Medications Development Update The Division of Treatment Research and Development National Institute on Drug Abuse National Advisory Council On Drug Abuse.

Medications Development Update

The Division of Treatment Research and DevelopmentNational Institute on Drug Abuse

National Advisory Council On Drug Abuse

May 22, 2003

Frank Vocci, Ph.D.

Beginnings of Drug Abuse Research

• Harrison Narcotics Act of 1914

• Physicians could only prescribe narcotics for the treatment of disease

• Narcotic addiction NOT considered a disease (antibody theory dispelled)

• 1919 Legal challenges upheld the Harrison Narcotic Act

• Treatment clinics shut down

Beginnings of Drug Abuse Research

• NAS/NRC “Committee on Drug Addiction” in 1929

• Proposed a program :

- Analyze literature on addictive alkaloids

- Formulate rules for legitimate use

& education of physicians and public

- Develop non-addicting replacements for morphine/codeine and cocaine

• Impetus for Lexington / ARC

Therapeutics of Narcotic Addiction

Dole, Nyswander, and Kreek-

• Proposed addiction to be a change in brain from prolonged exposure to opiates

• Looked for an orally active, long acting opiate that would manage withdrawal and craving

• Started evaluating methadone in the early 1960s

The Narcotic Treatment Program System

• System flourished as a research enterprise• FDA issued INDs for methadone to treat

opiate addiction• Ruling – researchers were required to submit

annual reports, and strict requirements were imposed on entry criteria, dose, and duration of treatment

The Narcotic Treatment Program System

• Initial regulations published: December 1972 …allowed methadone to be dispensed in approved programs …with revisions in 1980, 89, 93 to change tx requirements and approval of LAAM

• Narcotic Addict Treatment Act, 1974• Institute of Medicine, 1995 – recommended that

regulations be replaced with practice guidelines and minimal regulations – accreditation model (FDA and SAMHSA)

• Most recent regs…2001 Opiate Treatment Programs (OTPs)

Narcotic Addiction, The TreatmentGap, and The Public Health Imperative –

Early 1990’s

• 800,000 chronic opiate users in need of treatment• At best, @ 150,000 in all forms of opiate treatment• About 650 - 700,000 users not in treatment• All causes mortality @ 3.5 percent per year• HIV seroprevalence noted to be high in addicts in

East Coast cities ( NYC = 50%) • New treatments and /or new modalities needed

Work with FDA to Assure Efficacy of Compounds is Expeditiously Evaluated

and Approved

Conduct Studies to Gain Approval of New Medicines for Addiction Treatment

Establish Close Working Relationship with Industry

Program Mission of theMedications Development Program

National Program of Biological and Pharmacological Approaches re: Heroin

and Cocaine AddictionMedications Development

Division Established

March, 1990

Initial Medications Program – Early 90’s Operations

• LAAM, buprenorphine, depot naltrexone• Cocaine Pharmacotherapy program-

– Clinical effort …Grantees used primarily marketed medications in clinical studies

– Cocaine Treatment Discovery Program started with advice from PMA group

– Established series of contracts for in vitro and in vivo tests

– Met with industry, academic, and government sources soliciting compounds to test

• Meetings with FDA re development issues

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LAAM

LAAM

• Multicenter trials 1970s…4600 patients• New IND filed in 1991 …one Phase III trial and a PK

study were conducted • Following the collective review of dosing experience

in over 5,000 patients, LAAM was approved for marketing in the US in 1993

• FDA review & approval in 18 days• New York and California took 4 years to implement

LAAM into OTPs• 421 of an estimated 900 OTPs have registered to

dispense LAAM

LAAM

• Roxanne Laboratories, the US distributor of LAAM, estimates that 5100 patients are currently using LAAM

• LAAM has not been useful in narrowing the "treatment gap”

• Eissenberg et al 1997, tested LAAM at several doses- retention equal across groups- dose-related decrease in opiate use

• Recently received “Black Box” warning from US FDA for “ toursade de pointes” arrhythmia ( 10 episodes out of 33, 000 patient exposures)

Narcotic Addiction, The TreatmentGap, and The Public Health Imperative

• 980,000 chronic opiate users in need of treatment• At best, 280,000 in all forms of opiate treatment• LAAM introduction did not add substantially to an increase in treatment figures• About 700,000 users not in treatment• All causes mortality @ 3.5 percent per year• 50% of all new HIV seroprevalence (@ 20,000 infections)• HCV prevalence in narcotic addict population (90-95%)• New treatments and /or new modalities needed

Buprenorphine

Mu Opiate Partial Agonist

• Ceiling effect imparts safety

• Less respiratory depression

• Less risk of overdose

• Less physical dependence capacity

• Naloxone added to reduce abuse liability

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Missing Counted Positive

OPIATES

32%

19%

4%

26%

19%

2%

Bup BupM60 M60M20 M20

Study #999A: Buprenorphine’s Effect on Opiate Use

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Buprenorphine Status

• Buprenorphine Products Mono (SUBUTEX) and combo (SUBOXONE)– Approved by FDA in October 2002

