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Psychopharmacologic Drugs Advisory Committee Meeting March 27, 2018

CC-1 LUCEMYRA (lofexidine)

Kristen Gullo Vice President, Development & Regulatory Affairs US WorldMeds

CC-2 Agenda

Topic Speaker, Affiliation Louis Baxter, MD, DFASAM, DABAM Medical Landscape Executive Medical Director Professional Assistance Program of NJ, Inc. Kristen Gullo Lofexidine Development Vice President, Pharmaceutical Development & Regulatory Affairs US WorldMeds Marc Fishman, MD Lofexidine Trial Program Medical Director, Maryland Treatment Centers Assistant Professor, Johns Hopkins University School of Medicine Charles Gorodetzky, MD PhD Efficacy Consultant in Pharmaceutical Medicine US WorldMeds Mark Pirner, MD PhD Safety Senior Medical Director US WorldMeds Thomas Kosten, MD Clinical Perspective & Waggoner Chair and Professor of Psychiatry and Pharmacology Benefit-Risk Baylor College of Medicine CC-3 Medical Landscape

Louis E. Baxter, Sr., MD, DFASAM, DABAM Executive Medical Director Professional Assistance Program of NJ, Inc. Assistant Clinical Professor of Medicine Rutgers New Jersey Medical School Newark, NJ Co-Program Director Addiction Medicine Fellowship Howard University Past President American Society of Addiction Medicine Director, Addiction Medicine Foundation (ABAM) CC-4 Physical Dependence on Opioids

 Prolonged exposure

 Chemical changes in the brain

 Physical dependence develops

 Opioid discontinuation leads to withdrawal

 Opioid Withdrawal Syndrome

CC-5 Opioid Withdrawal Syndrome (OWS): Potential Symptoms

 Sleep problems  Fever

 Muscle aches  Nausea

 Heart racing  Vomiting

 Hypertension  Diarrhea

 Runny nose  Stomach cramps

 Agitation  Gooseflesh

 Yawning  Depression

 Tearing  Drug craving

 Sweating  Anxiety

CC-6 Time Course of Opioid Withdrawal Syndrome

Peak 2-4 days

Withdrawal Intensity

Diminishing Symptoms

Duration 1-2 Weeks

Last Opioid Dose CC-7 OWS Perpetuates Opioid Use

 Prescription Opioid Addiction Treatment Study (POATS study)1

 653 opioid dependent patients with and without chronic pain

 Assessed multiple factors influencing initial and current opioid use

 Avoiding withdrawal was the single highest rated reason for current opioid use

1. Weiss R.D. et. al. J Subst Abuse Treat. 2014 August; 47(2):140–145. CC-8 Withdrawal Management Overcomes Barrier of Opioid Withdrawal Syndrome

Withdrawal Management Opioid Post-Withdrawal Dependence Opioid Treatment Withdrawal

CC-9 Opioid Withdrawal Treatments

Pharmacological Special Licensing Product Class Indications Required Other Limitations

• Detoxification and • Black box warning FDA Full opioid Yes; Methadone maintenance of for addiction Approved agonist limited access opioid addiction • Diversion and abuse

Partial opioid • Treatment of Yes; • Dependence Buprenorphine agonist opioid dependence limited access • Diversion and abuse

• Off-label Off-label • Essential • Limited controlled data hypertension ɑ2 adrenergic • Inconsistent dosing Clonidine No agonist • Attention deficit hyperactivity • Side effects disorder • No generally accepted guidelines for use Opioid Taper

CC-10 Unmet Medical Need

 Non-opioid, FDA-approved treatment for management of opioid withdrawal

 Evidence-based treatment guidelines for management of withdrawal

 Proven and accessible treatments available to wider range of health care professionals and their patients

CC-11 Patient Selection Considerations

Motivation to discontinue opioids

Availability of caregiver support system appropriate to planned treatment setting

Appropriate expectations

Demonstrates understanding physician instructions for treatment

Planned post-withdrawal treatment, when appropriate

CC-12 Importance of Withdrawal Management

 When OWS presents a barrier to discontinuing opioids, withdrawal management is required

 Successful OWS management retains patients through opioid withdrawal, and into post-withdrawal care

 Patients face significant risks when opioid withdrawal fails

CC-13 Introduction to LUCEMYRA (lofexidine) Development

Kristen Gullo Vice President, Development & Regulatory Affairs US WorldMeds

CC-14 Lofexidine (LUCEMYRA)

 First non-opioid medication developed for use in opioid withdrawal management Selective α2 receptor agonist No other clinically relevant receptor activity, including those commonly associated with abuse potential

 Proposed indications Mitigation of symptoms associated with opioid withdrawal Facilitation of completion of opioid discontinuation treatment

 Recommended dosage 3.2 mg/day (4 x 0.2 mg, administered QID) for 7 days Additional 7 days with dosing guided by symptoms

CC-15 Lofexidine History

 Long history of use of α2 agonists for OWS

 Early lofexidine studies in OWS showed favorable results

 25 years of use experience in UK Supports favorable benefit:risk of lofexidine in OWS NICE guidelines provide specific recommendation for lofexidine in OWS

 USWM led US development in collaboration with National Institute on Drug Abuse (NIDA) US WorldMeds sponsored IND since 2003 Key NIDA support milestones in 2006, 2010 and 2012 Full NCE development package: CMC, nonclinical and clinical programs

CMC=Chemistry, Manufacturing and Controls; NCE=New Chemical Entity; NICE=National Institute for Health and Care Excellence CC-16 Clinical Development Overview

