rbp-6000 (extended-release buprenorphine) for the ... · rbp-6000 (extended-release buprenorphine)...
TRANSCRIPT
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CO-1
RBP-6000 (Extended-Release Buprenorphine) for the Treatment of Opioid Use Disorder
October 31, 2017Indivior, Inc.Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee
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CO-2
Introduction
Susan Learned, MD, PharmD, PhDSenior Vice President of Global Medicines DevelopmentIndivior, Inc.
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CO-3
0
5,000
10,000
15,000
20,000
25,000
More Than 53,000 Opioid Overdose Deaths Projected in 2017
CDC. Wonder Database.
Synthetic Opioids other than Methadone (N=20,145)
Heroin (N=15,446)
Natural and Semi-Synthetic Opioids (N=14,427)
Methadone (N=3,314)
Opioid Overdose
Deaths
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CO-4
ATRIGEL® Delivery System Biodegradable polymer and solvent create solid depot of
buprenorphine Two targeted release phases: rapid achievement of therapeutic
levels that are sustained over monthly dosing interval Used in 7 FDA-approved products
100 mg and 300 mg dosage strengths Prefilled syringe, administered subcutaneously
Recommended dosing regimen Two initial monthly 300 mg doses Monthly maintenance doses of 100 mg or 300 mg based on
clinical condition of patient
RBP-6000: Long-Acting Subcutaneous Injection Administered Monthly by HCP in Health Care Setting
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CO-5
RBP-6000 studied in and intended for patients attempting to recover from OUD May or may not have tried Medication Assisted Treatment (MAT) in the past
Utilized science on relationship between buprenorphine levels, mu-opioid receptor occupancy (µORO), and clinical effects to maximize benefits for patients with OUD
Overview of RBP-6000 Clinical Development Program
First-in-Human (FIH) Study(20 mg)
Single Ascending Dose (SAD) Study(50, 100, 200 mg)
Multiple Ascending Dose (MAD) Study(50, 100, 200, 300 mg)
Molecular Weight (MW) Study(300 mg)
Opioid Blockade (OB) Study(300 mg)
Phase 3 Double-Blind Placebo-Controlled Study(300/100, 300/300 mg)
Phase 3 Long-Term Open-Label Safety Study(300 mg Flex dosing)
TreatmentExtension Study(Flex dosing)
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CO-6
RBP-6000 designed to maximize benefits of buprenorphine Opioid blockade: ≥ 70-80% μORO achieved with ≥ 2-3 ng/mL
buprenorphine plasma concentration Two safe and effective dosing regimens
300/100 mg for many patients 300/300 mg for select patients who need higher concentrations
Significant benefits in abstinence, control of withdrawal symptoms, and reduction in opioid craving
Safety profile consistent with transmucosal buprenorphine products Exception of anticipated injection site reactions
Key Findings from Development Program
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CO-7
RBP-6000 Advances Treatment Options for OUD
Daily fluctuations in buprenorphine concentrations
• Delivers consistent buprenorphine concentrations that provide opioid blockade from first dose
Occasional need for supplemental dosing
• Controls withdrawal symptoms and craving• Efficacious in absence of supplemental buprenorphine
Subject to diversion, misuse,abuse, and accidental poisoning of children
• Restricted distribution system• Administered by health care professional
Limitations of Current MAT Options Advancements with RBP-6000Often requires daily medication adherence • Monthly dosing removes burden of daily adherence
Daily medications subject to “drug holidays” • Long-acting nature would not allow for “drug holidays”
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CO-8
Risk Evaluation and Mitigation Strategy (REMS) for Safe and Appropriate Use
Monitoring for Misuse, Abuse, & Diversion
Adverse Event
Monitoring
Intervention Strategies
Assessments of REMS
Effectiveness
Physician & Patient
EducationRestricted
Distribution System
Safe & Appropriate
Use
Goals of REMS:• Mitigate risks of diversion, misuse,
abuse, and accidental exposure• Inform prescribers, pharmacists,
and patients about RBP-6000:• Risks • Long-acting formulation
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CO-9
Goals: ensure product never distributed directly to patient; prevent diversion and IV injection
Under CSA, every step in distribution chain controlled and monitored by personnel registered with DEA
Specialty pharmacies and distributors must ensure RBP-6000 is dispensed only to HCPs with DATA-2000 waiver (~40,500 prescribers) Indivior and DEA will each audit specialty
pharmacies and distributors DEA will audit prescribing practices of HCPs
Restricted Distribution System to Ensure RBP-6000 Administered Only by Qualified HCPs
Restricted Distribution
System
CSA = Controlled Substances Act
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CO-10
RBP-6000 is indicated for the treatment of moderate-to-severe opioid use disorder (OUD) in patients who have undergone induction to suppress opioid withdrawal signs and symptoms with a transmucosal buprenorphine-containing product.
RBP-6000 should be used as part of a complete treatment program that includes counseling and psychosocial support.
Proposed Indication
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CO-11
Need for Improvements in the Treatment of Opioid Use Disorder
Brent Boyett, DO, DMDBoyett Health Services, Inc.
