1. Medications Development Update
The Division of Treatment Research and Development
National Institute on Drug Abuse
National Advisory Council On Drug Abuse
May 22, 2003
Frank Vocci, Ph.D.

2. 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

3. 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

4. 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

5. 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

6. 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)

7. Narcotic Addiction, The Treatment Gap, and The Public Health Imperative – Early 1990’s
800,000 chronic opiate users in need of treatment
At 150,000 in all forms of opiate treatment
About ,000 users not in treatment
All causes 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

8. Medications Development Division Established
Program Mission of the
Medications Development Program
National Program of Biological and Pharmacological Approaches re: Heroin and Cocaine Addiction
Medications Development Division Established
March, 1990
Establish Close Working Relationship with Industry
Conduct Studies to Gain Approval of New Medicines for Addiction Treatment
Work with FDA to Assure Efficacy of Compounds is Expeditiously Evaluated and Approved

9. 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

10. LAAM C H 3 C H C H C H C H C H N 3 2 2 C H C H O C H 3 3 3 O

11. 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

12. 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)

13. Narcotic Addiction, The Treatment Gap, 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 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

14. Buprenorphine

16. 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

21. Buprenorphine’s Effect on Opiate Use
Study #999A:
Buprenorphine’s Effect on Opiate Use 5 10 15 20 25 30 1 4 8 16
Buprenorphine Dose (mg)
% Ss with 13 Consecutive
Opiate Free Urines

22. 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

23. Opiate Medications in Development

24. 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

25. Drug Delivery Systems: Depot Naltrexone (resulting from SBIR & contract programs)
Biotek
Phase 1 & 2A (Safety, PK, heroin challenge) completed
Phase 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

26. 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

27. 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

29. 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

30. Medications to Treat Stimulant Addiction
Marketed medications with good
rationale to test in addicted subjects
Cocaine pharmacotherapies
MCTG approaches
Don’t need FDA Approval for
physicians to prescribe
“TOP DOWN”
APPROACH
A basic science, discovery,
driven process
Biochemical studies
Behavioral studies
“BOTTOM UP”
APPROACH

31. Cocaine Medications in Development

32. 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

33. 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)

34. 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

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

36. Modafinil STOP ‘mean go errors’

37. 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

38. GBR 12909 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

39. GBR and Cocaine

43. 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 will be tested in outpatients for effectiveness to reduce cocaine use

44. 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

45. 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

46. Cannabinoid Antagonist Blockade of Priming and Cueing

47. Immunization Strategies

48. Ongoing Funded Projects
Development of immunotherapies using:
Active and passive immunization using anti-cocaine
antibodies and anti-cocaine catalytic antibodies
(Janda, Scripps)
Passive immunization using anti-cocaine monoclonal
antibodies (Norman, Univ. Cincinnati)
Passive immunization using anti-PCP monoclonal
antibodies (Owens, Univ. Arkansas)
Passive immunization using anti-methamphetamine
monoclonal antibodies (Owens, Gentry)
Cocaine vaccine (Xenova, UK)
Nicotine vaccine (NicVax, NABI, Rockville)

49. The Division of Treatment Research and
Development
Established in 1999
Medications Development
Behavioral Therapies
Clinical Neurobiology

50. 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

51. Methamphetamine Clinical Trials Group (MCTG)
Des Moines, Iowa / Powell Chemical Dependency CTR
Dennis Wise, PI
Los Angeles, CA
UCLA Coordinating Lead Site
Rick Rawson, Steve Shoptaw &
Thomas Newton, PIs
Kansas City, MO
Comprehensive Medical Health
Services, Inc.
Jan Campbell,
Charles Gorodetzky, PIs
Costa Mesa, CA
Roger Donovick, PI
Honolulu, HI
John Burns School of
Medicine
William Haning, PI
San Diego, CA
South Bay Treatment Center
Joseph Mawhinney, PI

52. Methamphetamine Medications in
Development

53. 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

55. Lobeline Blocks Methamphetamine Self- Administration

56. Medications Development Program
Current Programs and Future Initiatives
Discovery Programs
Clinical Programs – Drug Specific
Medications Development Program
2003
Beyond Opiates and Cocaine
Integration of Medications with Behavioral Therapy
Informatics

57. 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

58. `
The Smoking-Gun

59. 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 ?

60. Medication Effects on Frontal Lobe
Processes - Modafinil NTOL Mean Attempts

61. Modafinil NTOL Latency