 24 total clinical studies

 16 clinical pharmacology studies

 Phase 3 program Study 1 (supporting efficacy) Study 2 (pivotal) Study 3-1 (pivotal) Study 3-2 (open-label safety)

 Safety database 1276 patients received lofexidine 1104 opioid-dependent patients

CC-17 Neurobiology of Withdrawal

 Opioid withdrawal characterized by symptomatology driven by increased levels of norepinephrine

 Driven by complex changes in brain associated with opioid dependence, wherein brain has achieved equilibrium in presence of opioids

 When opioids no longer present in dependent patient, predictable and rapid disruption of brain equilibrium occurs

 Causes extreme physical and emotional distress, encouraging return to opioid use

CC-18 Lofexidine Mechanism of Action

 Activates α2 receptors involved in regulation of norepinephrine Synaptic vesicle

 Closes a negative feedback loop involved in norepinephrine regulation

 Depresses activating signals, reducing Negative norepinephrine production feedback

 Net effect in withdrawing patient is to attenuate surging norepinephrine α2 receptor production to return toward normal Norepinephrine physiological level

Alpha-2 Adrenergic Receptor Agonists: A Review of Current Clinical Applications. Joseph A. Giovannitti, Jr, DMD,* Sean M. Thoms, DMD, MS,† and James J. Crawford, DMD†. Anesth Prog. 2015 Spring; 62(1): 31. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389556/) CC-19 Lofexidine Trial Program

Marc Fishman, MD Medical Director, Maryland Treatment Centers Assistant Professor, Johns Hopkins University School of Medicine

CC-20 Lofexidine Phase 3 Clinical Development

Double-Blind Study 2 Study 3-1 LFX HCI 2.4 mg/d; Dose LFX HCI 3.2 mg/d; Placebo LFX HCI 3.2 mg/d; Placebo Rx duration Days 1-5 active; Days 6-7 Placebo Days 1-7 active Open label/office-based N/A Optional LFX OLE Days 8-14 Randomized patients 134 ; 130 230 ; 222 ; 151

Open-Label Study 3-2 Dose LFX HCI 3.2 mg/d; option to reduce to 2.4 mg/d Rx duration Days 1-7 with optional 7 Days Office-based Optional beginning Day 4 Enrolled patients 286

CC-21 Site Characteristics

 Bed-based care settings because of demands of research protocol

 Heterogeneity of sites Academic research units Community treatment programs Private clinical research centers

CC-22 Key Enrollment Criteria

Study 2 Study 3-1 Study 3-2 Use of any opioid with half-life similar to heroin or morphine for at least 21 days of past 30 days Actively withdrawing as defined by Objective Opiate Withdrawal Scale (OOWS) Score ≥2 just prior to randomization Seeking treatment for partial or total withdrawal from opioids (without criteria above) No psychological or medical conditions preventing safe study participationa

Negative urine toxicology for methadone or buprenorphine

Permitted current dependence on any opioid including buprenorphine or methadone

a. Study 2 and 3-1 excluded patients currently or recent history of requiring: psychotropic (including sedatives/hypnotics, antidepressants, neuroleptics), prescription analgesic, anticonvulsant, antihypertensive, antiarrhythmic, antiretroviral, or cholesterol lowering medications CC-23 Demographics

Study 2 Study 3-1 LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo N=134 N=130 N=229 N=222 N=151 Age (years) 36 38 35 35 36 Mean (range) (18 - 62) (18 - 60) (19 - 74) (19 - 68) (19 - 63) Sex, % Male 75 76 71 71 71 Female 25 24 29 29 29 Race, % White 47 59 74 71 78 Black or African American 28 21 23 21 17 Other 00375 Ethnicity (Hispanic/Latino)a,% 25 21 15 13 15

a. In Study 2, ethnicity was included as a racial category CC-24 Opioid Use Patterns

Study 2 Study 3-1 LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo N=134 N=130 N=229 N=222 N=151 Primary opioid, % Heroin 61 64 86 82 81 Other 39 36 14 18 19 Opioid IV drug use, % 49 54 59 57 66 Positive urine drug screen for 60 59 56 64 50 other substances, % Stimulants 33 40 38 43 31 Benzodiazepines 18 18 11 15 13 Cannabinoids 28 22 28 36 27

CC-25 Protocol Allowed Supportive Medications

Medication Purpose Study 2 Study 3-1 Study 3-2 Guaifenesin Cough

Antacids Indigestion and nausea Dioctyl sodium sulfosuccinate Constipation Psyllium hydrocolloid suspension Bismuth sulfate Diarrhea

Acetaminophen Aches and pains

Zolpidem Insomnia Insomnia, depression, Benzodiazepines and anxiety Rescue ONLY, Required Full or Partial Opioid Agonist Assisted withdrawal Study D/C

CC-26 Efficacy and Safety Assessments

All Studies Study 3-1 & 3-2 Only

• SOWS-Gossop (Primary Measure) • OOWS-Handelsman Efficacy Assessments COWS • VAS-E • MCGI -Rater and -Subject

• AEs • Vital signs Safety Assessments C-SSRS •ECG • Clinical labs

COWS=Clinical Opiate Withdrawal Scale C-SSRS=Columbia Suicidality Severity Rating Scale MCGI=Modified Clinical Global Impression Scale OOWS-Handelsman=Objective Opiate Withdrawal Scale of Handelsman SOWS-Gossop=Short Opiate Withdrawal Scale of Gossop VAS-E=Visual Analog Scale-Efficacy CC-27 Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop)