Clinical PharmacologyCeline Laffont, PhDDirector, Quantitative Clinical PharmacologyIndivior, Inc.
EfficacyBarbara Haight, PharmDMedicines Development Leader, RBP-6000Indivior, Inc.
SafetyAnne Andorn, MDHead, Late Stage Global Clinical DevelopmentIndivior, Inc.
Clinical PerspectiveEric C. Strain, MDDirector, Johns Hopkins Center for Substance Abuse Treatment and Research, Johns Hopkins University
Agenda
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CO-12
Additional Experts
StatisticsJason Connor, PhDLead Statistical ScientistConfluenceStat, LLC
Epidemiology / REMSHoward Chilcoat, ScD, MHSHead, EpidemiologyIndivior, Inc.
ToxicologyRosonald Bell, PhDHead, ToxicologyIndivior, Inc.
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CO-13
Need for Improvements in the Treatment of Opioid Use Disorder
Brent Boyett, DO, DMDBoyett Health Services, Inc.Hamilton, Alabama
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CO-14
~1.8 million with prescription pain reliever use disorder1
~630,000 with heroin use disorder1
Patients with OUD have 14x higher mortality than general population2
Opioid overdose deaths quadrupled from 2000-20163
> 50,000 people died from opioid-related deaths last year As many deaths as from AIDS at peak of epidemic4
Injecting drug users at serious risk for HIV and hepatitis C5,6
Rapidly Escalating Epidemic of Illicit Opioid Use in the United States
1. SAMHSA. National Survey on Drug Use and Health. 2017.2. Degenhardt et al. Addiction 2011;106:32-51.3. National Center for Health Statistics, CDC. 2017.
4. CDC. HIV/AIDS Surveillance Report 2001.5. CDC. HIV/AIDS Surveillance Report 2015.6. Bruneau et al. Addiction 2012;107:1318-27.
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CO-15
OUD characterized by repeated, compulsive use of opioids Despite social, psychological, and physical consequences
Pathologically pursue reward or relief by substance use1
Similar to other chronic, relapsing conditions2
Periods of exacerbation and periods of remission Long-term management challenging, adherence often incomplete Can take time to extinguish long-standing behaviors, achieve
abstinence
Opioid Use Disorder is Chronic Disease With High Risk of Fatal Consequences
1. American Society of Addiction Medicine. The ASAM National Practice Guideline.2. O’Brien. Drug Addiction, Goodman & Gilman’s the Pharmacological Basis of Therapeutics 2011.
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CO-16
Goals of MAT Achieve abstinence Prevent overdose, death
Treatment reduces risk of mortality by 2.4 times2
Return to normal living
Standard of Care: Medication-Assisted Treatment (MAT) Combines Counseling with Medications
Medication-Assisted Treatment1
Individual Drug Counseling
Recovery plan, positive life outcomes
1. American Society of Addiction Medicine, 2015.
+Medication
Relieve withdrawal symptoms, block euphoric effects
2. Degenhardt et al. Addiction 2011;106:32-51.
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CO-17
Naltrexone Methadone Buprenorphine
Available Medications Offer Different Approaches for Patients with Opioid Use Disorder
Category μ-opioid antagonist
Frequency of Administration Daily or monthly
Clinical UsesReduces risk of
relapse following abstinence
Clinical Challenges Does not control withdrawal symptoms
μ-opioid full agonist
Daily
Reduces opioid withdrawal and
cravingPatients often have to
receive daily dose at certified clinic
μ-opioid partial agonist
Daily or every 6 months
Reduces opioid withdrawal and
cravingTransmucosal can be
diverted, requires daily adherence
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CO-18
Patients share, sell, trade medication In 2013, 33% entering opioid treatment reported use of diverted
buprenorphine in last month1
“Bridge” between periods of illicit opioid use Accidental poisoning in children is public health concern2
> 8100 ER visits for children < 6 years old for ingesting buprenorphine from 2008-2016
Three-quarters involved children 1-2 years old
Take-Home Buprenorphine Subject to Diversion, Misuse, Abuse, and Accidental Poisoning of Children
1. Cicero et al. Drug Alcohol Depend 2014;142:98-104.2. MMWR 2016;65:1148-1149.
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CO-19
Adherence to daily medication regimen often a challenge Human error Lost or stolen Dose splitting, treatment holidays
10 times greater likelihood of relapse when daily buprenorphine adherence drops below 80%1
Nonadherence to Daily Buprenorphine Dosing Leaves Patients Vulnerable to Relapse
1. Tkacz et al. Am J Addict 2011;21:55-62.
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CO-20
New buprenorphine treatment options could makemeaningful difference Reduce risk of diversion, misuse, abuse, and accidental
pediatric poisoning Remove burden of daily medication adherence to improve
outcomes and enhance retention in treatment Assures compliance, removing ability to take “drug holidays”
Need for New Treatment Option to Address Seriousness and Complexities of OUD
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CO-21
Clinical Pharmacology
Celine Laffont, PhDDirector, Quantitative Clinical PharmacologyIndivior, Inc.