• DATA of 2000 allows qualified physicians to prescribe FDA approved opiates for opiate addiction

• New mode of therapy… office-based

• Ongoing studies in clinics, studies ongoing in pregnant women

Opiate Medications in Development

Opiate Phase I Phase II Phase IIIBuspirone Buprenorphine Buprenorphine

Butorphanol Bupropion SR Buprenorphine/Naloxone

Cycloserine Clonidine LAAM

Depot Naltrexone Depot Naltrexone Lofexidine

Enadoline Desipramine

Hydromorphone Lofexidine

Lamotrigine Memantine

Tramadol Methlyphenidate

Naltrexone

Nefazodone

Depot Naltrexone

• Oral naltrexone has been available for over 15 years

• Depot dosage forms are desirable due to treatment adherence issues

• Naltrexone has been shown to reduce relapse in a criminal justice population

Drug Delivery Systems: Depot Naltrexone(resulting from SBIR & contract programs)

BiotekPhase 1 & 2A (Safety, PK, heroin challenge) completedPhase 2 (outpatient trial, 60 subjects): completed

• Kleber ( NY) & O’Brien ( PA)

Alkermes Phase 1 (Safety and PK): Completed Phase 2A (Efficacy) : Initiated at IRP

Drug Abuse Sciences Phase 1 & 2A (PK and heroin challenge) : completed

Lofexidine

• Alpha 2 agonist similar to clonidine

• Less hypotensive effects

• Phase III trial of 3.2 mg lofexidine versus placebo in an opiate dependent population undergoing withdrawal halted by DSMB……………………… due to overwhelming efficacy

• May be tested for prevention of relapse

Medications Development- The Present

• With approvals of LAAM and the buprenorphine products we are shifting towards developing meds for cocaine addiction …and more recently, methamphetamine addiction

• Dual strategy will still be employed

Current Market for Cocaine Treatment

• 2 million people are addicted or heavy users

• On any given day; 250,000 are enrolled in treatment and 11,500 centers provide treatment

• 40% are enrolled in primary treatment and 60% are enrolled in secondary treatment

• 2 billion total spending per year, $23 per patient per day enrolled (including inpatient and outpatient), $9 per day for non-intensive outpatients

“TOP DOWN” APPROACH

“BOTTOM UP”APPROACH

Marketed medications with goodrationale to test in addicted subjects

• Cocaine pharmacotherapies• MCTG approaches • Don’t need FDA Approval for physicians to prescribe

A basic science, discovery, driven process

• Biochemical studies• Behavioral studies

Medications to Treat Stimulant Addiction

CocainePhase I Phase II Phase IIICCKB - Food Effects Amantadine DisulfiramCCKB - Interaction Amlodipine Selegiline TSCocaine Vaccine BaclofenGBR 12909 Bupropion Planneddisulfiram Cabergoline BaclofenMetyrapone DisulfiramModafinil FluoxetineNS 2359 GabapentinQuitiapine Isradipine

L-dopa+carbidopa Memantine

Planned MethylphenidateBP 4897 NaltrexoneDAS 431 OndansetronGVG Oxazepam Biostream ProgesteroneCabergoline Propranolol

ReserpineTaurineTiagabineTriazolamVenlafaxine

Cocaine Medications in Development

Top Down Approach

• In placebo controlled, blinded trials the following medications have shown some evidence of efficacy:• Disulfiram• Amantadine and propranolol• Baclofen• Naltrexone

• CREST trials (2-3 meds with a placebo)• Cabergoline, reserpine, tiagabine, and sertraline

Top Down Approach

• Follow up studies are being conducted or planned for :– Disulfiram (MCT planned for ‘04)– Baclofen (MCT planned for summer/late fall)– Amantadine and propranolol (SST ongoing)– Cabergoline (SST ongoing)– Reserpine (SST ongoing)– Tiagabine (SST ongoing)– Phase 1 studies (aripiprazole, GVG, cabergoline,

disulfiram)– Phase 2 studies (modafinil)

Top Down Approach

• Cocaine pharmacotherapies-

• Interactions with Behavioral Therapies in

2 x 2 study designs :– Naltrexone and RP (Schmitz/ Grabowski)– Desipramine and CM (Kosten/ Oliveto)

• Suggests interplay with cognitive processes

Stop signal reaction time (ms)100

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Turner et al 2003

Stop signal reaction time (ms)100

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Turner et al 2003

Medication Effect on a Prepotent Response-Modafinil GO/STOP SSRT

Mean errors on 'go' trials

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Mean errors on 'go' trials

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Modafinil STOP ‘mean go errors’