0123

CC-28 SOWS-Gossop Study 2, Day 2 Patient Example

Total Score = 15 CC-29 Pivotal Study Key Efficacy Endpoints

Study 2 Study 3-1 Primary Endpoint: Co-Primary Endpoint: Mitigation of Difference between least squares Difference between mean Study Symptoms means from the Study Days 1-7 Day 3 SOWS-Gossop scores SOWS-Gossop overall scores

Co-Primary Endpoint: Facilitation of Key Secondary Endpoint: Time-to drop out for 5-day Completion Proportion of Day 7 completers treatment phase

CC-30 Efficacy Results

Charles W. Gorodetzky, MD, PhD Principal Investigator, Lofexidine Clinical Trials Consultant, Pharmaceutical Medicine

CC-31 Study 2: SOWS-Gossop: Co-Primary Endpoint (Day 3)

LFX HCl 3.2 mg Placebo 14 N=133 N=126

12

10

8

6

4

Mean SOWS-Gossop Score SOWS-Gossop Mean 2

0 01234567 Study Day p-value (difference vs placebo) LFX HCl 3.2 mg 0.0737 <0.0001 0.0028 0.1104 0.0708 NS NS CC-32 Study 2: Time to Study Discontinuation – Co-Primary Endpoint

1.0

0.9

0.8

0.7

0.6 Difference between treatments of 2 days the median time to dropout 0.5

0.4 LFX HCl 3.2 mg

0.3 Placebo Retention Probability 0.2 Log-rank test for active treatment period on Day 5: p=0.0034 0.1

0.0 1 2345678 Study Day

CC-33 Study 2: Completion Rates – ITT Population

LFX HCl 3.2 mg Placebo N=134 N=130 p-value Completed 5-day Treatment and Discharged 49.3 33.1 0.009 on Day 6 or Later, %

CC-34 Study 3-1: SOWS-Gossop – Primary Endpoint

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo 12 Least Squares Mean Difference vs Placebo p-value 10 LFX HCl 2.4 mg 0.0166 8 LFX HCl 3.2 mg 0.0033

6

4

2 Mean SOWS-Gossop Score SOWS-Gossop Mean 0 01234567 p-value (different vs placebo) Study Day LFX HCl 2.4 mg 0.0168 0.0005 0.0092 0.0061 0.0193 NS NS LFX HCl 3.2 mg 0.0005 0.0002 0.0008 0.0008 0.0175 NS NS CC-35 Study 3-1: Retention Analysis

1.0

0.9

0.8

0.7

0.6 Difference between treatments of 1.75 days 0.5 in the median time to dropout LFX HCl 2.4 mg 0.4 LFX HCl 3.2 mg 0.3

Retention Probability Placebo 0.2 Cox regression comparison versus placebo of 2.4 mg/day: p=0.0016; of 3.2 mg/day: p=0.0087 0.1

0.0 12345678 Study Day

CC-36 Study 3-1: Completion Rates – MITT Population

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo N=229 N=222 N=151

Day 7 Completion Rate, % 41.5 39.6 27.8

Pairwise Comparison vs Placebo (OR, 95% CI) 1.85 (1.18, 2.88) 1.71 (1.09, 2.67)

P-value 0.0067 0.0191

CC-37 Study 3-1: Patterns in Mean SOWS-Gossop and COWS Scores

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo SOWS-Gossop Scores COWS Scores 12 12

10 10

8 8

6 6

4 4 Mean Score COWS

Mean SOWS-Gossop Score 2 2

0 0 01234567 01234567 Study Day Study Day

CC-38 Efficacy Trends Across Multiple Measures

Standardized Treatment Time Effect (95% CI) Endpoint Study Period LFX HCl 2.4 mg LFX HCl 3.2 mg Study 2 Day 3 -0.43 (-0.67, -0.18) SOWS-Gossop Study 3-1 Overall -0.51 (-0.79, -0.23) Study 3-1 Overall -0.37 (-0.65, -0.09)

COWS Study 3-1 Overall -0.79 (-1.05, -0.53) Study 3-1 Overall -0.62 (-0.89, -0.36)

Study 2 Day 3 -0.49 (-0.80, -0.19) OOWS-Handelsman Study 3-1 Overall -0.48 (-0.71, -0.25) Study 3-1 Overall -0.33 (-0.56, -0.10)

MCGI Study 2 Day 3 -0.47 (-0.78, -0.17) Study 3-1 Overall -0.46 (-0.73, -0.19) (Patient – Severity of Opiate Withdrawal) Study 3-1 Overall -0.38 (-0.65, -0.11)

MCGI Study 2 Day 3 -0.47 (-0.77, -0.16) Study 3-1 Overall -0.50 (-0.78, -0.22) (Rater – Severity of Illness) Study 3-1 Overall -0.44 (-0.72, -0.16)

Study 2 Day 3 -0.45 (-0.76, -0.15) VAS-E Study 3-1 Overall -0.95 (-1.25, -0.65) Study 3-1 Overall -0.78 (-1.08, -0.47) -1.5 -1 -0.5 0 MCGI=Modified Clinical Global Impressions; OOWS=Objective Opiate Withdrawal Scale of Handelsman; VAS=Visual Analog Scale. The VAS-E scale is reversed to be consistent with other endpoints, where lower scores indicate a more positive clinical outcome Favors Lofexidine Favors Placebo CC-39 Lofexidine Efficacy Summary

 Achieved primary efficacy endpoints

 Effective on multiple efficacy measures

 Both doses effective

 Alleviated withdrawal symptoms

 Higher completion rate

CC-40 Lofexidine Safety

Mark Pirner, MD, PhD Senior Medical Director US WorldMeds

CC-41 Safety Presentation Outline

 Exposure

CC-42 Safety Presentation Outline

 Exposure

 Overall treatment emergent adverse events (AEs)