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CO-22
Effect of μ-Opioid Receptor Occupancy (μORO) on Withdrawal Suppression and Blockade of Opioid Subjective Effects
ReinforcingEffect
AnalgesicEffect
μ-Opioid Receptor Occupancy
Greenwald et al. Drug Alc Depend 2014;144:1-11. Nasser et al. Clin Pharmacokinetics 2014;53:813-24.*Bickel & Amass. Exp Clin Psychopharmacol 1995;3:477-89. Comer et al. Psychopharmacol 2005;181:664-75.
0% 100%
WithdrawalSuppression
50-60% µORO(BUP ≥ 1 ng/mL)
OpioidBlockade
≥ 70-80% µORO(BUP ≥ 2-3 ng/mL)
Individuals abusing high doses of opioids
may require higher concentrations for opioid blockade*
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CO-23
Two Studies Evaluated Relationship Between Buprenorphine Concentration and Pharmacodynamic Effects
Greenwald et al, 2003 32 mg, 16 mg, 2 mg sublingual (SL) buprenorphine and placebo PET scans at 4 hours post-dose
Greenwald et al, 2007 16 mg SL buprenorphine PET scans 4, 28, 52, and 76 hours after last dose
Both studies administered hydromorphone challenges to assess ability of buprenorphine to block effects of μ-opioid full agonist
Greenwald et al. Neuropsychopharm 2003;28:2000-9. Greenwald et al. Biol Psych 2007;61:101-10.
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CO-24
PET Scans Illustrate Effect of Increasing Buprenorphine Exposure on μORO
Placebo
MRI
BUP 16 mg
BUP 32 mg
BUP 2 mg
Greenwald et al. Neuropsychopharm 2003;28:2000-9.
0
Distribution Volume
Ratio (DVR)
4
PET Scan Results at Various Doses
(Greenwald et al, 2003)
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CO-25
Relationship Between Buprenorphine Concentration, Brain µORO, and Pharmacodynamics
Nasser et al. Clin Pharmacokinetics 2014;53:813-24.
At least 70% receptor occupancy needed to achieve both:
Suppression of subjective effects of a μ-opioid full agonist (hydromorphone)
Suppression of withdrawal symptoms
Pharmacodynamic Results
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10
Buprenorphine Plasma Concentration(ng/mL)
Median prediction90% prediction intervalsObservations
μ-Opioid Receptor Occupancy vs. PK
µORO(%)
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CO-26
Multiple Ascending Dose (MAD) study assessed 4 doses of RBP-6000 (50, 100, 200, and 300 mg)
Evaluated ability of doses to achieve average target of 2 ng/mL at: First dose Steady-state
RBP-6000 Doses Selected to Achieve Sustained Target Concentration and μORO Levels
300 mg dose
Reaches average target of 2 ng/mL buprenorphine after first dose
Achieves average concentration of 5-6 ng/mL at steady-state
Reaches average target of 2 ng/mL buprenorphine at steady-state
2 initial doses of 300 mg reach average target levels more quickly
100 mg dose
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CO-27
Opioid Blockade Study
Designed to assess ability of RBP-6000 to block subjective effects of μ-opioid full agonist
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CO-28
Opioid Blockade Study Designed to Assess Ability of RBP-6000 to Block Subjective Effects of μ-Opioid Full Agonist
RBP-6000 300 mg
Hydromorphone 18 mg
1st
Injection2nd
InjectionRandomization
SUBOXONE
Screening Run-in (SUBOXONE)
Hydromorphone 6 mg
Placebo
1 2 3 4 5 6 7 8 9 10 11 12
Challenges (IM injections):
N = 39 non-treatment-seeking, opioid-dependent subjects
Weeks
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CO-29
Mean Buprenorphine Plasma Concentrations from Opioid Blockade Study
0
2
4
6
8
10
12
14
-7 0 7 14 21 28 35 42 49 56 63 70 77 84
Mean Buprenorphine
Plasma Concentration
(ng/mL)[SD]
Time (Weeks)
SUBOXONERBP-6000 Dose
1 2 3 4 5 6 7 8 9 10 11 12Run-in
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CO-30
RBP-6000 300 mg Blocked Opioid Subjective Effects
41 2 3 5 6 7 8 9 10 11 12-10
0
10
20
30
40
50
60
70
80
90
100
Hydromorphone 6 mgHydromorphone 18 mg
Placebo
SUBOXONERBP-6000 Dose
LS MeanDrug LikingVAS Score[95% CI]
Time (Weeks)
Extremely
Not at allRun-inScreening
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CO-31
RBP-6000 designed based on totality of data to maximize the benefits of buprenorphine for patients with OUD
Clinical pharmacology program led to dosing regimens for Phase 3
Summary of Clinical Pharmacology
Doses 300/100 mg 300/300 mg
Two Initial Doses 300 mg provides opioid blockade from first dose
SubsequentMaintenanceDoses
100 mg would maintain average target concentrations (2-3 ng/mL)
300 mg would provide average levels of 5-6 ng/mL at steady-state
Exposures needed for certain patients, e.g., using high doses of opioids
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CO-32
Efficacy
Barbara Haight, PharmDMedicines Development Leader, RBP-6000Indivior, Inc.
