Transcript The company has a wealth of experience in rare

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· Premier Research is a CRO serving highly
innovative biotech, pharmaceutical, and
medical device companies.
· The company operates in 84 countries and
employs over1,000 professionals
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Confidential | © 2014 Premier Research, LLC | Version 1.0
· The company has a wealth of experience in
CNS having successfully completed 325
clinical trials in the last five years alone.
Jaakko Lappalainen, MD, PhD
Executive Director, Global Drug Development
Neuroscience at Premier Research
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Board certified psychiatrist with long experience in neuroscience research and clinical treatment of
psychiatric disorders and addictions
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Post-doctoral training at National Institutes of Health (NIH/NIAAA)
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Residency at Yale University
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Following graduation he became Assistant Professor at Yale University
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Held clinical appointments at the West Haven VA Medical Center (2001-2006)
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Joined AstraZeneca where he specialized in the design, execution and interpretation of clinical trials
across Phase I-III development in the CNS therapeutic area (2006)
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Lead physician for Phase 3 development of naloxegol (Movantik®) and played a key role in the
regulatory submission of naloxegol in US, Europe and Canada 2010-2014
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Fellowship in Addiction Psychiatry, University of Pennsylvania 2014-2015
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Staff Psychiatrist (part-time), Crozer-Chester Hospital, Chester, PA 2015 - current
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Recipient of many research and clinical awards and authored or co-authored over 60 scientific
original publications
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Confidential | © 2014 Premier Research, LLC | Version 1.0
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Challenges in Medication
Development for Addictions
Jaakko Lappalainen, MD, PhD
Executive Director, Premier Research
Confidential | © 2014 Premier Research, LLC | Version 1.0
SPEAKER:
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Challenges in Medication Development for Addiction
 Background on addictions
 Overview of medications that have been developed for addictions
 FDA accepted study endpoints
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 Review of challenges when developing medications for addictions
Addiction Is Similar to Other Chronic Diseases
 Pathophysiology understood
 Chronic relapsing-remitting course
 Combination of genes and environment
 Heritability 30-60%
 Bad outcome if left untreated
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McLellan et al., 2000; www.drugabuse.gov
Confidential | © 2014 Premier Research, LLC | Version 1.0
 Effective medical treatments available
Drug/Alcohol Use Disorders: DSM-V definition
Severity
 Mild: 2-3 symptoms
 Moderate: 4-6 symptoms
 Severe: 6 or more
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Symptoms
 Tolerance
 Craving
 Withdrawal
 Larger amounts taken than intended
 Unsuccessful efforts to cut down
 A great deal of time spent in opioid activities
 Failure to fulfill role obligations
 Continued use despite social problems
 Important activities given up
 Continued use despite medical and psychological problems
 Recurrent use in hazardous situations
Drug Addictions are Common
Marijuana
Pain Relievers
Cocaine
Heroin
Stimulants
Tranquilizers
Hallucinogens
Inhalants
Sedatives
4,206
1,879
855
0
1,000
2,000
3,000
4,000
Numbers in Thousands
Specific illicit drug dependence or abuse in the past year age >12
SAMHSA National Survey on Drug Use and Health 2013; US data
5,000
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Confidential | © 2014 Premier Research, LLC | Version 1.0
517
469
423
277
132
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Recent Data Shows Increase in Heroin
Addiction and Overdose Deaths
Rates of past-year heroin abuse or dependence and
heroin-related overdose deaths — US, 2002–2013
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CDC Vital Signs 10 July 2015
Confidential | © 2014 Premier Research, LLC | Version 1.0
Heroin-related
overdose deaths
increased by 286%
from 2002 to 2013
Alcohol Use Disorder (AUD) is Common in the US
 Alcohol Dependence life-time prevalence in
the United States = 29.1%
 88,000 people die annually from
alcohol-related causes
Lifetime AUD Diagnosis
Past 12-month AUD
Diagnosis
Any
29.1%
Any
13.9%
 Economic burden in the US $223.5 billion
Mild
8.6%
Mild
7.3%
 10% of children live with an alcoholic
parent
Moderate
6.6%
Moderate
3.2%
Severe
13.9%
Severe
3.4%
 Third leading preventable cause of death
in the United States
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B Grant et al., 2015 JAMA Psychiatry, www.niaaa.gov
Confidential | © 2014 Premier Research, LLC | Version 1.0
 19.8% ever sought treatment
Tobacco is Still the Biggest Killer
but the Rates of Smoking are Slowly Declining
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MMWR 28 November 2014
Confidential | © 2014 Premier Research, LLC | Version 1.0
“Current cigarette smoking among
U.S. adults declined from 20.9% (an
estimated 45.1 million persons) in
2005 to 17.8% (42.1 million) in
2013”
Cannabis Use Rates are Increasing
Daily or Almost Daily Marijuana Use in the Past Year and
Past Month among Persons Aged 12 or Older: 2002-2013
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7
5
7.1
6.2
4.8
3.1
4.9
3.1
4.9
5.1
3.2
3.4
5.1
3.1
5.1
3.6
5.5
3.9
4.1
4.6
5
5.4
8.1
5.7
3
1
-1
Used Marijuana on 300 or…
Used Marijuana on 20 or…
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SAMHSA National Survey on Drug Use and Health 2013; US data
Confidential | © 2014 Premier Research, LLC | Version 1.0
Numbers in millions
6.9
7.6
FDA Approved Medications to Treat Addictions
 Methadone
 Buprenorphine
 Naltrexone depot
IM
 Naloxone (OD only)
Alcoholism