CC-43 Safety Presentation Outline

 Exposure

 Overall treatment emergent adverse events (AEs)

 Drug class AEs and vital sign analyses

CC-44 Safety Presentation Outline

 Exposure

 Overall treatment emergent adverse events (AEs)

 Drug class AEs and vital sign analyses

 Serious adverse events and AEs leading to discontinuation

CC-45 Safety Presentation Outline

 Exposure

 Overall treatment emergent adverse events (AEs)

 Drug class AEs and vital sign analyses

 Serious adverse events and AEs leading to discontinuation

 Topics of special interest (QTc, renal/hepatic dose adjustment)

CC-46 Safety Presentation Outline

 Exposure

 Overall treatment emergent adverse events (AEs)

 Drug class AEs and vital sign analyses

 Serious adverse events and AEs leading to discontinuation

 Topics of special interest (QTc, renal/hepatic dose adjustment)

 UK Safety Experience

CC-47 All Phase 3 Studies: Total Exposure

LFX HCl LFX HCl Day 2.4 mg 3.2 mg Placebo 1 229 676 312

2 196 566 217

3 148 456 152

5 106 372 99

7 96 258 84

10 30 58 NA

14724NA

CC-48 Phase 3 Pivotal Studies: Daily Exposure

Proportion Received At Least One Dose (%) Study 2 Study 3-1 LFX HCI 3.2 mg Placebo LFX HCI 2.4 mg LFX HCI 3.2 mg Placebo Day N=134 N=129 N=229 N=222 N=151 1 100 100 100 100 100

28578868067

37257655947

46043535139

55435464732

64932434330

74229424128

Placebo only CC-49 Phase 3 Pivotal and Open-Label Studies: Treatment Emergent Adverse Events (TEAEs)

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 TEAEs % % % % % %

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal 85.1 87.7 79.0 79.7 84.8 81.5 Related* TEAE Any Non-Opioid 59.7 43.1 76.9 79.3 40.4 72.7 Withdrawal-Related* TEAE

Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 (n=1) 0 0

TEAE Leading to 3.7 4.6 18.8 24.8 29.1 12.9 Discontinuation

*Opioid Withdrawal-Related (OWR) and Non-Opioid Withdrawal-Related (NOWR) determines by Principal Investigator

CC-50 Phase 3 Pivotal and Open-Label Studies: Opioid Withdrawal-Related (OWR) TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 TEAEs % % % % % % Any Opioid Withdrawal- 85.1 87.7 79.0 79.7 84.8 81.5 Related TEAE Insomnia 34.3 36.9 46.3 53.2 45.7 47.9 Headache 26.1 30.8 8.3 7.2 13.2 11.9 Anxiety 23.1 23.1 3.1 3.6 6.6 34.6 Rhinorrhea 6.7 16.9 3.5 2.7 6.0 * Diarrhea 24.6 34.6 21.4 21.2 22.5 17.1 Pain 12.7 19.2 21.8 18.5 22.5 8.4 Nausea 23.1 32.3 20.1 12.2 21.2 16.1 Myalgia 9.7 16.2 12.7 9.9 16.6 13.6 Vomiting 5.2 20.0 9.2 8.6 15.9 8.7

*<5% CC-51 Phase 3 Pivotal and Open-Label Studies: Non-Opioid Withdrawal (NOWR) TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=129 N=229 N=222 N=151 N=286 TEAEs % % % % % % Any Non-Opioid 59.7 43.1 76.9 79.3 40.4 72.7 Withdrawal-Related TEAE

Hypotension 17.2 0.8 30.1 30.2 1.3 28.7

Orthostatic Hypotension * * 29.3 42.3 4.6 31.5

Bradycardia 8.2 1.5 23.6 31.5 5.3 25.2

Dizziness 19.4 5.4 17.9 21.6 2.6 15.7

Sedation 7.5 1.5 12.2 12.2 5.3 15.7

*<5% CC-52 Phase 3 Pivotal and Open-Label Studies: Syncope or Fall TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=129 N=229 N=222 N=151 N=286 TEAEs n (%) n (%) n (%) n (%) n (%) n (%)

Total patients 2 (1.5) 0 2 (0.9) 4 (1.8) 0 1 (0.3)

Syncope 1 (0.7) 0 2 (0.9) 3 (1.4) 0 1 (0.3)

Fall 1 (0.7) 0 0 2 (0.9) 0 1 (0.3)

CC-53 Phase 3 Pivotal Studies: Mean Change in Standing Blood Pressure and Pulse

Study 2 Mean Change Standing BP Study 3-1 Mean Change Standing BP LFX SBP P SBP LFX DBP P DBP LFX 2.4 SBP LFX 3.2 SBP P SBP 10 10 LFX 2.4 DBP LFX 3.2 DBP P DBP 5 0 0 -5 01234567 01234567 -10 -10 -15 mmHG mmHG -20 -20 -25 -30 -30 Study Day Study Day

Study 2 Mean Change Standing Pulse Study 3-1 Mean Change Standing Pulse LFX Pulse P Pulse LFX 2.4 Pulse LFX 3.2 Pulse P Pulse 20 20 15 15 10 10

BPM 5 BPM 5 0 0 01234567 01234567 -5 -5 Study Day Study Day CC-54 Pivotal Study 3-1: Lowest Change Observed Orthostatic Standing Systolic Blood Pressure

Sitting Zero Decrease with standing Orthostatic Systolic Blood Pressure Change (mmHg)

Sitting Systolic Blood Pressure (mmHg)