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CO-33
300 mg RBP-6000 (Doses 1-6) + IDC
300 mg RBP-6000 (Doses 1-2)100 mg RBP-6000 (Doses 3-6) + IDC
300 mg Placebo (Doses 1-6) + IDC
300 mg Placebo (Doses 1-2)100 mg Placebo (Doses 3-6) + IDC
Design of Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Study
Scre
enin
g(2
wee
ks)
Ran
dom
izat
ion
3 Day Induction
(SUBOXONE)
4-11 Day Dose Stabilization(SUBOXONE)
300 mg RBP-6000 (Doses 1-6) + IDC
300 mg RBP-6000 (Doses 1-2)100 mg RBP-6000 (Doses 3-6) + IDC
300 mg Placebo (Doses 1-6) + IDC
300 mg Placebo (Doses 1-2)100 mg Placebo (Doses 3-6) + IDC
Treatment Period(24 weeks)
SC dose every 28 ± 2 days
Optional Open-Label Safety Study
Run-in Period
IDC = individual drug counseling
Supplemental buprenorphine notpermitted after randomization
4
4
1
1
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CO-34
Key Inclusion and Exclusion Criteria
Key Inclusion Criteria: Age 18-65 years Moderate or severe OUD Seeking MAT No MAT for OUD within
90 days
Key Exclusion Criteria: Other diagnosis requiring
prescription opioids Recent history of suicidality Significant medical problems
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CO-35
Primary endpoint: percentage abstinence from Week 5 through 24 Abstinence: urine samples negative for opioids with self-reports
negative for illicit opioid use (TLFB interview) Urine drug screen (UDS) and self-reports collected weekly
First 4 weeks of Treatment Period designated as “grace period” Missing UDS or self-report (due to missed visits or early
discontinuation) considered positive for opioids
Primary Efficacy Endpoint: Percentage Abstinence from Illicit Opioids
TLFB = Timeline Followback
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CO-36
Efficacy data analyzed using Full Analysis Set Intention-to-treat (ITT) analysis of all randomized subjects
In agreement with FDA, 1 site (15 subjects) removed from efficacy analyses (compliance issues), but included in safety analyses
Analysis Populations and Statistical Considerations
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CO-37
Disposition of All Screened SubjectsScreenedN=1187
Randomizedn=504
Failed Screening n=522Run-in Failure n=161
RBP-6000 300/300 mgn=201
RBP-6000 300/100 mgn=203
Placebon=100
Completed n=129 (64.2%)
Completedn=125 (61.6%)
Completedn=34 (34.0%)
Lost to follow-up 23 (11.4%)Withdrew consent 21 (10.4%)Other 8 (4.0%)Lack of efficacy 5 (2.5%)Adverse event 10 (5.0%)Protocol deviation 5 (2.5%)
Lost to follow-up 26 (12.8%)Withdrew consent 20 (9.9%)Other 21 (10.4%)Lack of efficacy 3 (1.5%)Adverse event 6 (3.0%)Protocol deviation 2 (1.0%)
Lost to follow-up 12 (12.0%)Withdrew consent 18 (18.0%)Other 16 (16.0%)Lack of efficacy 18 (18.0%)Adverse event 2 (2.0%)Protocol deviation 0 (0.0%)
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CO-38
Treatment Groups Balanced on Demographic Characteristics
RBP-6000300/300 mg
N=201
RBP-6000300/100 mg
N=203PlaceboN=100
Age, years (mean, range) 39 (19-64) 40 (20-64) 39 (20-63)
Male, % 67 66 65
Race, %
White 71 68 78
Black or African American 28 29 20
American Indian or Alaska Native <1 2 1
Multiple <1 1 1
Hispanic or Latino Ethnicity, % 9 6 10
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CO-39
History of Opioid Use at BaselineRBP-6000
300/300 mgN=201
RBP-6000300/100 mg
N=203PlaceboN=100
Severity of OUD, %Moderate 34 26 32Severe 66 74 68
Duration of Opioid Use, yearsMean (SD) 11 (9) 12 (10) 11 (9)
Users by Injectable Route, %Injecting Users 41 43 51Non-injecting Users 59 57 49
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CO-40
RBP-6000 PK in Phase 3 Double-Blind Study
Mean Buprenorphine
Plasma Concentration
(ng/mL)[SD]
Time (Weeks)
0
2
4
6
8
10
12
0 4 8 12 16 20 24
RBP-6000 300/300 mg
0
2
4
6
8
10
12
0 4 8 12 16 20 24
RBP-6000 300/100 mg
Observed Data – Double-blind Study
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CO-41
Primary and Key Secondary Endpoints Met: Significantly Higher Percentage Abstinence with RBP-6000
Full Analysis Set
0
20
40
60
80
100
RBP-6000300/300 mg
RBP-6000300/100 mg
Placebo
60% to <80%40% to <60%20% to <40%1% to <20%0%
80% to 100%
Percentage of Weeks AbstinentSubjects
(%)
P < 0.0001 for both RBP-6000 groups vs. Placebo
0%
80-100%80-100%
0% 0%
80-100%
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CO-42
Consistent Abstinence Rates Over Time
Full Analysis Set
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
SubjectsAbstinent
(%)[95% CI]
Time (Weeks)
RBP-6000 300/300 mg RBP-6000 300/100 mg Placebo
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CO-43
MMRM models determined time-averaged responder estimates
