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· Premier Research is a CRO serving highly innovative biotech, pharmaceutical, and

medical device companies. 

· The company has a wealth of experience in CNS having successfully completed 325 clinical trials in the last five years alone.

 · The company operates in 84 countries and

employs over1,000 professionals

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· 

• Board certified psychiatrist with long experience in neuroscience research and clinical treatment of psychiatric disorders and addictions

• Post-doctoral training at National Institutes of Health (NIH/NIAAA)

• Residency at Yale University

• Following graduation he became Assistant Professor at Yale University

• Held clinical appointments at the West Haven VA Medical Center (2001-2006)

• 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)

• 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

• Fellowship in Addiction Psychiatry, University of Pennsylvania 2014-2015

• Staff Psychiatrist (part-time), Crozer-Chester Hospital, Chester, PA 2015 - current

• Recipient of many research and clinical awards and authored or co-authored over 60 scientific original publications

Jaakko Lappalainen, MD, PhDExecutive Director, Global Drug DevelopmentNeuroscience at Premier Research

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Challenges in Medication Development for Addictions

SPEAKER:

Executive Director, Premier ResearchJaakko Lappalainen, MD, PhD

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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 Review of challenges when developing medications for addictions

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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 Effective medical treatments available

McLellan et al., 2000; www.drugabuse.gov

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Drug/Alcohol Use Disorders: DSM-V definition

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

Severity Mild: 2-3 symptoms Moderate: 4-6 symptoms Severe: 6 or more

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Drug Addictions are Common

Specific illicit drug dependence or abuse in the past year age >12SAMHSA National Survey on Drug Use and Health 2013; US data

SedativesInhalants

HallucinogensTranquilizers

StimulantsHeroin

CocainePain Relievers

Marijuana

0 1,000 2,000 3,000 4,000 5,000

99132

277423469517

8551,879

4,206

Numbers in Thousands

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Recent Data Shows Increase in Heroin Addiction and Overdose Deaths

CDC Vital Signs 10 July 2015

Rates of past-year heroin abuse or dependence and heroin-related overdose deaths — US, 2002–2013

Heroin-related overdose deaths

increased by 286% from 2002 to 2013

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Alcohol Use Disorder (AUD) is Common in the US

Alcohol Dependence life-time prevalence in the United States = 29.1%

19.8% ever sought treatment 88,000 people die annually from

alcohol-related causes Third leading preventable cause of death

in the United States Economic burden in the US $223.5 billion 10% of children live with an alcoholic

parent

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B Grant et al., 2015 JAMA Psychiatry, www.niaaa.gov

Lifetime AUD Diagnosis Past 12-month AUD

Diagnosis

Any 29.1% Any 13.9%

Mild 8.6% Mild 7.3%

Moderate 6.6% Moderate 3.2%

Severe 13.9% Severe 3.4%

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Tobacco is Still the Biggest Killer but the Rates of Smoking are Slowly Declining

“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”

MMWR 28 November 2014

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Cannabis Use Rates are Increasing

20022003

20042005

20062007

20082009

20102011

20122013

0123456789

4.8 4.9 4.9 5.1 5.1 5.15.5

6.26.9 7.1

7.68.1

3.1 3.1 3.2 3.4 3.13.6 3.9 4.1

4.65

5.4 5.7

Used Marijuana on 300 orMore Days in the Past Year

Daily or Almost Daily Marijuana Use in the Past Year and Past Month among Persons Aged 12 or Older: 2002-2013

SAMHSA National Survey on Drug Use and Health 2013; US data

Num

bers

in m

illio

ns

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FDA Approved Medications to Treat Addictions

Opioid addiction

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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How do these medications work?

4 are receptor agonists (“re-placement”)

4 work through other CNS mecha-nism (e.g. GABA,

dopamine, receptor blockade)

1 is aversive Methadone Buprenorphine (naloxone) Nicotine replacement Varenicline

Naltrexone Acamprosate Bupropion Naloxone

Disulfiram

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What are the end-points that FDA has accepted for addiction studies?

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Endpoint for Opioid Addiction

“The proportion of urine samples that were negative for opiates was greater in the combined-treatment (buprenorphine/naloxone) and buprenorphine groups (17.8% and 20.7%, respectively) than in the placebo group (5.8%, p<0.001 for both comparisons)”

Fudala at el, N Engl J Med 2003;349:949-58

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Endpoint for Smoking Cessation

FDA Varenicline Medical Review

“…abstinence throughout treatment following pharmacologically-justified grace period”

Primary end point: carbon monoxide- confirmed abstinence

(self-report)

Gonzalez at el, JAMA. 2006;296(1):56-63. doi:10.1001

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Endpoint for Alcoholism

“trials showing a difference in the proportion of patients who attain or sustain abstinence may support an indication of treatment of 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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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 Dual diagnosis

Be a TRAILBLAZER

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Challenges

Patient

Regulatory

Operational

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Patient Challenges

Stigma Lack of support Traditional treatment approaches often do not support medications Relapse & Retention in Treatment Poly-substance use

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Retention in Treatment in Opioid Use Disorder

Kakko at el, The Lancet. 2003; 361: 662–68.

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Use of Multiple Substances is Common

National Survey on Drug Use and Health (NSDUH), 2011-2013CDC Vital Signs: http://www.cdc.gov/vitalsigns/heroin/index.html

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Regulatory Challenges

No regulatory pathway for many forms of addiction treatments Lack of interest by large pharmaceutical companies in addictions

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Operational Challenges

Detoxification before the treatment trial Patient retention Compliance with the study drug Scheduled study drug Abuse liability of the study drug

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Poor Adherence to Study Medication Can Obscure Results

“... Post-hoc vigabatrin urine concentration levels suggested that approximately 40% to 60% of the patients taking Vigabatrin may not have been adherent…”

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Abuse Liability & Diversion

Sponsors should make every effort to do the following:

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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Summary

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Huge unmet medical need Public awareness Recent advances Opportunities in this area A lot of work still to be done Understand the challenges

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· Jaakko Lappalainen, MD, PhDExecutive Director, Global Drug DevelopmentNeuroscience at Premier Research

Q&A Type in your questions using the chat box at the bottom of the control panel on the right side of your screen

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· Additional Questions:

info@premier-research.com

Email: info@premier-research.com

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