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo CC-55 Pivotal Study 3-1: Lowest Observed Orthostatic Standing Systolic Blood Pressure Orthostatic Systolic Blood Pressure Change (mmHg)

Sitting Systolic Blood Pressure (mmHg)

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo CC-56 Phase 3 Pivotal and Open-Label Studies: Serious TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 TEAEs % % % % % %

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal 85.1 87.7 79.0 79.7 84.8 81.5 Related TEAE Any Non-Opioid 59.7 43.1 76.9 79.3 40.4 72.7 Withdrawal-Related TEAE

Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 (n=1) 0 0

TEAE Leading to 3.7 4.6 18.8 24.8 29.1 12.9 Discontinuation

CC-57 Phase 3 Pivotal and Open-Label Studies: Serious TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 n (%) n (%) n (%) n (%) n (%) n (%) Any Serious Any Serious Any Serious TEAE 2 (0.7) 8 (6.0) 8 (6.2) 0 5 (2.3) 2 (1.3) TEAE TEAE Delusion 1 (0.4) Severe opioid Acute Cerebral vascular withdrawal 4 (3.0) 5 (3.8) 1 (0.7) 1 (0.4) hepatitis C accident symptoms QTc 1 (0.7) Hypertension 1 (0.8) prolonged Diarrhea 1 (0.8) Toxicity to 2○ heart block 1 (0.8) various 1 (0.5) agents Hypotension 1 (0.75) Bradycardia 1 (0.75) Overdose 1 (0.5) Chest pain 1 (0.75) Syncope 2 (0.9) Orthostatic Suicidal 1 (0.75) 1 (0.5) hypotension ideation

CC-58 Phase 3 Pivotal and Open-Label Studies: Serious TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 n (%) n (%) n (%) n (%) n (%) n (%) Any Serious Any Serious Any Serious TEAE 2 (0.7) 8 (6.0) 8 (6.2) 0 5 (2.3) 2 (1.3) TEAE TEAE Delusion 1 (0.35) Severe opioid Acute Cerebral vascular withdrawal 4 (3.0) 5 (3.8) 1 (0.7) 1 (0.35) hepatitis C accident symptoms QTc 1 (0.7) Hypertension 1 (0.8) prolonged Diarrhea 1 (0.8) Toxicity to 2○ heart block 1 (0.8) various 1 (0.5) agents Hypotension 1 (0.75) Bradycardia 1 (0.75) Overdose 1 (0.5) Chest pain 1 (0.75) Syncope 2 (0.9) Orthostatic Suicidal 1 (0.75) 1 (0.5) hypotension ideation

Higher Placebo Higher Lofexidine CC-59 Phase 3 Pivotal and Open-Label Studies: Serious TEAEs

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 n (%) n (%) n (%) n (%) n (%) n (%) Any Serious Any Serious Any Serious TEAE 2 (0.7) 8 (6.0) 8 (6.2) 0 5 (2.3) 2 (1.3) TEAE TEAE Delusion 1 (0.35) Severe opioid Acute Cerebral vascular withdrawal 4 (3.0) 5 (3.8) 1 (0.7) 1 (0.35) hepatitis C accident symptoms QTc 1 (0.7) Hypertension 1 (0.8) prolonged Diarrhea 1 (0.8) Toxicity to 2○ heart block 1 (0.8) various 1 (0.5) agents Hypotension 1 (0.75) Bradycardia 1 (0.75) Overdose 1 (0.5) Chest pain 1 (0.75) Syncope 2 (0.9) Orthostatic Suicidal 1 (0.75) 1 (0.5) hypotension ideation

CC-60 Phase 3 Pivotal and Open-Label Studies: One TEAE Death

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 TEAEs % % % % % %

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal 85.1 87.7 79.0 79.7 84.8 81.5 Related TEAE Any Non-Opioid 59.7 43.1 76.9 79.3 40.4 72.7 Withdrawal-Related TEAE

Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 0 0

TEAE Leading to 3.7 4.6 18.8 24.8 29.1 12.9 Discontinuation

CC-61 Phase 3 Pivotal and Open-Label Studies: TEAEs Leading to Study Discontinuation

Study 2 Study 3-1 Study 3-2 LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 TEAEs % % % % % %

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal 85.1 87.7 79.0 79.7 84.8 81.5 Related TEAE Any Non-Opioid 59.7 43.1 76.9 79.3 40.4 72.7 Withdrawal-Related TEAE

Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 0 0

TEAE Leading to 3.7 4.6 18.8 24.8 29.1 12.9 Discontinuation

CC-62 Phase 3 Pivotal and Open-Label Studies: AEs and Study Discontinuation

Study 2 Study 3-1 Study 3-2

LFX HCI LFX HCI LFX HCI LFX HCI 3.2 mg Placebo 2.4 mg 3.2 mg Placebo 3.2/2.4 mg N=134 N=130 N=229 N=222 N=151 N=286 % % % % % % Any TEAE Any TEAE Any TEAE 3.7 4.6 18.8 24.8 29.1 12.6 discontinuation discontinuation discontinuation ECG QTc interval Events >3% Anxiety 3.1 0.7 1.5 prolonged Vomiting 1.7 0.9 7.3 Vomiting 2.1 Yawning 0.8 Diarrhea 2.2 2.3 6.6 Dizziness 1.7 Hypertension 0.8 Nausea 2.2 0.5 6.6 Hypotension 1.7 Second degree 0.8 Orthostatic heart block Pain 1.3 2.3 6.6 1.0 hypotension Severe opioid Anxiety 1.7 1.4 3.3 withdrawal 1.6 0.8 Restlessness 1.0 Insomnia 2.2 3.2 4.0 symptoms Syncope 0.3 Heart rate Bradycardia 04.50 0.7 increased Dizziness 3.5 2.7 0.7 Hypotension 0.7 Hypotension 1.3 3.2 0