> 90% of placebo subjects tested positive for illicit opioids throughout study
RBP-6000 Provided Control of Opioid Craving and Withdrawal Symptoms
MMRM = Mixed Model for Repeated Measures Full Analysis Set
Secondary EndpointRBP-6000
300/300 mgRBP-6000
300/100 mg PlaceboControl of Opioid Craving (≤ 5 mm)
% Responders 81% 81% 48%95% CI 77-84 77-84 41-56
Control of Withdrawal (COWS ≤ 12)% Responders 99% 99% 97%95% CI 99-100 99-100 96-98
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CO-44
Role of 300 mg Maintenance Dose for Select Patients
Scientific Literature RBP-6000 Exposure-Response (> 11,000 PK samples) RBP-6000 Clinical Outcomes
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CO-45
Bickel and Amass, 19951
Developed buprenorphine treatment guidelines based on drug consumption
Patients using high doses of illicit opioids required higher buprenorphine doses to abstain
Comer et al, 20052
Heroin-dependent subjects required higher (32 mg buprenorphine or ~90% μORO) to reduce liking and self-administration
Greenwald et al, 20143
Review of published data concluded that users of high doses of illicit opioids require higher buprenorphine doses and >90% μORO
Scientific Literature Supports That Select Patients Require Higher Buprenorphine Doses
1. Bickel & Amass. Exp Clin Psychopharmacol 1995;3:477-89.2. Comer et al. Psychopharmacol 2005;181:664-75.3. Greenwald et al. Drug Alcohol Depend 2014;0:1-11.
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CO-46
Injecting Drug Users Required Higher Buprenorphine Plasma Concentrations to Maximize Abstinence
Probability of
Abstinence(%)
[95% CI]
0
20
40
60
80
100
Buprenorphine Plasma Concentration (ng/mL)
0
20
40
60
80
100 Injecting UsersNon-injecting Users
11,362 PK Samples from Phase 3 Double-blind Study
Average concentration of 100 mg maintenance dose
Average concentration of 300 mg maintenance dose
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CO-47
0
2
4
6
8
10
12
0 4 8 12 16 20 24
Consistency Between PK and PD for 300 mg Maintenance Dose Among Injecting Users
0
20
40
60
80
100
0 4 8 12 16 20 24
300/300 mg300/100 mg
Time (Weeks)
First Maintenance Dose
First Maintenance Dose
Full Analysis Set
Mean Buprenorphine
Plasma Concentration
(ng/mL)
SubjectsAbstinent
(%)
54%
32%
Pharmacodynamics ofInjecting Users
Pharmacokinetics of Injecting Users
Relative Risk of Abstinence at Week 24 1.7 (95% CI: 1.2 - 2.4)
Time (Weeks)
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CO-48
Phase 3 Long-Term Safety Study
Interim Analysis
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CO-49
De-novo subjects (N=412) Did not participate in Phase 3 double-blind study 48-week treatment phase 12 injections of RBP-6000
Roll-over subjects (N=257) Participated in Phase 3 double-blind study (RBP-6000 or placebo groups) 24-week treatment phase 6 injections of RBP-6000
All subjects received initial dose of 300 mg Flex dosing thereafter (100 or 300 mg) at investigator’s discretion
Interim Analysis of Maintenance of Efficacy in Phase 3 Long-Term Safety Study
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CO-50
RBP-6000 300 mg Dose Reaches Steady-State After Six Monthly Injections
0
2
4
6
8
10
12
14
0 4 8 12 16 20 24 28 32 36 40 44 48
Mean Buprenorphine
Plasma Concentration
(ng/mL)[SD]
Time (Weeks)Roll-over subjects who received 12 consecutive 300 mg doses.
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CO-51
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Roll-Over Subjects Show Maintenance of Efficacy Through 12 Monthly Doses
Subjects Abstinent
(%)
RBP-6000 300/300 mg 113 112 112 110 113 109 110 109 101 94 87 66 56RBP-6000 300/100 mg 112 112 111 111 111 110 107 109 108 104 92 81 65
Time (Weeks)
Subjects censored after last visit. Missed visits prior to last visit considered positive for opioids.
300/300 mg (roll-over)300/100 mg (roll-over)
All Subjects(Flex Dosing)
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CO-52
Both RBP-6000 dosage regimens superior to placebo in percentage abstinence on primary and secondary endpoints
RBP-6000 effectively controlled opioid craving and withdrawal symptoms Totality of results support monthly dosing recommendations
Two initial 300 mg doses for all patients 100 mg or 300 mg maintenance dose based on clinical condition
Consistency between literature, exposure-response modeling, and clinical outcomes support 300 mg maintenance dose for select patients
Abstinence rates maintained through 12 monthly doses
Summary of RBP-6000 Efficacy
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CO-53
Safety
Anne Andorn, MDHead, Late Stage Global Clinical DevelopmentIndivior, Inc.
