Drug and Market Development

Overview

DrugAbuse Sciences (DAS; Hayward, CA) was founded in 1994 to improve the treatment of alcohol and drug addictions/dependence through the discovery, development, and commercialization of innovative and cost-effective medications. The company’s strategy is to be the leader in technology and providing products for alcohol and substance abuse treatment. DAS’s clinical portfolio includes five products in development, three of which have been developed in the company’s proprietary extended-release depot technology (Lactiz™). In April 2001, DAS competed a $24 million financing, led by Canaan Partners, a new investor, and principally supported by its existing investors, 3i and Nomura Securities. In December 2002, the company will obtain $5 million in government grants. DAS is using the proceeds to execute clinical plans, including the filing of an NDA for Naltrexone Depot for alcohol dependence and development of other products in human clinical trials.

Lead Candidate—Naltrexone Depot

The lead drug candidate at DAS is Naltrexone Depot, which is in Phase III clinical trials as a potential treatment for alcohol dependence. Naltrexone is a pure opioid antagonist that competitively binds two mu opioid receptors in the brain and has no opioid agonist properties. It is approved for use in the US for the treatment of alcohol and opiate dependence and for the blockade of exogenously administered opiates; and it is contraindicated in patients receiving opioid analgesics, in patients currently dependent upon opioids, in patients experiencing acute opioid withdrawal, in anyone who has failed a naloxone challenge test or has a positive urine-screening test for opioids, in anyone with a history of sensitivity to naltrexone, or in anyone with acute hepatitis or liver failure. The precise mechanism of action of naltrexone in the treatment of alcoholism is unknown; however, when used in combination with a comprehensive treatment program, the oral form of naltrexone demonstrates statistically significant reductions in relapse rates in alcoholics. Naltrexone Depot, a long-acting injectable formulation intended for once-per-month administration, was developed in the company’s LACTIZ extended-release injectable technology.

Lactiz™: Extending Release, Increasing Efficacy?

Many studies have shown that extended-release technologies are generally well accepted by patients—including those treated for chronic psychiatric/behavioral disorders—because they offer more convenient dosing regimens. Most drugs currently approved in the US for the treatment of alcohol or opiate addiction require at least once-per-day administration. DAS is developing extended-release therapeutics as part of its mandate to improve the treatment of addictions. Extended release frees patients from the daily decision to take their medication. The clinical goals are to increase medication compliance and, ultimately, efficacy. The company’s Lactiz system is an extended-release injectable drug delivery technology that combines a therapeutic compound within a poly(D,L-lactide) polymer matrix. The combination of drug product within the biocompatible polymer forms a dry powder of microspheres that are formulated into a suspension that can be administered by intramuscular injection. The Lactiz system can be designed to provide timed drug release over periods ranging from 14 to 60 days or longer. DAS is developing three medications in the Lactiz platform: Naltrexone Depot, NALTREL™, and Buprenorphine Depot.

According to DAS’s CEO, Elizabeth M. Greetham, “our six-month data indicate that Naltrexone Depot impacts the compliance problem with more patient retention in the Naltrexone Depot arm than the placebo arm, which is very encouraging.” DAS will present data on Naltrexone Depot the December 2002 Annual Meeting of the American College of Neuropsychopharmacology. The company is hopeful that Naltrexone Depot will lead to increased treatment successes and anticipates significant improvements in the treatment of alcoholism during the next decade through the combination of pharmacologic management and behavioral therapy modules. In October 2001, DAS announced that US Patent #6,306,425 had been issued, covering the company’s extended-release injectable technology for administering naltrexone. The company may find itself in competition with Alkermes, which is also developing a sustained-release naltrexone formulation and which has recently entered Phase III clinical trials.

Candidates for Treating Opiate Addiction

DAS is developing two products in its Lactiz delivery system for the treatment of opiate dependence. The company’s second drug candidate, Naltrel™ (long-acting naltrexone for injection), is in preparation for Phase III clinical trials for the treatment (i.e., prevention of relapse) of heroin addiction. It is intended for once-per-month administration. Naltrexone blocks the euphoric and other effects of opiates such as heroin. The oral, once-daily form is approved in the US for the treatment of opiate dependence. When used in combination with a comprehensive treatment program, oral naltrexone demonstrates statistically significant reductions in relapse rates. Analysis of a Phase IIb clinical trial with Naltrel demonstrated its ability to block the effects of the opiate hydromorphone over the six-week trial period.

