LUCEMYRA (lofexidine) Cl - fda.gov · American Society of Addiction Medicine ... •Black box warning for addiction •Diversion and abuse Off-label Buprenorphine Partial opioid

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Psychopharmacologic Drugs Advisory Committee MeetingMarch 27, 2018

LUCEMYRA (lofexidine)

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Kristen Gullo

Vice President, Development & Regulatory AffairsUS WorldMeds


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AgendaTopic Speaker, Affiliation

Medical LandscapeLouis Baxter, MD, DFASAM, DABAMExecutive Medical DirectorProfessional Assistance Program of NJ, Inc.

Lofexidine DevelopmentKristen GulloVice President, Pharmaceutical Development & Regulatory AffairsUS WorldMeds

Lofexidine Trial ProgramMarc Fishman, MDMedical Director, Maryland Treatment CentersAssistant Professor, Johns Hopkins University School of Medicine

EfficacyCharles Gorodetzky, MD PhDConsultant in Pharmaceutical MedicineUS WorldMeds

SafetyMark Pirner, MD PhDSenior Medical DirectorUS WorldMeds

Clinical Perspective & Benefit-Risk

Thomas Kosten, MD Waggoner Chair and Professor of Psychiatry and PharmacologyBaylor College of Medicine

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Louis E. Baxter, Sr., MD, DFASAM, DABAMExecutive Medical DirectorProfessional Assistance Program of NJ, Inc.Assistant Clinical Professor of MedicineRutgers New Jersey Medical School Newark, NJCo-Program Director Addiction Medicine FellowshipHoward UniversityPast PresidentAmerican Society of Addiction MedicineDirector, Addiction Medicine Foundation (ABAM)

Medical Landscape

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Physical Dependence on Opioids

Prolonged exposure Chemical changes in the brainPhysical dependence developsOpioid discontinuation leads to withdrawalOpioid Withdrawal Syndrome

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Opioid Withdrawal Syndrome (OWS): Potential Symptoms

Sleep problems Muscle aches Heart racing Hypertension Runny nose Agitation Yawning Tearing Sweating

Fever Nausea Vomiting Diarrhea Stomach cramps Gooseflesh Depression Drug craving Anxiety

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Duration 1-2 Weeks

Time Course of Opioid Withdrawal Syndrome

Last Opioid Dose

Withdrawal Intensity

Diminishing Symptoms

Peak 2-4 days

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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.

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Withdrawal Management Overcomes Barrier of Opioid Withdrawal Syndrome

Opioid Dependence Post-Withdrawal

TreatmentOpioid Withdrawal

WithdrawalManagement

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Opioid Withdrawal Treatments

ProductPharmacological

Class IndicationsSpecial Licensing

Required Other Limitations

FDA Approved Methadone Full opioid

agonist

• Detoxification and maintenance of opioid addiction

Yes; limited access

• Black box warningfor addiction

• Diversion and abuse

Off-label

Buprenorphine Partial opioid agonist

• Treatment of opioid dependence

Yes; limited access

• Dependence• Diversion and abuse

Clonidine ɑ2 adrenergic agonist

• Essential hypertension

• Attention deficit hyperactivity disorder

No

• Off-label• Limited controlled data• Inconsistent dosing• Side effects• No generally accepted

guidelines for use

Opioid Taper

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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

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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

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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

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Kristen Gullo

Vice President, Development & Regulatory AffairsUS WorldMeds

Introduction to LUCEMYRA (lofexidine) Development

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Lofexidine (LUCEMYRA) First non-opioid medication developed for use in opioid

withdrawal management Selective α2 receptor agonistNo other clinically relevant receptor activity, including those

commonly associated with abuse potential

Proposed indicationsMitigation of symptoms associated with opioid withdrawalFacilitation of completion of opioid discontinuation treatment

Recommended dosage3.2 mg/day (4 x 0.2 mg, administered QID) for 7 daysAdditional 7 days with dosing guided by symptoms

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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 UKSupports favorable benefit:risk of lofexidine in OWSNICE 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 2003Key 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

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Clinical Development Overview 24 total clinical studies 16 clinical pharmacology studies Phase 3 programStudy 1 (supporting efficacy)Study 2 (pivotal)Study 3-1 (pivotal)Study 3-2 (open-label safety)