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CO-54
RBP-6000 Exposure in Phase 3 Program
Treatment Group
Number of Subjects Exposed
Phase 3 Double-Blind Study
Phase 3Long-Term Safety Study
Total Exposures in Phase 3 848 (138 with 12 doses)
RBP-6000 300/300 mg 201 113 (roll-over)
RBP-6000 300/100 mg 203 112 (roll-over)
Placebo - 32 (roll-over)
De-novo - 412
Subjects in long-term safety study administered 300 mg as first dose Flex dosing (300 mg or 100 mg) thereafter
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CO-55
Overall Summary of Safety in Phase 3 Studies
Treatment-Emergent Adverse Event, %
Phase 3 Double-Blind Study
Phase 3 Long-Term Safety Study
RBP-6000300/300 mg
N=201
RBP-6000300/100 mg
N=203PlaceboN=100
RBP-6000De-novoN=412
RBP-6000Roll-over
N=257Any TEAE 66.7 76.4 56.0 70.6 54.9
TEAE leading to discontinuation 5.0 3.4 2.0 2.7 1.6
Serious TEAE 3.5 2.0 5.0 4.1 3.5
Severe TEAE 6.5 7.4 4.0 8.5 2.7
Death 0.5* 0 0 0 0
* Homicide
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CO-56
Injection Site TEAEs in Phase 3 Studies
Most common injection site TEAEs: pain, pruritus, erythema, and induration
No injection site SAEs 99% of TEAEs were mild or moderate < 1% of subjects discontinued for injection site TEAE
Treatment-Emergent Adverse Event, %
Phase 3 Double-Blind Study
Phase 3 Long-Term Safety Study
RBP-6000300/300 mg
N=201
RBP-6000300/100 mg
N=203PlaceboN=100
RBP-6000De-novoN=412
RBP-6000Roll-over
N=257Any injection site AE 18.9 13.8 9.0 14.8 8.2
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CO-57
Hepatic Enzyme Elevations Consistent with Known Safety Profile of Buprenorphine
Liver Enzyme Elevation, %
Phase 3 Double-Blind Study
Phase 3 Long-Term Safety Study
RBP-6000300/300 mg
N=201
RBP-6000300/100 mg
N=203PlaceboN=100
RBP-6000De-novoN=412
RBP-6000Roll-over
N=257ALT & AST at same visit
> 3× ULN to < 5× ULN 3.0 1.5 0 1.9 2.3
≥ 5× ULN to < 8× ULN 2.5 1.5 0 3.2 2.7
≥ 8× ULN 2.0 1.0 1.0 4.4 1.9
Total Bilirubin > 2× ULN 0.5 0.5 0 1.2 0ALT or AST > 3× ULN+ Bilirubin > 2× ULN (Hy’s Law) 0 0 0 0 0
