Medications Development Update The Division of Treatment Research and Development National Institute on Drug Abuse Natio

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 early1960s

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 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

8. Medications Development Division Established March, 1990 Program Mission of the Medications Development Program National Program of Biological and Pharmacological Approaches re: Heroin and Cocaine Addiction 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 N C H C H C H 2 3 2 C H C H C H O 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 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

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. 30 25 20 % Ss with 13 Consecutive Opiate Free Urines 15 10 5 0 1 4 8 16 Buprenorphine Dose (mg) Study #999A: Buprenorphine’s Effect on Opiate Use

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. Marketed medications with good rationale 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 “TOP DOWN” APPROACH “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 12909 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 12909 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 AntagonistBlockade 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