Safety database1276 patients received lofexidine1104 opioid-dependent patients

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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

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Lofexidine Mechanism of Action Activates α2 receptors involved in

regulation of norepinephrine Closes a negative feedback loop involved

in norepinephrine regulation Depresses activating signals, reducing

norepinephrine production Net effect in withdrawing patient is to

attenuate surging norepinephrine production to return toward normal physiological level

Synaptic vesicle

Norepinephrine

Negative feedback

α2 receptor

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/)

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Marc Fishman, MD

Medical Director, Maryland Treatment CentersAssistant Professor, Johns Hopkins University School of Medicine

Lofexidine Trial Program

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Double-Blind Study 2 Study 3-1

Dose LFX HCI 3.2 mg/d; Placebo LFX HCI 2.4 mg/d; 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

Lofexidine Phase 3 Clinical Development

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

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Bed-based care settings because of demands of research protocol Heterogeneity of sitesAcademic research unitsCommunity treatment programsPrivate clinical research centers

Site Characteristics

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Study 2 Study 3-1 Study 3-2Use 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

Key Enrollment Criteria

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

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Study 2 Study 3-1LFX HCI3.2 mgN=134

PlaceboN=130

LFX HCI2.4 mgN=229

LFX HCI3.2 mgN=222

PlaceboN=151

Age (years)Mean (range)

36(18 - 62)

38(18 - 60)

35 (19 - 74)

35(19 - 68)

36(19 - 63)

Sex, %Male 75 76 71 71 71Female 25 24 29 29 29

Race, %White 47 59 74 71 78Black or African American 28 21 23 21 17Other 0 0 3 7 5

Ethnicity (Hispanic/Latino)a, % 25 21 15 13 15

Demographics

a. In Study 2, ethnicity was included as a racial category

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Opioid Use PatternsStudy 2 Study 3-1

LFX HCI3.2 mgN=134

PlaceboN=130

LFX HCI2.4 mgN=229

LFX HCI3.2 mgN=222

PlaceboN=151

Primary opioid, %Heroin 61 64 86 82 81Other 39 36 14 18 19

Opioid IV drug use, % 49 54 59 57 66Positive urine drug screen for other substances, % 60 59 56 64 50

Stimulants 33 40 38 43 31Benzodiazepines 18 18 11 15 13Cannabinoids 28 22 28 36 27

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Protocol Allowed Supportive MedicationsMedication Purpose Study 2 Study 3-1 Study 3-2Guaifenesin Cough

Antacids Indigestion and nausea

Dioctyl sodium sulfosuccinatePsyllium hydrocolloid suspension Constipation

Bismuth sulfate Diarrhea

Acetaminophen Aches and pains

Zolpidem Insomnia

Benzodiazepines Insomnia, depression,and anxiety

Full or Partial Opioid Agonist Assisted withdrawal Rescue ONLY, Required Study D/C

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All Studies Study 3-1 & 3-2 Only

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

COWS

Safety Assessments• AEs• Vital signs• ECG• Clinical labs

C-SSRS

Efficacy and Safety Assessments

COWS=Clinical Opiate Withdrawal ScaleC-SSRS=Columbia Suicidality Severity Rating ScaleMCGI=Modified Clinical Global Impression ScaleOOWS-Handelsman=Objective Opiate Withdrawal Scale of HandelsmanSOWS-Gossop=Short Opiate Withdrawal Scale of GossopVAS-E=Visual Analog Scale-Efficacy

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Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop)

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SOWS-Gossop Study 2, Day 2 Patient Example

Total Score = 15

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Pivotal Study Key Efficacy EndpointsStudy 2 Study 3-1

Mitigation of Symptoms

Co-Primary Endpoint: Difference between mean Study Day 3 SOWS-Gossop scores

Primary Endpoint: Difference between least squares means from the Study Days 1-7 SOWS-Gossop overall scores

Facilitation of Completion

Co-Primary Endpoint: Time-to drop out for 5-day treatment phase

Key Secondary Endpoint: Proportion of Day 7 completers

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Charles W. Gorodetzky, MD, PhD

Principal Investigator, Lofexidine Clinical TrialsConsultant, Pharmaceutical Medicine