Higher Placebo Higher Lofexidine CC-63 Pivotal Study 3-1: Discontinuations Resulting from AEs and Lack of Efficacy

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo

Adverse Event Lack of Efficacy Lack of Efficacy 40 40 40 and Adverse Event

35 35 35

30 30 30

25 25 25

20 20 20

15 15 15

10 10 10

Cumulative Cumulative (%) Rate Dropout 5 5 5

0 0 0 1234567 1234567 1234567 Study Day CC-64 Topics of Special Interest: QTc, Renal/Hepatic Dose Adjustment

CC-65 Pivotal Study 3-1: QTcF Interval Change: Lofexidine Plasma Concentration

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo

10

5

0

-5

-10 Baseline (95% Baseline (95% CI)

QTcF Mean Change from QTcF -15 1:00 PM 4:00 PM 5:00 PM 8:00 AM 8:00 AM 8:00 AM 1:00 PM 4:00 PM 5:00 PM

Lofexidine Plasma Day 1 Day 2 Day 4 Day 7 Concentration (ng/mL) LFX HCI 2.4 mg 1.02 1.73 1.72 2.18 3.04 3.00 3.5 3.72 3.51 LFX HCI 3.2 mg 1.33 2.23 2.31 2.87 4.00 4.03 4.23 5.32 5.02

CC-66 Pivotal Study 3-1: Maximum QTc by Patient QTc Change (ms) –QTc Fridericia Correction

Baseline QTc (ms) – Fridericia Correction

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo CC-67 Dose Adjustment Renal or Hepatic Insufficiency

 Renal impairment ‒ Reduce dose by 25% - 62.5% depending on degree of renal impairment

 Hepatic impairment ‒ Reduce dose by 25% - 62.5% depending on degree of hepatic impairment

CC-68 UK Safety

CC-69 UK Spontaneous AE Reports

Serious Non Serious Total Total events 45 98 143 MedDRA Preferred Terms (reported ≥5 times) Bradycardia 6 6 12 Hypotension 5 6 11 Blood pressure decreased 4 5 9 Heart rate decreased 4 5 9 Headache 0 7 7 Hypertension 0 5 5

MedDRA: Medical Dictionary for Regulatory Activities CC-70 UK Safety Assessment of Marketed Medicines (SAMM) Survey 19991

 1074 opiate detoxifications

 62.5% community setting

 Mean dose lofexidine 2.2 mg/day; mean duration 10 days

 Most frequent AEs Dizziness (9%) Sedation (7%) Dry mouth (5%)

 60% successful detoxification No difference community vs. inpatient

1. Akhurst, JS. The Use of Lofexidine by Drug Dependency Units in the United Kingdom. Eur Add. 1999;Res 5:43–9 CC-71 Summary Lofexidine Safety

 Exposure adequate

 Confirm placebo lack of efficacy

 Expected and manageable drug class effects at both doses

 Well-tolerated

 Precautions: Hypotension and bradycardia in at risk patients Rebound hypertension QTc prolongation in high risk patients Renal or hepatic insufficiency CNS sedation

CC-72 Sponsor Education Materials

 Patient selection Appropriate withdrawal management setting Concomitant psychiatric and medical conditions Concomitant medications Appropriate and available support

 Patient counseling Dosing instructions and precautions (e.g. hydration, reduced activity) Appropriate expectations What to look for and when to call

 Clinical management Dose hold/reduction Precautions and warnings CC-73 Clinical Perspective

Thomas R. Kosten, MD Waggoner Chair and Professor of Psychiatry and Pharmacology, Baylor College of Medicine Director, Division of Addictions Past President, American Academy of Addiction Psychiatry Past President, College on Problems of Drug Dependence Director, Department of Defense National Substance Use Disorders Consortium Past Director, VA National Substance Abuse Quality Evaluation Research Initiative QUERI CC-74 Withdrawal Management Critical for Successful Transition to Post-Withdrawal Treatment

Withdrawal Management Opioid Post-Withdrawal Dependence Opioid Treatment Withdrawal

CC-75 Limitations with Current Opioid Withdrawal Management

Opioids Off-Label Use

Opioid Withdrawal Management Variable Limited Access Evidence

CC-76 Lofexidine Addresses Unmet Need in Opioid Withdrawal Management

Label to Non-Opioid Guide Usage • FDA-approved • Comprehensive clinical • Lower risk of abuse program established dose and diversion • Clear precautions • Patient counseling Lofexidine

Broader Access Safe & Effective • Does not require special • Reduces symptoms licensing • Improves completion • Broad HCP availability • Manageable side effects • Available in underserved areas

CC-77 Lofexidine Addresses Unmet Need in Opioid Withdrawal Management

Label to Non-Opioid Guide Usage • FDA-approved • Comprehensive clinical • Lower risk of abuse program established dose and diversion • Clear precautions • Patient counseling Lofexidine

Broader Access Safe & Effective • Does not require special • Reduces symptoms licensing • Improves completion • Broad HCP availability • Manageable side effects • Available in underserved areas

CC-78 Lofexidine Addresses Unmet Need in Opioid Withdrawal Management

Label to Non-Opioid Guide Usage • FDA-approved • Comprehensive clinical • Lower risk of abuse program established dose and diversion • Clear precautions • Patient counseling Lofexidine

Broader Access Safe & Effective • Does not require special • Reduces symptoms licensing • Improves completion • Broad HCP availability • Manageable side effects • Available in underserved areas