DAS is also in development with buprenorphine depot, an extended-release injectable formulation for the treatment of opiate/heroin dependence. Buprenorphine is a mixed agonist-antagonist opiate. An NDA for an oral tablet formulation of buprenorphine for the treatment of opiate addiction has been submitted to the US Food and Drug Administration (FDA) by another company, and its approval would support the validity of this approach. Buprenorphine Depot is in preclinical development and designed for administration once every four to six weeks.

Candidates for Treating Cocaine Addiction and Cognitive Function

The company’s third drug candidate, DAS-431™ IV, a dopamine D1 receptor agonist, is in Phase II evaluation for the treatment of cognitive impairment in the elderly and cocaine addiction and is in development for a broad range of CNS diseases, including schizophrenia. Dopamine D1 receptors are thought to play a role in mediating cognitive processes in the prefrontal cortex, particularly working memory. The number of D1 receptors appears to be decreased in the elderly, chronic addicts, patients with schizophrenia and, possibly, patients with Parkinson’s disease and those who have experienced a stroke. DAS-431 directly activates D1 receptors in the prefrontal cortex and may be useful in treating these conditions.

In two initial human clinical trials, DAS-431 showed potential for the treatment of cocaine abuse; in animal studies, it showed efficacy on working/learning memory impairments. A Phase II study in cocaine dependent patients has been successfully completed. Further studies in chronic addiction, the elderly, and patients with schizophrenia are underway. Worldwide development and marketing rights for all human therapeutic indications of DAS-431 were licensed from Abbott Laboratories in September 2000.

Two additional drug candidates are in preclinical development at DAS for the treatment of cocaine addiction. COC-AB™, an equine F(ab′)2 cocaine antibody, is in development as an emergency antidote for cocaine overdose (manufactured under an exclusive agreement with Aventis Pasteur). ITAC™ is a cocaine vaccine in development for prevention of relapse to cocaine following treatment. ITAC is based on a new platform technology developed in collaboration with The Scripps Research Institute.

Alcoholism/Addiction Education

DAS is the sponsor of www.AlcoholMD.com, a medical education and information Web site that currently draws thousands of visitors each month and provides anonymous, online self-evaluations of potential alcohol problems using standardized questionnaires.

Licensing—Products, Sales Partners, and Technologies

DAS is a research and development company with a licensing strategy that includes technology (including drug delivery technology), product (including preclinical and clinical) and commercial goals. At present, DAS seeks commercial partners in the US, Europe, and Asia for its near-term product candidates. Technology licensing at DAS includes deals with:

• Southern Research Institute (Birmingham, AL). In 1997, DAS in-licensed Southern Research Institute’s proprietary micro-encapsulation technology for the development of a sustained-release formulation of naltrexone and other products.

• Abbott Laboratories (Abbott Park, IL). In August 2000, DAS obtained worldwide exclusive license for all therapeutic indications for DAS-431.

• The Scripps Research Institute (La Jolla, CA). In 1996, Scripps granted DAS an exclusive license to develop and commercialize the institute’s patents related to cocaine vaccines.

• University Paris V (Paris, France). In 1999, DAS entered into a research and development agreement with the University of Paris V to jointly develop DAS’s proprietary antibody platform technology. COC-AB, a polyclonal antibody against cocaine, and MAP-AB, a polyclonal antibody against methamphetamine, are in development. The contract was extended to include the development of monoclonal antibodies.

• EON Laboratories (Laurelton, NY). In 2000, DrugAbuse Sciences was granted the license to market and distribute oral naltrexone hydrochloride tablets (50 mg) from EON Laboratories.

Management

DAS was founded in 1994 by Philippe Pouletty, MD. He is the founder of SangStat Medical Corporation and practiced hematology and immunology in Paris. Elizabeth M. Greetham, Chairman and CEO, previously worked for nearly ten years as a portfolio manager for Weiss, Peck & Greer, where she managed the WPG Life Sciences Funds LP, which invests in select biotechnology stocks. Among the scientific advisors of DAS are Walter Ling, MD, UCLA, who serves as Chairman; Herve Galons, PhD, University of Paris; George Koob, PhD, Scripps Research Institute; and Jean-Marc Rouzioux, MD, PhD, LD, Aventis Pasteur.

Timothy Tankosic

Contact Information

DrugAbuse Sciences, Inc. 25954 Eden Landing Road Hayward, CA 94545-3816 USA Tel: 510-259-3200 Fax: 510-259-3201 URL: www.drugabusesciences.com

In Europe

DrugAbuse Sciences SAS 30, Boulevard Pasteur 75015 Paris FRANCE Tel: 33 (1) 53 58 14 84 Fax: 33 (1) 53 28 14 47

Also see New Developments in Pharmacotherapy of Drug and Alcohol Addiction, an article that appeared in the December 2002 issue of D&MD Newsletter.

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