Efficacy Results

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

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LFX HCl 3.2 mgN=133

PlaceboN=126

0.0737 <0.0001 0.0028 0.1104 0.0708 NS NSp-value (difference vs placebo)LFX HCl 3.2 mg

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Log-rank test for active treatment period on Day 5: p=0.0034

LFX HCl 3.2 mg

Placebo

Difference between treatments of 2 days the median time to dropout

Study 2: Time to Study Discontinuation –Co-Primary Endpoint

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0.02 3 4 5 6 7

Study Day8

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Study 2: Completion Rates – ITT Population

LFX HCl 3.2 mgN=134

PlaceboN=130 p-value

Completed 5-day Treatment and Discharged on Day 6 or Later, % 49.3 33.1 0.009

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p-value (different vs placebo)LFX HCl 2.4 mgLFX HCl 3.2 mg

0.01680.0005

0.00050.0002

0.00920.0008

0.00610.0008

0.01930.0175

NSNS

NSNS

Study 3-1: SOWS-Gossop – Primary Endpoint

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Mea

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Gos

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LFX HCl 2.4 mg LFX HCl 3.2 mg Placebo

Least Squares MeanDifference vs Placebo p-valueLFX HCl 2.4 mg 0.0166

LFX HCl 3.2 mg 0.0033

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Study 3-1: Retention Analysis

1 2 3 4 5 6 7Study Day

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0.9

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0.7

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entio

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obab

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0.4

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LFX HCl 3.2 mg

Placebo

LFX HCl 2.4 mg

Difference between treatments of 1.75 days in the median time to dropout

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Cox regression comparison versus placebo of 2.4 mg/day: p=0.0016; of 3.2 mg/day: p=0.0087

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Study 3-1: Completion Rates – MITT Population

LFX HCl 2.4 mgN=229

LFX HCl 3.2 mgN=222

PlaceboN=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

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

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SOWS-Gossop Scores COWS Scores

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Study Day

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Efficacy Trends Across Multiple Measures

Endpoint StudyTime

Period

Standardized Treatment Effect (95% CI)

SOWS-GossopStudy 2 Day 3 -0.43 (-0.67, -0.18)

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)

OOWS-HandelsmanStudy 2 Day 3 -0.49 (-0.80, -0.19)


MCGI (Patient – Severity of Opiate Withdrawal)

Study 2 Day 3 -0.47 (-0.78, -0.17)Study 3-1 Overall -0.46 (-0.73, -0.19)Study 3-1 Overall -0.38 (-0.65, -0.11)

MCGI (Rater – Severity of Illness)


VAS-EStudy 2 Day 3 -0.45 (-0.76, -0.15)


Favors Lofexidine Favors Placebo

LFX HCl 2.4 mg LFX HCl 3.2 mg

-1.5 -1 -0.5 0MCGI=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

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Lofexidine Efficacy Summary

Achieved primary efficacy endpointsEffective on multiple efficacy measuresBoth doses effectiveAlleviated withdrawal symptomsHigher completion rate

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Mark Pirner, MD, PhD

Senior Medical DirectorUS WorldMeds

Lofexidine Safety

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Safety Presentation Outline

Exposure

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ExposureOverall treatment emergent adverse events (AEs)

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ExposureOverall treatment emergent adverse events (AEs)Drug class AEs and vital sign analyses

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ExposureOverall treatment emergent adverse events (AEs)Drug class AEs and vital sign analysesSerious adverse events and AEs leading to discontinuation

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ExposureOverall treatment emergent adverse events (AEs)Drug class AEs and vital sign analysesSerious adverse events and AEs leading to discontinuationTopics of special interest (QTc, renal/hepatic dose adjustment)

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ExposureOverall treatment emergent adverse events (AEs)Drug class AEs and vital sign analysesSerious adverse events and AEs leading to discontinuationTopics of special interest (QTc, renal/hepatic dose adjustment)UK Safety Experience

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All Phase 3 Studies: Total Exposure

DayLFX HCl 2.4 mg

LFX HCl 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

14 7 24 NA

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Phase 3 Pivotal Studies: Daily Exposure