CC-79 Lofexidine Addresses Unmet Need in Opioid Withdrawal Management

Label to Non-Opioid Guide Usage • FDA-approved • Comprehensive clinical • Lower risk of abuse program established dose and diversion • Clear precautions • Patient counseling Lofexidine

Broader Access Safe & Effective • Does not require special • Reduces symptoms licensing • Improves completion • Broad HCP availability • Manageable side effects • Available in underserved areas

CC-80 Patient Risk

1 - 2 Week Treatment Duration

Symptomatic orthostasis • Low rates of dizziness • Rare reports of syncope fall Low rates of sedation Transient QTc changes

PATIENT RISKS

CC-81 Positive Efficacy Across Multiple Measures

Standardized Treatment Time Effect (95% CI) Endpoint Study Period LFX HCl 2.4 mg LFX HCl 3.2 mg Study 2 Day 3 -0.43 (-0.67, -0.18) SOWS-Gossop Study 3-1 Overall -0.51 (-0.79, -0.23) Study 3-1 Overall -0.37 (-0.65, -0.09)

COWS Study 3-1 Overall -0.79 (-1.05, -0.53) Study 3-1 Overall -0.62 (-0.89, -0.36)

Study 2 Day 3 -0.49 (-0.80, -0.19) OOWS-Handelsman Study 3-1 Overall -0.48 (-0.71, -0.25) Study 3-1 Overall -0.33 (-0.56, -0.10)

MCGI Study 2 Day 3 -0.47 (-0.78, -0.17) Study 3-1 Overall -0.46 (-0.73, -0.19) (Patient – Severity of Opiate Withdrawal) Study 3-1 Overall -0.38 (-0.65, -0.11)

MCGI Study 2 Day 3 -0.47 (-0.77, -0.16) Study 3-1 Overall -0.50 (-0.78, -0.22) (Rater – Severity of Illness) Study 3-1 Overall -0.44 (-0.72, -0.16)

Study 2 Day 3 -0.45 (-0.76, -0.15) VAS-E Study 3-1 Overall -0.95 (-1.25, -0.65) Study 3-1 Overall -0.78 (-1.08, -0.47) -1.5 -1 -0.5 0 MCGI=Modified Clinical Global Impressions; OOWS=Objective Opiate Withdrawal Scale of Handelsman; VAS=Visual Analog Scale. The VAS-E scale is reversed to be consistent with other endpoints, where lower scores indicate a more positive clinical outcome Favors Lofexidine Favors Placebo CC-82 Patient Benefit

1 - 2 Week Treatment Duration

Reduces OWS symptom severity

Symptomatic orthostasis Complete opiate withdrawal treatment • Low rates of dizziness • Rare reports of syncope fall Opens door to post- withdrawal treatment Low rates of sedation Public health benefit Transient QTc changes

PATIENT RISKS PATIENT BENEFITS

CC-83 Education and Labeling Further Optimizes Benefit:Risk

1 - 2 Week Treatment Duration

Reduces OWS symptom severity Complete opiate withdrawal treatment Symptomatic orthostasis Opens door to post- withdrawal treatment Sedation Public health benefit QTc

PATIENT RISKS PATIENT BENEFITS

CC-84 Comprehensive Risk:Benefit Analysis

 Opioid use disorder consequences demand attention

 Current withdrawal management options leave unmet need

 Lofexidine benefits for opioid withdrawal significant and its risks manageable

 Both lofexidine doses safe and effective; 3.2 mg dose has best risk/benefit profile

 Labeling and education plans can optimize appropriate product use

 Holistic treatment approaches essential in opioid dependent patients, including withdrawal management

Lofexidine has positive benefit risk profile and provides valuable therapeutic option for managing opioid withdrawal.

CC-85 Cl HN

O N

LUCEMYRA (lofexidine) Cl

Psychopharmacologic Drugs Advisory Committee Meeting March, 2018

CC-86 Future Research Directions

 Pediatric Programs PK Study in Adolescents to Determine Dose (12-17) Pediatric Iatrogenic Opioid Withdrawal (2-17) Neonatal Opioid Withdrawal Syndrome (0 to few weeks)

 Opioid Taper Scenario Focus on analgesic taper scenario, higher unmet need and consistent with recommended treatment Characterize benefits in enhancing taper efficiency and comfort

CC-87 Supporting LUCEMYRA Patients

Patient and HCP websites Encouragement phone application Patient and caregiver handouts “What to expect” for patients and caregivers Collaborations with medical associations and societies Connections to local resources Support education for HCPs

CC-88 Additional Responders

President Richard Bittman, PhD Statistician Bittman Biostat, Inc.

COO Joseph Pergolizzi, MD Pain Specialist NEMA Research Inc

William Wikoff Smith Chair in Cardiovascular Research; Peter Kowey, MD, FACC, Cardiologist Professor of Medicine and Clinical Pharmacology FHRS, FAHA Jefferson Medical College

Founder, President James Longstreth, PhD Pharmacokineticist Longstreth & Associates, Inc.

Abuse/Dependence Director, Co-Founder Kerri Schoedel, PhD Pharmacologist Altreos Research Partners, Inc.

