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Notice

Opportunity for a Cooperative Research and Development Agreement (CRADA) for Research and Development of Vigabatrin as a Potential Pharmacotherapy for the Treatment of Cocaine and Methamphetamine Dependence

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AGENCY:

National Institutes of Health, PHS, DHHS.

ACTION:

Notice.

SUMMARY:

The National Institute on Drug Abuse, a component of the National Institutes of Health, Department of Health and Human Services (DHHS) seeks an agreement with a pharmaceutical or biotechnology company to test the hypotheses that vigabatrin may be a safe and effective medication for the treatment of cocaine and methamphetamine dependence.

A body of literature relevant to preclinical studies of vigabatrin as a potential treatment agent for various types of substance dependence (including cocaine and methamphetamine) and a more limited body of literature concerning clinical results exists. As there are currently no medications approved by the U. S. Food and Drug Administration (FDA) for the treatment of cocaine and/or methamphetamine dependence, and cocaine and methamphetamine dependence have substantial negative public health impacts, the National Institute on Drug Abuse is interested in evaluating the safety and efficacy of vigabatrin for the treatment of cocaine and methamphetamine dependence. Start Printed Page 29331

Rationale for Studying Vigabatrin in Stimulant(s) Dependence

The dependence-producing properties of stimulants have been associated with their pharmacological actions on the mesolimbic dopamine reward pathways in the central nervous system (CNS). Gamma-amino butyric acid (GABA) inhibits striatal dopamine release, and attenuates cocaine-induced increases in extracellular dopamine in the striatum and nucleus accumbens (Molina et. al., 1999). Selective increases in GABAergic tone attenuate cocaine-induced dopamine release without the apparent side effects typically associated with GABA agonists. Therefore, targeting brain GABAergic systems is a potentially effective pharmacologic treatment strategy for cocaine and methamphetamine dependence (Molina et. al., 1999). Data from proof of concept clinical trials of similar GABAergic medications e.g. topiramate, baclofen, and tiagabine show efficacy in reducing cocaine use or in preventing relapse to use. These data suggest that vigabatrin, which possesses more potent GABAergic action, may be more efficacious than these medications. Preclinical studies in animal models have confirmed that dosing with vigabatrin can block the manifestations of consumption of cocaine typically seen in these models (Stromberg et. al., 2001), without impairing the usual dopamine mechanisms necessary to maintain a stable equilibrium. In rodent models, vigabatrin has been shown to reduce self-administration of cocaine and alcohol (Stromberg et. al., 2001; Kushner et al., 1999), and to block conditioned place preference induced by cocaine (Dewey et. al, 1998), nicotine (Dewey et. al., 1999), and heroin (Paul, et. al., 2001). Further, vigabatrin can reduce the increases in nucleus accumbens dopamine induced by cocaine (Schiffer et. al., 2003), as well as methamphetamine, heroin, and ethanol (Gerasimov et. al., 1999).

Vigabatrin (GVG) is an irreversible gamma-amino butyric acid (GABA) transaminase inhibitor that produces a two to three fold rise in brain GABA concentrations (Guberman et. al., 2000). Following oral administration, vigabatrin readily crosses the blood-brain barrier and is active within the central nervous system. It has been shown to be effective, both as an add-on agent and in monotherapy in resistant and newly-diagnosed epilepsy (Guberman et. al., 2000) and as first line monotherapy in the treatment of infantile spasms (West syndrome) (Hancock et. al., 1999). After oral dosing, vigabatrin is well absorbed (bioavailability c. 75%) and widely distributed. The drug is eliminated primarily by the renal route and is not significantly bound to plasma proteins. The elimination half-life is approximately 5-9 hours in healthy subjects and may be prolonged in elderly patients or those with impaired renal function (Rey et. al., 1992). The usual adult dose of vigabatrin for epilepsy is 1-3 g/day. There is no evidence that plasma concentrations of vigabatrin correlate closely with therapeutic effects (Brodie et. al., 2003).