Placebo only

Day

Proportion Received At Least One Dose (%)Study 2 Study 3-1

LFX HCI 3.2 mgN=134

PlaceboN=129

LFX HCI 2.4 mgN=229

LFX HCI 3.2 mgN=222

PlaceboN=151

1 100 100 100 100 100

2 85 78 86 80 67

3 72 57 65 59 47

4 60 43 53 51 39

5 54 35 46 47 32

6 49 32 43 43 30

7 42 29 42 41 28

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

TEAEs

Study 2 Study 3-1 Study 3-2LFX HCI3.2 mgN=134

%

PlaceboN=130

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI3.2/2.4 mg

N=286%

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal Related* TEAE 85.1 87.7 79.0 79.7 84.8 81.5

Any Non-Opioid Withdrawal-Related* TEAE 59.7 43.1 76.9 79.3 40.4 72.7

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 Discontinuation 3.7 4.6 18.8 24.8 29.1 12.9

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

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

TEAEs


%

PlaceboN=130

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI3.2/2.4 mg

N=286%

Any Opioid Withdrawal-Related TEAE 85.1 87.7 79.0 79.7 84.8 81.5

Insomnia 34.3 36.9 46.3 53.2 45.7 47.9Headache 26.1 30.8 8.3 7.2 13.2 11.9Anxiety 23.1 23.1 3.1 3.6 6.6 34.6Rhinorrhea 6.7 16.9 3.5 2.7 6.0 *Diarrhea 24.6 34.6 21.4 21.2 22.5 17.1Pain 12.7 19.2 21.8 18.5 22.5 8.4Nausea 23.1 32.3 20.1 12.2 21.2 16.1Myalgia 9.7 16.2 12.7 9.9 16.6 13.6Vomiting 5.2 20.0 9.2 8.6 15.9 8.7

*<5%

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Phase 3 Pivotal and Open-Label Studies:Non-Opioid Withdrawal (NOWR) TEAEs

TEAEs


%

PlaceboN=129

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI 3.2/2.4 mg

N=286%

Any Non-Opioid Withdrawal-Related TEAE 59.7 43.1 76.9 79.3 40.4 72.7

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%

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Phase 3 Pivotal and Open-Label Studies:Syncope or Fall TEAEs

TEAEs

Study 2 Study 3-1 Study 3-2LFX HCI3.2 mgN=134n (%)

PlaceboN=129n (%)

LFX HCI2.4 mgN=229n (%)

LFX HCI3.2 mgN=222n (%)

PlaceboN=151n (%)

LFX HCI 3.2/2.4 mg

N=286n (%)

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)

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BPM

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Study 3-1 Mean Change Standing PulseLFX 2.4 Pulse LFX 3.2 Pulse P Pulse

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

-30-25-20-15-10

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0 1 2 3 4 5 6 7

mm

HG

Study Day

Study 2 Mean Change Standing BPLFX SBP P SBP LFX DBP P DBP

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BPM

Study Day

Study 2 Mean Change Standing PulseLFX Pulse P Pulse

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mm

HG

Study Day

Study 3-1 Mean Change Standing BPLFX 2.4 SBP LFX 3.2 SBP P SBPLFX 2.4 DBP LFX 3.2 DBP P DBP

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Pivotal Study 3-1: Lowest Change Observed Orthostatic Standing Systolic Blood Pressure

LFX HCl 2.4 mg PlaceboLFX HCl 3.2 mg

Sitting Zero

Decrease w

ith standing

Ort

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Sys

tolic

Blo

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Cha

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(mm

Hg)

Sitting Systolic Blood Pressure (mmHg)

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Pivotal Study 3-1: Lowest Observed Orthostatic Standing Systolic Blood Pressure

Sitting Systolic Blood Pressure (mmHg)

Ort

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(mm

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Phase 3 Pivotal and Open-Label Studies: Serious TEAEs

TEAEs


%

PlaceboN=130

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI3.2/2.4 mg

N=286%

Any TEAE 97.0 93.8 94.3 95 88.7 82.9

Any Opioid Withdrawal Related TEAE 85.1 87.7 79.0 79.7 84.8 81.5


Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

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


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Phase 3 Pivotal and Open-Label Studies:Serious TEAEs

LFX HCI 3.2 mgN=134n (%)

PlaceboN=130n (%)

Any Serious TEAE 8 (6.0) 8 (6.2)

