withdrawal symptoms eliminating opioid withdrawal symptoms; reducing illicit opioid use; preventing illicit opioid use; or a combination of two or more thereof.

23. Buprenorphine for use according to any one of claims 20 to 22, wherein the medicament comprises: (i) about 300 mg buprenorphine free base at about wt% to about 30 wt%; (ii) about 10 wt% to about 60 wt% of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt% to about 70 wt% of N-methy1-2-pyrrolidone.

24. Buprenorphine for use according to any one of claims 20 to 22, wherein the medicament comprises:(i) about 300 mg buprenorphine free base at about 14 wt% to about 22 wt%; (ii) about 22 wt% to about 42 wt% of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt% to about 60 wt% of N-methy1-2-pyrrolidone.

25. Buprenorphine for use according to any one of claims 20 to 22, wherein the medicament comprises: (i) about 300 mg buprenorphine free base at 18 wt%;
Date Recue/Date Received 2022-03-02 (ii) about 32 wt% of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt% of N-methy1-2-pyrrolidone.

26. Buprenorphine for use according to any one of claims 19 to 25, wherein the medicament is for use subcutaneously once per month for at least twelve months.

27. Buprenorphine for use according to any one of claims 19 to 26, wherein the use of the medicament produces opioid abstinence in the injection drug user.

28. Buprenorphine for use according to any one of claims 19 to 27, wherein the injection drug patient is: an intravenous injection drug patient;
an intramuscular injection drug patient, a subcutaneous injection drug patient, or a combination of two or more thereof.

29. Buprenorphine for use in the manufacture of a medicament for treating opioid use disorder in an injection drug patient in need thereof, wherein the medicament is for use subcutaneously once per month in the injection drug patient; and wherein the medicament comprises about 300 mg buprenorphine free base, a poly(lactide-co-glycolide) copolymer, and N-methy1-2-pyrrolidone.

30. Buprenorphine for use according to claim 29, wherein the medicament comprises: (a) (i) about 300 mg buprenorphine free base at about 10 wt% to about 30 wt%; (ii) about 10 wt% to about 60 wt% of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt% to about 70 wt% of N-methy1-2-pyrrolidone.

31. Buprenorphine for use according to claim 29, wherein the medicament comprises: (i) about 300 mg buprenorphine free base at about 14 wt%
to about 22 wt%; (ii) about 22 wt% to about 42 wt% of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having a weight average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt% to about 60 wt% of N-methy1-2-pyrrolidone;.

32. Buprenorphine for use according to claim 29, wherein the medicament comprises: (i) about 300 mg buprenorphine free base at about 18 wt%; (ii) Date Recue/Date Received 2022-03-02 about 32 wt% of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and a weight average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt% of N-methy1-2-pyrrolidone.

33. Buprenorphine for use according to any one of claims 29 to 32, wherein the opioid use disorder is: moderate-to-severe opioid use disorder, moderate opioid use disorder, or severe opioid use disorder.

34. Buprenorphine for use according to any one of claims 29 to 33, wherein the medicament is for use in reducing opioid craving, eliminating opioid craving, reducing opioid withdrawal symptoms, eliminating opioid withdrawal symptoms, reducing illicit opioid use, eliminating illicit opioid use, or a combination of two or more thereof.

35. Buprenorphine for use according to any one of claims 29 to 34, wherein the use of the medicament produces opioid abstinence in the injection drug user.

36. Buprenorphine for use according to any one of claims 29 to 35, wherein the injection drug patient is: an intravenous injection drug patient, an intramuscular injection drug patient, a subcutaneous injection drug patient, or a combination of two or more thereof.

Date Recue/Date Received 2022-03-02