CC-89 Backup Slides Shown

CC-90 Study 3-1: Mean SOWS Item-Level Scores by Time (mITT)

LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo

Feeling Sick Stomach Cramps Muscle Spasms/ Feeling of Coldness Heart Pounding 2 2 2 Twisting 2 2

1 1 1 1 1

0 0 0 0 0 0246 0246 0246 0246 0246

Muscular Tension Aches & Pains Yawning Runny Eyes Insomnia/ Problems Sleeping

Mean Scores 2 2 2 2 2

1 1 1 1 1

0 0 0 0 0 0246 0246 0246 0246 0246

Study Days BU-322 Study 1: Design

Phase I Phase II Phase III Morphine Study Medication Administrationa Post Treatment Stabilization

Morphine Sulfate Lofexidine HCl Lofexidine HCl Placebo No 0.8 QID 0.4 QID Treatment 3.2 mg/day Oral 3.2 mg/day Oral QID Oral Up to 25 mg 25 mg QID QIDb Placebo Placebo No QID Oral QID Oral Treatment

Days 1 2 to 3 4 to 7 8 9 to 10 11

a. Patients received 4 tablets of study medication for each dose: lofexidine 0.8 mg (4 x 0.2 mg lofexidine HC1 tablets); lofexidine 0.4 mg (2 x 0,2 mg Lofexidine HC1 tablets + 2 placebo tablets); placebo (4 placebo tablets). b. Maximum morphine sulfate subcutaneous dose of 25 mg QID; dose for each patient varied, depending on the time of day the patient enrolled. BU-41 Study 2: Categorical Systolic Blood Pressure Values Study Days 6-8

Lofexidine HCl 3.2 mg/day Placebo N=134 N=129 Increase from Baseline Post-Lofexidine Day N at Risk % N at Risk % 1 66 13.6 43 16.3 ≥140 mmHg and ≥20 mmHg 2 58 39.7 37 16.2 3 50 20.0 35 14.3 1 66 12.1 43 9.3 ≥150 mmHg and ≥20 mmHg 2 58 31.0 37 13.5 3 50 14.0 35 2.9 1 66 7.6 43 2.3 ≥160 mmHg and ≥20 mmHg 2 58 20.7 37 2.7 3 50 8.0 35 2.9 1661.5430 ≥170 mmHg and ≥20 mmHg 2588.6370 3506.0350

Days after discontinuation of lofexidine or placebo (Day 1, Day 2 and Day 3 are Day 6, Day 7 and Day 8 respectively)

BU-437 Study 3-1: Discontinuation Due to TEAE by Dose

MedDRA LFX HCl 2.4 mg LFX HCl 3.2 mg Preferred Term % % Bradycardia 0 4.5 Hypotension 1.3 3.2 Orthostatic hypotension 1.3 2.7 Insomnia 2.2 3.2 Somnolence 0.4 1.8 Syncope 0.4 1.4 Myalgia 2.2 0.5 Nausea 2.2 0.5 Pain 1.3 2.3

BU-14 Study 3-1: Completion Status – Subgroup Analyses

Number of Patients Odd Ratio Endpoint Placebo LFX (95% CI) Overall - LFX HCI 2.4 vs Placebo 151 229 1.88 (1.21, 2.93) Overall - LFX HCI 3.2 vs Placebo 151 222 1.74 (1.11, 2.72)

Male - LFX HCI 2.4 vs Placebo 107 162 1.65 (0.99, 2.74) Male - LFX HCI 3.2 vs Placebo 107 158 1.40 (0.84, 2.34) Female - LFX HCI 2.4 vs Placebo 44 67 2.95 (1.14, 7.63) Female - LFX HCI 3.2 vs Placebo 44 64 3.39 (1.31, 8.77)

Age ≤35 LFX HCI 2.4 vs Placebo 93 128 1.66 (0.92, 2.99) Age ≤35 LFX HCI 3.2 vs Placebo 93 139 1.79 (1.01, 3.20) Age >35 LFX HCI 2.4 vs Placebo 58 101 2.12 (1.07, 4.19) Age >35 LFX HCI 3.2 vs Placebo 58 83 1.68 (0.83, 3.40)

White - LFX HCI 2.4 vs Placebo 117 169 1.54 (0.92, 2.59) White - LFX HCI 3.2 vs Placebo 117 158 1.85 (1.10, 3.11) Black or African American - LFX HCI 2.4 vs Placebo 26 54 2.68 (1.02, 7.04) Black or African American - LFX HCI 3.2 vs Placebo 26 48 1.35 (0.51, 3.59) Other - LFX HCI 2.4 vs Placebo 86 3.59 (0.24, 53.45) Other - LFX HCI 3.2 vs Placebo 816 2.34 (0.22, 25.31)

LFX HCl 2.4 mg LFX HCl 3.2 mg 0123456 Favors Placebo Favors Lofexidine BU-302 Study 3-1: Mean of the QTcF Change from Baseline for Patients who had ECGs on Day 1 Through Day 14

LFX HCI 2.4 mg LFX HCI 3.2 mg Placebo 70 60 50 40 30 20 10 0 -10 from Baseline -20 Mean of QTcF Change -30 -40 -50 Day 1 Day 7 Day 8 Day 14

LFX HCI 2.4 mg 37 37 37 37 LFX HCI 3.2 mg 36 36 36 36 Placebo 24 24 24 24 BU-459 Study 3-1: Mean of the QTcF Change from Baseline

LFX HCI 2.4 mg LFX HCI 3.2 mg Placebo 70 60 50 40 30 20 10 0 -10 from Baseline -20

Mean of QTcF Change -30 -40 -50 Day 1 Day 7 Day 8 Day 14

LFX HCI 2.4 mg 252 120 74 37 LFX HCI 3.2 mg 251 128 79 36 Placebo 162 61 42 25 BU-458 Study 3-1: 30-Day Phone Follow-Up

30-Day Follow-Up N=345 57%

Completed Study Did Not Complete Study n=157 n=188 46% 54%

Patient Reported Abstinence Patient Reported Abstinence n=118 n=57 75% 30%

BU-495