There are anecdotal reports that dosing with vigabatrin prevents the “high” associated with cocaine intake in humans dependent on cocaine and can, therefore, result in decreased cocaine consumption. Two open label pilot studies suggest a therapeutic effect in most patients recruited in abstaining from cocaine or methamphetamine (Brodie et. al., 2005) use (Brodie et. al., 2003; Brodie et. al., 2005).

Therefore, it may be predicted that dosing with vigabatrin in a cocaine dependent population might prevent the cocaine “high” and the subsequent “craving”, and possibly reduce the perceived need for repeated use, and often higher, drug doses (Dewey et. al., 1999).

As an initial step in the clinical development of vigabatrin for stimulants dependence, it is important to assess the potential efficacy and safety of this compound in cocaine and methamphetamine dependent subjects.

References

Brodie JD, Figueroa E, Dewey SL (2003). Treating cocaine addiction: From preclinical to clinical experience with gamma-vinyl GABA. Synapse 50: 261-265.

Brodie JD, Figueroa E, Lasha EM, Dewey SL (2005). Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and cocaine addiction. Synapse 55(2): 122-125.

Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, Ashby CR (1999). A pharmacological strategy for the treatment of nicotine addiction. Synapse 31: 76-86.

Dewey SL, Morgan SE, Ashby CR, Horan B, Gardner EL, Brodie JD (1998). A novel strategy for the treatment of cocaine addiction. Synapse 30: 119-129.

Gerasimov MR, Ashby CR, Gardner EL, Mills MJ, Brodie JD, Dewey SL (1999). Gamma-Vinyl GABA inhibits methamphetamine, heroin, or ethanol-induced increases in nucleus accumbens dopamine. Synapse 34: 11-19.

Gillis MC (2005). CPS: Compendium of Pharmaceutical and Specialties (CPS). 37th Edition, Canadian Pharmaceutical Association, Ottawa, pp: 1513-1515.

Guberman A, Bruni J & The Canadian Vigabatrin Study Group (2000). Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. Seizure 9:112-118.

Hancock E, Osborne JP (1999). Vigabatrin in the treatment of infantile spasms in tuberous sclerosis. J Child Neurol 14:71-74.

Kushner SA, Dewey SL, Kornetsky C (1999). The irreversible gamma-amino butyric acid (GABA) transaminase inhibitor gamma vinyl-GABA blocks cocaine self-administration in rats. J.Pharmacol ExpTher 290(2): 797-802.

Molina PE, Ahmed N, Ajmal M, Dewey S, Volkow N, Fowler J, Abumrad N (1999). Co-administration of Gamma-Vinyl GABA and Cocaine: Preclinical Assessment of Safety. Life Sciences 11:1175-1182.

Rey E, Pons G, Olive G (1992). Vigabatrin. Clinical pharmacokinetics. Clin Pharmacokinet 23:267-278.

Schiffer WK, Martsteller D, Dewey SL (2003). Sub-chronic low dose gamma vinyl GABA (vigabatrin) inhibits cocaine-induced increases in nucleus accumbens dopamine. Psychopharmacology 168: 339-343.

Stromberg MF, Mackler SA, Volpicelli JR, O'Brien CP, Dewey SL (2001). The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat. Pharmacol Biochem Behav 68:291-299.

DATES:

NIDA will consider all proposals received within 45 days of the date of publication of this notice. This notice is active until July 5, 2005.

ADDRESSES:

Proposals and questions about this opportunity may be addressed to Frank Vocci, Ph.D., Division of Pharmacotherapy and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, 6001 Executive Blvd., MSC 9551, Bethesda, Maryland 20892-9551. For overnight mail service, 6001 Executive Blvd., Room 4123, Rockville, Maryland 20852. Tel: (301) 443-2711, Fax: (301) 443-2599.

