# Presentation: 213767

## 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.

## 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 TreatmentGap, 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**

## Program Mission of the

- Conduct Studies to Gain Approval of New Medicines for Addiction Treatment

- Establish Close Working Relationship with Industry

- Medications Development Program

- National Program of Biological and Pharmacological Approaches re: Heroin and Cocaine Addiction

## 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

## LAAM

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## 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 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 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

## Slide 15

## 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

## Slide 17

## Slide 18

## Slide 19

## Slide 20

## Study #999A: 

- Buprenorphine’s Effect on Opiate Use

## 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

## 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)

- 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

## 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

## Slide 28

## 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

## Medications to Treat Stimulant Addiction

**“****TOP DOWN” **
**APPROACH**

**“****BOTTOM UP”**
**APPROACH**

## 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

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

## 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

## GBR 12909

-     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 and Cocaine

## Slide 40

## Slide 41

## Slide 42

## 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 AntagonistBlockade of Priming and Cueing

- 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

## Methamphetamine Clinical Trials Group (MCTG)

- Methamphetamine Clinical Trials Group (MCTG)

**Los Angeles, CA**
**UCLA Coordinating Lead Site**
**Rick Rawson, Steve Shoptaw &**
**Thomas Newton, PIs**

## Methamphetamine Medications in 

- 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

## Slide 54

## Lobeline Blocks Methamphetamine Self- Administration

## Current Programs and Future Initiatives

- Clinical Programs – Drug Specific

- Integration of Medications with Behavioral Therapy

- Beyond Opiates and Cocaine

- Informatics

## 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

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- 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 ?

## Medication Effects on Frontal Lobe 

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

## Modafinil NTOL Latency

## Slide 62