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CO-58
Treatment Decisions Based on Liver Chemistry Elevations
Treatment Decisions forLiver Chemistry Elevation, %
Phase 3 Double-Blind Study
Phase 3 Long-Term Safety Study
RBP-6000300/300 mg
N=201
RBP-6000300/100 mg
N=203PlaceboN=100
RBP-6000De-novoN=412
RBP-6000Roll-over
N=257
Discontinuation 1.5 0 0 0.5 0
Dose Reduction - - - 2.4 1.2
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CO-59
RBP-6000 Hepatic Safety Profile Similar to SUBOXONE
Liver Enzyme Elevation, %
Phase 3 Double-Blind StudyRBP-6000
300/300 mgN=201
RBP-6000300/100 mg
N=203
ALT & AST at same visit
> 3× ULN to < 5× ULN 3.0 1.5
≥ 5× ULN to < 10× ULN 2.5 1.5
≥ 10× ULN 2.0 1.0
Total Bilirubin > 2× ULN 0.5 0.5
1. NIDA CTN-0027 Final Report (mean dose 22 mg; median 24 mg).
NIDA Study1
SUBOXONE2-32 mgN=625
3.4
2.1
1.0
0.3
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CO-60
OUD patient population at high risk for pre-existing liver disease (e.g., Hepatitis B, C, D; HIV; alcohol-induced)
Hepatic safety profile of RBP-6000 similar to SUBOXONE Current SUBOXONE label and proposed RBP-6000 label address
these issues by recommending: Liver chemistry at baseline Periodic monitoring Investigation of etiology if liver chemistry values rise Not for patients with severe hepatic impairment
RBP-6000 Hepatic Safety Conclusions
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CO-61
Ph3OL study allowed for flex dosing after initial 300 mg dose Ph3DB results not available during Ph3OL study
463 (70%) subjects remained on 300 mg 201 (30%) subjects had dose reduced to 100 mg at some time
140 – investigator thought subject was doing well or at subject request 12 – investigator discretion 49 – adverse events 16 for sedation – all resolved 13 for liver chemistry elevations – 12 resolved, 1 pregnant & withdrawn 5 for constipation – all resolved
Ph3OL Flex Dosing: Most Dose Reductions Due to Investigator or Subject Request
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CO-62
No depot removals in Phase 3 studies 1 subject in opioid blockade study
Depot removed after withdrawing consent 1 subject in single-dose molecular weight study
Depot removed due to SAE (abnormal LFT) Subject tested positive for new onset hepatitis C 18 days after
first abnormal LFT Abnormal LFT recovered and resolved
No complications following depot removal for either subject
Two Elective Depot Removals Across All Studies
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CO-63
Safety of RBP-6000 evaluated extensively 1048 total subjects 848 subjects in Phase 3, with up to 12 monthly doses
Safety profile similar to transmucosal buprenorphine with exception of anticipated injection site reactions Known risks for elevations in liver chemistry
Injection site reactions generally mild or moderate, self-limiting, and led to treatment discontinuation in < 1%
Safety profiles of 300/100 and 300/300 mg regimens generally similar Injection site reactions and liver chemistry elevations occurred at higher
frequency with 300/300 mg
Summary of RBP-6000 Safety
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CO-64
Clinical Perspective
Eric C. Strain, MDDirector, Johns Hopkins Center for Substance Abuse Treatment and ResearchExecutive Vice Chair for Psychiatry, Johns Hopkins Bayview Medical Center
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CO-65
Benefit-Risk Analysis of RBP-6000
Patient Benefits
Public Health Benefits
Patient Risks
Public Health Risks
• Convenience of monthly vs. daily dosing• Reduces adherence burden• Ensures compliance (no “drug holidays”)• Opioid blockade from first dose• Benefits without supplemental buprenorphine
• Restricted distribution and administration only by HCPs reduces risk of diversion
• Depot formulation reduces risks of misuse• Eliminates accidental pediatric exposures
• Safety profile similar to currently-approved transmucosal buprenorphine products
• Injection site reactions• Cannot immediately discontinue treatment• Depot may require surgical removal if
treatment needs to be discontinued
• If RBP-6000 could be diverted:• Abuse potential of buprenorphine• Risks associated with IV injection
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CO-66
Two current buprenorphine treatment options for OUD1. Transmucosal buprenorphine (e.g., SUBOXONE, other forms) Daily administration Wide dose range (2-32 mg buprenorphine used in clinical practice)
2. Subdermal implant (PROBUPHINE) 6-month administration For patients clinically stable on low-moderate dose (≤ 8 mg) of
transmucosal buprenorphine If approved, RBP-6000 would offer a monthly treatment option
Addresses a need in continuum of buprenorphine products
How RBP-6000 Fits in Current Treatment Paradigm for Buprenorphine
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CO-67
Considering when to use RBP-6000: Concern about diversion or misuse Concern about adherence or compliance At risk for “drug holidays” Children in the home Clinically stable patients who need long-term buprenorphine
treatment
RBP-6000 Offers New Treatment Option for Patients with OUD
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CO-68
Both dosing regimens safe and effective Choice of maintenance dose based on history and clinical condition 100 mg maintenance dose appropriate for many patients 300 mg maintenance dose for select patients
Need higher buprenorphine concentrations to maximize abstinence and retention in treatment
Balancing injection site reactions and LFT elevations against risks of continued illicit opioid use
RBP-6000 Dosing Regimens Provide Flexibility to Individualize Patient Care
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CO-69
RBP-6000 (Extended-Release Buprenorphine) for the Treatment of Opioid Use Disorder
October 31, 2017Indivior, Inc.Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee
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CO-70
BACK-UP SLIDES SHOWN ONSCREEN
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CO-71