Severe opioid withdrawal symptoms

4 (3.0) 5 (3.8)

Hypertension 1 (0.8)Diarrhea 1 (0.8)2○ heart block 1 (0.8)Hypotension 1 (0.75)Bradycardia 1 (0.75)Chest pain 1 (0.75)Orthostatic hypotension 1 (0.75)



PlaceboN=151n (%)

Any Serious TEAE 0 5 (2.3) 2 (1.3)

Acute hepatitis C 1 (0.7)

QTc prolonged 1 (0.7)

Toxicity to various agents

1 (0.5)

Overdose 1 (0.5)Syncope 2 (0.9)Suicidal ideation 1 (0.5)

LFX HCI3.2/2.4 mg

N=286n (%)

Any Serious TEAE 2 (0.7)Delusion 1 (0.4)Cerebral vascular accident 1 (0.4)

Study 2 Study 3-1 Study 3-2

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PlaceboN=130n (%)



4 (3.0) 5 (3.8)




PlaceboN=151n (%)





1 (0.5)


LFX HCI3.2/2.4 mg

N=286n (%)



Higher Placebo Higher Lofexidine

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PlaceboN=130n (%)



4 (3.0) 5 (3.8)




PlaceboN=151n (%)





1 (0.5)


LFX HCI3.2/2.4 mg

N=286n (%)



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

TEAEs


%

PlaceboN=130

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI3.2/2.4 mg

N=286%

Any TEAE 97.0 93.8 94.3 95 88.7 82.9



Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 0 0


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

TEAEs


%

PlaceboN=130

%

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%

LFX HCI3.2/2.4 mg

N=286%

Any TEAE 97.0 93.8 94.3 95 88.7 82.9



Serious TEAE 6.0 6.2 0 2.3 1.3 0.7

Death 0 0 0 0.5 0 0


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

LFX HCI3.2 mgN=134

%

PlaceboN=130

%Any TEAE discontinuation 3.7 4.6

ECG QTc interval prolonged 0.7 1.5

Yawning 0.8Hypertension 0.8Second degree heart block 0.8


1.6 0.8

Heart rate increased 0.7

Hypotension 0.7

LFX HCI2.4 mgN=229

%

LFX HCI3.2 mgN=222

%

PlaceboN=151

%Any TEAE discontinuation 18.8 24.8 29.1

Events >3%

Vomiting 1.7 0.9 7.3Diarrhea 2.2 2.3 6.6Nausea 2.2 0.5 6.6Pain 1.3 2.3 6.6Anxiety 1.7 1.4 3.3Insomnia 2.2 3.2 4.0Bradycardia 0 4.5 0Dizziness 3.5 2.7 0.7Hypotension 1.3 3.2 0

LFX HCI3.2/2.4 mg

N=286%

Any TEAE discontinuation 12.6

Anxiety 3.1Vomiting 2.1Dizziness 1.7Hypotension 1.7Orthostatic hypotension 1.0

Restlessness 1.0Syncope 0.3


Higher Placebo Higher Lofexidine

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Pivotal Study 3-1: Discontinuations Resulting from AEs and Lack of Efficacy

0

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Adverse Event Lack of Efficacy Lack of Efficacy and Adverse Event

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Topics of Special Interest: QTc, Renal/Hepatic Dose Adjustment

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

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

-15

-10

-5

0

5

10

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

QTc

F M

ean

Cha

nge

from

B

asel

ine

(95%

CI)


Day 1 Day 7Day 4Day 2

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Pivotal Study 3-1: Maximum QTc by Patient


QTc

Cha

nge

(ms)

–Fr

ider

icia

Cor

rect

ion

Baseline QTc (ms) – Fridericia Correction

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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

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UK Safety

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UK Spontaneous AE ReportsSerious Non Serious Total

Total events 45 98 143MedDRA Preferred Terms (reported ≥5 times)

Bradycardia 6 6 12Hypotension 5 6 11Blood pressure decreased 4 5 9Heart rate decreased 4 5 9Headache 0 7 7Hypertension 0 5 5

MedDRA: Medical Dictionary for Regulatory Activities

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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 AEsDizziness (9%)Sedation (7%)Dry mouth (5%)

60% successful detoxificationNo 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