Bottom Up “ Translational” Research

• Translation of laboratory findings to clinical studies

• Relies on behavioral, biochemical and neuroimaging techniques

• Dopamine transporter inhibitors have been a program target for 10 years

• May have multiple mechanisms of efficacy

• High affinity for Dopamine Transporter• Slow onset of action & slow dissociation• Modest elevations in intrasynaptic DA at doses (ED80 = 1 mg/kg) that suppress cocaine self-administration in non-human primates• Antagonizes cocaine-induced increases in intrasynaptic DA

GBR 12909

GBR 12909 and Cocaine

GBR 12909

• Currently being evaluated in cocaine experienced individuals for effects on the cardiovascular system and for interactions with cocaine

• Assuming no safety problems arise, GBR 12909 will be tested in outpatients for effectiveness to reduce cocaine use

New Directions in Medications Development for Cocaine Dependence

Modulation of factors that may maintain addiction or increase probability of relapse :

• Cue - induced craving• Priming• Stress• Negative affective states/ depression• Weakened frontal cortex inhibitory states• Altered neurotransmitter levels/ allostasis

New Meds- Mechanisms of Interest Based on Neuroscience Discoveries• Dopamine stabilizers (Aripiprazole, Carlsson compounds)• D1 agonists, D3 partial agonists and antagonists• CRF antagonists• CB1 antagonists• Kappa opioid antagonists• GABA B “agonists” (allosteric modulators)• MGluR 2/3 agonists, M GluR 5 antagonists• NMDA modulators (Glycine agonists)• 5-HT 3 antagonists• Modafinil

Cannabinoid AntagonistBlockade of Priming and Cueing

Immunization Strategies

Ongoing Funded Projects

Active and passive immunization using anti-cocaine antibodies and anti-cocaine catalytic antibodies (Janda, Scripps)

Cocaine vaccine (Xenova, UK)

Passive immunization using anti-PCP monoclonal antibodies (Owens, Univ. Arkansas)

Passive immunization using anti-cocaine monoclonal antibodies (Norman, Univ. Cincinnati)

Passive immunization using anti-methamphetamine monoclonal antibodies (Owens, Gentry)

Development of immunotherapies using:

Nicotine vaccine (NicVax, NABI, Rockville)

The Division of Treatment Research and Development

Established in 1999

• Medications Development

• Behavioral Therapies

• Clinical Neurobiology

New Programmatic Initiatives

Expansion of methamphetamine program– Methamphetamine epidemic in western US– Created a new clinical trial group to perform methamphetamine pharmacotherapy trials– Created a new discovery program similar to CTDP

San Diego, CA

South Bay Treatment Center

Joseph Mawhinney, PI

Methamphetamine Clinical Trials Group (MCTG)

Costa Mesa, CA

Roger Donovick, PI

Des Moines, Iowa / Powell Chemical Dependency CTR

Dennis Wise, PI

Kansas City, MOComprehensive Medical Health

Services, Inc.Jan Campbell,

Charles Gorodetzky, PIs

Honolulu, HIJohn Burns School of MedicineWilliam Haning, PI

Los Angeles, CAUCLA Coordinating Lead SiteRick Rawson, Steve Shoptaw &Thomas Newton, PIs

Methamphetamine Phase I Phase IIBupropion BaclofenDisulfiram GabapentinLobeline IsradipineReserpine OlanzapineSelegiline Ondansetron

SelegilinePlanned VenlafaxineAripiprazole

Methamphetamine Medications in Development

Medications for Methamphetamine-Bottom up Approach

Three strategies:

• Based on the pharmacology of methamphetamine

• Based on the pharmacology of cocaine and medications or interventions altering its effects

• Based on the addictive processes that may be common to all drugs of abuse

Lobeline Blocks Methamphetamine Self- Administration

Discovery Programs

Clinical Programs – Drug Specific

Integration of Medications with Behavioral Therapy

Beyond Opiates and Cocaine

Informatics

Medications Development

Program

2003

Current Programs and Future Initiatives

Beyond Opiates & Cocaine: Development of Medications for

Smoking Cessation

• Although the division has grants evaluating already marketed smoking cessation treatments, the only development project we have is the Nicotine Vaccine project (NicVAX®)

• Multiple non-nicotinic molecular targets could be evaluated

• Other NIH institutes interested • Pharmaceutical companies interested in

partnering with NIDA

The Smoking-Gun`

http://www.drkoop.com/wellness/tobacco/smoking-gun.asp

Medications Development Summary

• Progress in Development of Opiate and Cocaine Pharmacotherapies

• Immunological Therapies Progressing• Interactions of Medications with Behavioral

Therapies• Methamphetamine Epidemic and

Rapid Treatment Research Response• Augmented Smoking Cessation Program ?

Number of moves

Mean attempts taken to correctly solve problem0.8

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Turner et al 2003Number of moves

Mean attempts taken to correctly solve problem0.8

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PlaceboLowHigh

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Turner et al 2003

Medication Effects on Frontal Lobe Processes - Modafinil NTOL Mean Attempts

Number of moves

1 2 3 4 5 6

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Turner et al 2003Number of moves

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Modafinil NTOL Latency