Naltrexone oral
Naltrexone depot IM
Acamprosate
Disulfiram
Tobacco
 Nicotine
Replacement
 Varenicline
 Bupropion
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Opioid addiction
How do these medications work?
 Disulfiram
1 is aversive




Methadone
Buprenorphine (naloxone)
Nicotine replacement
Varenicline




4 work through
Naltrexone
other CNS
Acamprosate
mechanism (e.g.
Bupropion
Naloxone
GABA, dopamine,
receptor
blockade)
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Confidential | © 2014 Premier Research, LLC | Version 1.0
4 are receptor
agonists
(“replacement”)
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Confidential | © 2014 Premier Research, LLC | Version 1.0
What are the end-points that FDA
has accepted for addiction studies?
“The proportion of urine samples that were
negative for opiates was greater in the combinedtreatment (buprenorphine/naloxone) and
buprenorphine groups (17.8% and 20.7%,
respectively) than in the placebo group (5.8%,
p<0.001 for both comparisons)”
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Fudala at el, N Engl J Med 2003;349:949-58
Confidential | © 2014 Premier Research, LLC | Version 1.0
Endpoint for Opioid Addiction
Endpoint for Smoking Cessation
Primary end point: carbon
monoxide- confirmed abstinence
(self-report)
Gonzalez at el, JAMA. 2006;296(1):56-63. doi:10.1001
FDA Varenicline Medical Review
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Confidential | © 2014 Premier Research, LLC | Version 1.0
“…abstinence throughout treatment
following pharmacologicallyjustified grace period”
Endpoint for Alcoholism
We believe analyses of existing data also support the use of another valid surrogate
endpoint defined by a pattern of reduced drinking, described as no heavy drinking
days. Heavy drinking days are defined by the National Institute on Alcohol Abuse and
Alcoholism (NIAAA) as days when the patient consumes more than four standard
drinks (men) or more than three standard drinks (women).”
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Confidential | © 2014 Premier Research, LLC | Version 1.0
“trials showing a difference in the proportion of patients who attain or sustain
abstinence may support an indication of treatment of alcoholism.…
Addictions for which there are no Approved Medications
 Stimulant (cocaine/methamphetamine) Use Disorder
 Sedative/Anxiolytic/Hypnotic Use Disorder (benzodiazepines)
 Cannabis Use Disorder
 Hallucinogen Use Disorder
Be a TRAILBLAZER
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 Dual diagnosis
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Challenges
 Patient
 Regulatory
 Operational
Patient Challenges
 Stigma
 Lack of support
 Traditional treatment approaches often do not support medications
 Relapse & Retention in Treatment
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 Poly-substance use
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Kakko at el, The Lancet. 2003; 361: 662–68.
Confidential | © 2014 Premier Research, LLC | Version 1.0
Retention in Treatment in Opioid Use Disorder
National Survey on Drug Use and Health (NSDUH), 2011-2013
CDC Vital Signs: http://www.cdc.gov/vitalsigns/heroin/index.html
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Use of Multiple Substances is Common
Regulatory Challenges
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 No regulatory pathway for many forms of addiction treatments
 Lack of interest by large pharmaceutical companies in addictions
Operational Challenges
 Detoxification before the treatment trial
 Patient retention
 Compliance with the study drug
 Scheduled study drug
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 Abuse liability of the study drug
Poor Adherence to Study Medication Can Obscure Results
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Confidential | © 2014 Premier Research, LLC | Version 1.0
“... Post-hoc vigabatrin urine concentration
levels suggested that approximately 40% to
60% of the patients taking Vigabatrin may not
have been adherent…”
Abuse Liability & Diversion
1. Set criteria, collect data, and tabulate the abuse, misuse, noncompliance, and
diversion cases across the studies and study sites with special attention to
aberrant drug behaviors that may be indicative of drug abuse, misuse and/or
diversion.
2. Provide complete information, including case report forms and final outcomes,
on all instances of addiction, abuse, misuse, overdose, drug diversion/drug
accountability, discrepancies in amount of the clinical supplies of the study
drug, noncompliance, protocol violations, lack of efficacy, individuals lost to
follow-up, and any other reasons why subjects dropped out of the study.
3. Provide information on the risks of addiction, abuse, misuse, overdose, and
drug diversion in the study populations.
Pertinent data can include measurements of drug accountability, tolerance,
physical dependence, or withdrawal symptoms…
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Sponsors should make every effort to do the following:
Summary
 Huge unmet medical need
 Public awareness
 Recent advances
 Opportunities in this area
 A lot of work still to be done
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Confidential | © 2014 Premier Research, LLC | Version 1.0
 Understand the challenges
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Confidential | © 2014 Premier Research, LLC | Version 1.0
premier-research.com
·
Jaakko Lappalainen,
MD, PhD
Executive Director, Global Drug Development
Neuroscience at Premier Research
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Q&A
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Additional Questions:
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[email protected]
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Confidential | © 2014 Premier Research, LLC | Version 1.0
Email: [email protected]
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