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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 patientsRebound hypertensionQTc prolongation in high risk patientsRenal or hepatic insufficiencyCNS sedation

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Sponsor Education Materials Patient selectionAppropriate withdrawal management settingConcomitant psychiatric and medical conditionsConcomitant medicationsAppropriate and available support

Patient counselingDosing instructions and precautions (e.g. hydration, reduced activity)Appropriate expectationsWhat to look for and when to call

Clinical managementDose hold/reductionPrecautions and warnings

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Thomas R. Kosten, MDWaggoner Chair and Professor of Psychiatry and Pharmacology,Baylor College of MedicineDirector, Division of AddictionsPast President, American Academy of Addiction PsychiatryPast President, College on Problems of Drug DependenceDirector, Department of Defense National Substance Use Disorders ConsortiumPast Director, VA National Substance Abuse Quality Evaluation ResearchInitiative QUERI

Clinical Perspective

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Withdrawal Management Critical for Successful Transition to Post-Withdrawal Treatment

Opioid Dependence Post-Withdrawal

TreatmentOpioid Withdrawal

WithdrawalManagement

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Limitations with Current Opioid Withdrawal Management

OpioidWithdrawal

Management

Opioids

Limited AccessVariable Evidence

Off-Label Use

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Lofexidine Addresses Unmet Need in Opioid Withdrawal Management

Lofexidine

Non-Opioid

Broader Access Safe & Effective

Label to Guide Usage• Comprehensive clinical

program established dose• Clear precautions• Patient counseling

• Does not require special licensing

• Broad HCP availability • Available in underserved

areas

• Reduces symptoms• Improves completion• Manageable side effects

• FDA-approved• Lower risk of abuse

and diversion

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Lofexidine

Non-Opioid






areas



and diversion

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Lofexidine

Non-Opioid






areas



and diversion

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Lofexidine

Non-Opioid


Label to Guide Usage


and diversion

• Comprehensive clinical program established dose

• Clear precautions• Patient counseling



areas


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Patient Risk1 - 2 Week Treatment Duration

PATIENT RISKS

Symptomatic orthostasis• Low rates of dizziness• Rare reports of syncope fall

Low rates of sedationTransient QTc changes

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Positive Efficacy Across Multiple Measures

Endpoint StudyTime

Period

Standardized Treatment Effect (95% CI)

SOWS-GossopStudy 2 Day 3 -0.43 (-0.67, -0.18)


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

OOWS-HandelsmanStudy 2 Day 3 -0.49 (-0.80, -0.19)


MCGI (Patient – Severity of Opiate Withdrawal)


MCGI (Rater – Severity of Illness)


VAS-EStudy 2 Day 3 -0.45 (-0.76, -0.15)


Favors Lofexidine Favors Placebo

LFX HCl 2.4 mg LFX HCl 3.2 mg

-1.5 -1 -0.5 0MCGI=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

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Patient Benefit1 - 2 Week Treatment Duration

PATIENT BENEFITSPATIENT RISKS

Reduces OWS symptom severityComplete opiate withdrawal treatmentOpens door to post-withdrawal treatmentPublic health benefit

Symptomatic orthostasis• Low rates of dizziness• Rare reports of syncope fall

Low rates of sedationTransient QTc changes

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PATIENT RISKS

Education and Labeling Further Optimizes Benefit:Risk

1 - 2 Week Treatment Duration

Symptomatic orthostasisSedationQTc

PATIENT BENEFITS

Reduces OWS symptom severityComplete opiate withdrawal treatmentOpens door to post-withdrawal treatmentPublic health benefit

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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.

Comprehensive Risk:Benefit Analysis

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Psychopharmacologic Drugs Advisory Committee MeetingMarch, 2018


Cl

O

Cl

HN

N

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

Opioid Taper ScenarioFocus on analgesic taper scenario, higher unmet need and consistent with

recommended treatment Characterize benefits in enhancing taper efficiency and comfort

Future Research Directions

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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

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Additional Responders

Richard Bittman, PhD Statistician PresidentBittman Biostat, Inc.