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SUPPLEMENTARY INFORMATION:

NIDA will consider proposals from all qualified entities and will, subject to negotiation of the details of a mutually agreed upon Research Plan, provide the CRADA Collaborator access to its comprehensive preclinical and clinical trials resources with the understanding that the CRADA Collaborator will be able to utilize data derived from the CRADA to pursue regulatory filings in the U.S. and abroad. NIDA's Medications Development Program possesses the capacity to perform chemical synthesis, dosage form development, pharmacokinetics, pharmacodynamics, toxicology, regulatory management, and clinical testing (Phase I through Phase III) meeting FDA requirements for Good Manufacturing, Good Laboratory Procedures, and Good Clinical Practices standards. NIDA may apply these capacities in the assessment of vigabatrin, as may be warranted based Start Printed Page 29332on NIDA's evaluation of the information, capacities, and plans provided by potential Collaborator(s).

NIDA follows stepwise development processes and procedures common to the medications development paradigm, i.e., a candidate compound must successfully complete each necessary pre-requisite step prior to being advanced for further testing and development. It is NIDA's intention to provide, assuming pre-requisite preclinical and clinical safety, preclinical and clinical trials services sufficient to permit the completion of Phase II hypothesis testing trials for cocaine and methamphetamine dependence indications. Assuming demonstration and review of safety and efficacy at the conclusion of Phase II trials and subject to negotiation, NIDA will consider undertaking Phase III trials sufficient to permit Collaborator to seek a U.S. New Drug Application (NDA).

Please note that a CRADA is not a funding mechanism. No NIH funding may be provided to a Collaborator under a CRADA. All assistance is provided “in-kind”. Therefore the Collaborator will bear the financial and organizational costs of meeting its share of obligations under any Research Plan that may be negotiated in connection with the CRADA.

“Cooperative Research and Development Agreement” or “CRADA” means the anticipated joint agreement to be entered into by NIDA pursuant to the Federal Technology Transfer Act of 1986 and Executive Order 12591 of October 10, 1987 to collaborate on the specific research project described below.

The National Institute on Drug Abuse seeks an agreement with a pharmaceutical or biotechnology company for joint research, development, evaluation, and potential commercialization of vigabatrin for the treatment of cocaine and methamphetamine dependence.

The CRADA aims include the rapid publication of research results and the timely exploitation of commercial opportunities. The CRADA partner will enjoy rights of first negotiation for licensing Government rights to any inventions arising under the agreement and will advance funds payable upon signing the CRADA to help defray Government expenses for patenting such inventions and other CRADA-related costs.

The expected duration of the CRADA will be 3 to 5 years.

Selection criteria for choosing the CRADA partner will include but not be limited to:

1. Ability to collaborate with NIDA on further research and development of this technology in Phase I and Phase II clinical studies. All such studies will occur in the United States and under FDA IND rules. Demonstration of experience and expertise in this or related areas of technology and the ability to provide intellectual contribution to the ongoing research and development. Ability to accomplish objectives according to an appropriate timetable to be outlined in the Collaborator's proposal. At an absolute minimum, Collaborator must be able to provide vigabatrin and placebo sufficient to complete all clinical and preclinical studies required in the Research Plan.

2. Demonstration of the resources (facilities, personnel and expertise) necessary to perform research, development and commercialization of this technology.

3. Commitment of reasonable effort and resources on research, development and commercialization of this technology.

4. Expertise in the commercial development, production, marketing and sales of products related to this area of technology .

5. The level of financial support, if any, the Collaborator will supply for CRADA-related Government activities.

6. A willingness to cooperate with the National Institute on Drug Abuse in the publication of research results.

7. An agreement to be bound by the DHHS rules involving human subjects, patent rights and ethical treatment of animals.

8. A willingness to accept the legal provisions and language of the CRADA with only minor modifications (if any).

9. Provisions for equitable distribution of patent rights to any inventions made during the course of the subject CRADA research. Generally, the rights of ownership are retained by the organization which is the employer of the inventor, with (1) an irrevocable, nonexclusive, royalty-free license to the Government (when a company employee is the sole inventor) or (2) an option to negotiate an exclusive or nonexclusive license to the company on terms that are appropriate (when a Government employee is an inventor).

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Dated: May 11, 2005.

Steven M. Ferguson,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.

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[FR Doc. 05-10066 Filed 5-19-05; 8:45 am]

BILLING CODE 4140-01-P