0
20
40
60
80
100
0 2 4 6 8 10
Exposure-Response for AbstinenceModeling vs Observations for Injectable vs Non-injectable Route
% Subjects Abstinent [95% CI]
Buprenorphine concentration (ng/mL)
0
20
40
60
80
100
Non-Injectable Route
Injectable Route
Predicted % of
Subjects Abstinent
Buprenorphine concentration (ng/mL)
Non-Injectable Route
Injectable Route
Observations Model
ER-16
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CO-72
Higher Rate of Abstinence at End of Study with 300/300 mg Regimen among Injecting Users
34
18
0
20
40
60
80
100
Injecting Drug Users
Subjects Abstinent
Last 4 Weeks(%)
[95% CI] 28 28
0
20
40
60
80
100
Non-injecting Drug Users
RBP-6000 300/300 mgRBP-6000 300/100 mg
N=80 N=84 N=115 N=110
PE-15
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CO-73
Most Common Reasons for Screen Failuresn (%) Reason
212 (41) Use of barbiturates, benzodiazepines, methadone, or buprenorphine (within past 30 days prior to informed consent) or positive UDS result at screening
91 (17) Unable to comply fully with study requirements(Based on opinion of Investigator or medically responsible physician)
55 (11) Total bilirubin ≥ 1.5x ULN, ALT ≥ 3x ULN, AST ≥ 3x ULN, serum creatinine > 2x ULN, lipase > 3x ULN, or amylase > 3x ULN
58 (11) Willing to adhere to study procedures and provide informed consent prior to study start
30 (5) Missing
13 (2.5) Current substance use disorder, as defined by DSM-5 criteria, with regard to any substances other than opioids, cocaine, cannabis, tobacco, or alcohol
13 (2.5) Uncontrolled medical or psychiatric illness that, may place subject at risk or interfere with outcome measures or ability to participate in study
SD-26
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CO-74
RBP-6000 Should be Injected in Abdominal Region and Site Should be Rotated Within That Region
Figure 4, USPI
Transpyloric Plane
Transtubercular Plane
1 2
34
DO-4
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CO-75
0
20
40
60
80
100
0 4 8 12 16 20 24 28
Greater Retention of Subjects Over Time in RBP-6000 Groups
Retention(%)
Time (Weeks)
RBP-6000 300/300 mg RBP-6000 300/100 mg Placebo
DI-15
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CO-76
Substance, %
RBP-6000300/300 mg
N=194
RBP-6000300/100 mg
N=196Placebo
N=99Baseline Follow-up Baseline Follow-up Baseline Follow-up
Amphetamines 15 7 – 12 25 11 – 22 19 5 – 19
Barbiturates 1 0 – 2 2 0 – 2 0 0 – 3
Benzodiazepines 10 3 – 9 12 3 – 10 13 3 – 20
Cocaine 40 27 – 39 47 25 – 33 42 20 – 45
Cannabinoids 47 28 – 38 55 28 – 39 53 32 – 43
Phencyclidine 1 1 – 4 0 0 – 2 1 0 – 6
Use of Other Substances Did Not Increase During Phase 3 Double-Blind Study
Follow-up use is shown as the range of observed values over follow-up.Use defined as positive UDS, positive self-report on TLFB, or concomitant medication.
Use decreasedNo changeUse increased
SE-10
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CO-77
EMIT II Plus Opiate Assay & EMIT II Plus Methadone Assay* Competition between drug in specimen and labelled drug
DRL Oxycodone Assay* Specific antibodies to detect oxycodone and oxymorphone
CEDIA Buprenorphine Assay Competition between drug in specimen and confugated
drug
Immunoassays Used for UDS
*Positive for opiate, methadone, or oxycodone prompted confirmation by GC/MS
SD-14
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CO-78
Clinical Courses Differed Between RBP-6000 and Placebo Groups
Patient
Placebo (N=99)1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Week
RBP-6000 300/100 mg (N=194)1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
RBP-6000 300/300 mg (N=196)1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.01 5 9 13 17 21 24
Missing
Opioid PositiveOpioid Negative
1 5 9 13 17 21 24 1 5 9 13 17 21 24
SE-2
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CO-79
The data on use of buprenorphine in pregnancy, are limited and do not indicate an increased risk of major malformations specifically due to buprenorphine exposure.
RBP-6000 should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. This risks should be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.
Prescribers should discuss the importance of management of opioid addiction throughout pregnancy.
Label: Use of RBP-6000 in Pregnant Patients
PG-5
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CO-80
Total 21 pregnancies 6 live births (5 pregnancies) 11 cases outcome is unknown 1 spontaneous and 4 elective abortion 1 neonate treated for NAS No reports of neonatal defects
RBP-6000 Program: Pregnancy Summary
PG-2
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CO-81
Restricted Distribution System for RBP-6000
Specialty Pharmacy
HCP
Specialty Distributor Healthcare Setting
IndiviorManufacturer
SP sends directly to DATA-2000-waivered HCP
--OR--
Healthcare setting (e.g., OTP, hospital pharmacy) purchases product from SD
and distributes only to DATA-2000-waivered HCP in that setting
Specialty Pharmacy (SP) or Specialty Distributor (SD)
purchases product from manufacturer
RM-2
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CO-82
Higher Rate of Abstinence at End of Study with 300 mg Maintenance Dose among Injecting Users
SubjectsAbstinent
(%)
0
20
40
60
80
100
0 4 8 12 16 20 240
20
40
60
80
100
0 4 8 12 16 20 24
Full Analysis Set
300/300 mg300/100 mg
Time (Weeks) Time (Weeks)
Pharmacodynamics ofInjecting Users
Pharmacodynamics ofNon-injecting Users
First Maintenance Dose
First Maintenance Dose
54%
32%
Relative Risk of Abstinence at Week 24 1.7 (95% CI: 1.2 - 2.4)
Relative Risk of Abstinence at Week 24 1.1 (95% CI: 0.8 – 1.4)
38%40%
AA-8
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CO-83
34%28%
18%
28%
0%
20%
40%
60%
80%
100%
Injecting Drug Users Non-injecting Drug Users
RBP-6000 300/300 mgRBP-6000 300/100 mg
Higher Abstinence in Last 4 Weeks of Study with 300/300 mg Among Injecting Drug Users
Completers – Double-blind Study
Subjects Abstinent for Weeks 21-24
(%)[95% CI]
RR = 1.0 (95% CI: 0.6 - 1.5)RR = 1.9 (95% CI: 1.1 - 3.3)
AA-1