Joseph Pergolizzi, MD Pain Specialist COONEMA Research Inc

Peter Kowey, MD, FACC, FHRS, FAHA Cardiologist

William Wikoff Smith Chair in Cardiovascular Research; Professor of Medicine and Clinical Pharmacology Jefferson Medical College

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

Kerri Schoedel, PhD Abuse/Dependence Pharmacologist

Director, Co-FounderAltreos Research Partners, Inc.

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Backup Slides Shown

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

Mea

n Sc

ores 0

1

2

0 2 4 6

Feeling Sick Stomach Cramps Muscle Spasms/Twisting

Feeling of Coldness Heart Pounding

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

Study Days


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0

1

2

0 2 4 60

1

2

0 2 4 60

1

2

0 2 4 60

1

2

0 2 4 6

0

1

2

0 2 4 60

1

2

0 2 4 60

1

2

0 2 4 60

1

2

0 2 4 60

1

2

0 2 4 6

Study 1: Design

Morphine Stabilization Study Medication Administrationa Post Treatment

8 9 to 10

PlaceboQID Oral

PlaceboQID Oral

NoTreatment

NoTreatment

4 to 71Days

Lofexidine HCl0.8 QID

3.2 mg/day Oral

PlaceboQID Oral

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.

2 to 3 11

Phase I Phase II Phase III

Morphine SulfateLofexidine HCl

0.4 QID3.2 mg/day Oral

Up to 25 mg QIDb

25 mg QID

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Study 2: Categorical Systolic Blood Pressure Values Study Days 6-8

Increase from Baseline Post-Lofexidine Day

Lofexidine HCl 3.2 mg/dayN=134

PlaceboN=129

N at Risk % N at Risk %

≥140 mmHg and ≥20 mmHg1 66 13.6 43 16.32 58 39.7 37 16.23 50 20.0 35 14.3

≥150 mmHg and ≥20 mmHg1 66 12.1 43 9.32 58 31.0 37 13.53 50 14.0 35 2.9

≥160 mmHg and ≥20 mmHg1 66 7.6 43 2.32 58 20.7 37 2.73 50 8.0 35 2.9

≥170 mmHg and ≥20 mmHg1 66 1.5 43 02 58 8.6 37 03 50 6.0 35 0

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

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Study 3-1: Discontinuation Due to TEAE by Dose MedDRAPreferred Term

LFX HCl 2.4 mg%

LFX HCl 3.2 mg%

Bradycardia 0 4.5Hypotension 1.3 3.2Orthostatic hypotension 1.3 2.7Insomnia 2.2 3.2Somnolence 0.4 1.8Syncope 0.4 1.4Myalgia 2.2 0.5Nausea 2.2 0.5Pain 1.3 2.3

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Study 3-1: Completion Status – Subgroup AnalysesEndpoint

Number of Patients Odd Ratio(95% CI)Placebo LFX

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 8 6 3.59 (0.24, 53.45)Other - LFX HCI 3.2 vs Placebo 8 16 2.34 (0.22, 25.31)

Favors Placebo Favors LofexidineLFX HCl 2.4 mg LFX HCl 3.2 mg 0 1 2 3 4 5 6

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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 37 37 37 37LFX HCI 3.2 mg 36 36 36 36Placebo 24 24 24 24

70605040

-20-30-40-50

20100

-10

30

Day 1 Day 7 Day 8 Day 14

Mea

n of

QTc

FC

hang

efr

om B

asel

ine

LFX HCI 2.4 mg LFX HCI 3.2 mg Placebo

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LFX HCI 2.4 mg 252 120 74 37LFX HCI 3.2 mg 251 128 79 36Placebo 162 61 42 25

Study 3-1: Mean of the QTcF Change from Baseline70605040

-20-30-40-50

20100

-10

30

Day 1 Day 7 Day 8 Day 14

Mea

n of

QTc

FC

hang

efr

om B

asel

ine

LFX HCI 2.4 mg LFX HCI 3.2 mg Placebo

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Study 3-1: 30-Day Phone Follow-Up

30-Day Follow-UpN=34557%

Completed Studyn=15746%

Did Not Complete Studyn=18854%

Patient Reported Abstinence n=11875%

Patient Reported Abstinence n=5730%

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Documents

LUCEMYRA (lofexidine) Cl - fda.gov · American Society of Addiction Medicine ... •Black box warning for addiction •Diversion and abuse Off-label Buprenorphine Partial opioid