Xenova is developing a therapeutic vaccine, TA-CD, for the treatment of cocaine dependence, for which there is no currently available effective treatment.

Current treatment programs for cocaine addiction consist primarily of counselling services and medication to treat the symptoms of depression and anxiety associated with cocaine withdrawal. Currently, there is no medication that addresses the strong cravings for cocaine that an addicted individual experiences. These cravings can last for long periods of time following abstinence and frequently lead to recidivism. For those cocaine users in the US who seek treatment, the
overall retention rates in treatment programs are low; recidivism rates are typically greater than 50%. Currently, no pharmacotherapies have been shown to be clinically effective and there is an urgent need for novel therapeutic approaches.

TA-CD is designed to induce cocaine-specific antibodies which bind to cocaine in the blood, blocking its uptake into the brain. Therefore, the human physiological response to cocaine is altered, reducing the reinforcing properties of cocaine and permitting patients to break the cycle of addiction and abuse.
The active ingredient of the TA-CD vaccine is a protein conjugate: a cocaine derivative coupled to recombinant
cholera toxin B (rCTB). The finished TA-CD vaccine consists of the protein conjugate adsorbed onto aluminium hydroxide
gel adjuvant in saline. The vaccine is administered by intramuscular injection and it is anticipated that a short
course of injections will be required to induce antibody responses.

In a preclinical model of cocaine self-administration, immunisation with TA-CD vaccine reduced drug-seeking behaviour compared to that observed in cocaine naïve rodents. Analysis of serum from immunised rodents showed the presence of cocaine-specific antibodies.

Two clinical studies have been conducted to assess the
safety and immunogenicity of TA-CD vaccine to date. Up to 3 vaccinations (at 0, 4 and 8 weeks) of TA-CD 709 µg, 82 µg,
13 µg or TA-CD placebo were administered to 34 cocaine abstinent patients in a phase I study. In a phase IIa study,
up to 4 vaccinations (at 0, 2, 4 and 8 weeks) of TA-CD 82 µg were administered im in 9 outpatient cocaine abusers. In both studies, TA-CD vaccine was well tolerated both locally and systemically. There have not been any severe or moderate adverse events that have been considered related to the vaccine. Antibody levels correlated both with the dose of vaccine given and with the number of vaccinations. Anti-cocaine antibodies were detected subsequent to the second injection, levels peaked about 12 weeks after the initial injection and declined at further time points until one year.

The antibody levels in the clinical trials approach those produced in the rodent self-administration model and have
the appropriate specificity for cocaine. The highest level of
anti-cocaine IgG was detected after 4 vaccinations during
the phase II clinical trial.

This Phase IIa clinical trial, supported by the US National Institute on Drug Abuse (NIDA), was completed and the successful results of this trial were announced in July 2001. Attenuation of the usual euphoric effects of cocaine was reported amongst patients who relapsed during the study, providing anecdotal evidence of the benefit TA-CD may provide.

The start of a Phase IIa cocaine administration trial was announced on 14 April 2003. The ten-patient open label trial is being conducted in the United States and is designed to evaluate the effect of TA-CD on behavioural changes associated with cocaine administration.

The results of a second Phase IIa dose escalation trial were reported on 17 June 2003. This study, which started in April 2002, was designed to evaluate the safety and immunogenicity of TA-CD using 4 or 5 dose vaccination schedules. The trial involved the enrolment of 13 subjects, all of whom were cocaine abusers seeking help with their addiction at the start of the trial. Patients were treated with up to five injections of the vaccine over a twelve week period using doses up to 360 µg each. Of the thirteen enrolled, twelve subjects completed the 12 month evaluation period to assess safety, immune response and cocaine usage.

As for the previous study, the results showed the vaccine to be safe and well tolerated with a dose-related immune response. Of those 16 patients in the two Phase IIa studies who used cocaine at any time following vaccination, 14 reported a reduction of the usual euphoric effect normally associated with cocaine use, providing further anecdotal evidence of the vaccine's proposed mode of action.

On 24 October 2003, Xenova announced the start of the first randomised, placebo controlled Phase IIb clinical trial for TA-CD. The primary objective of this new study is to determine the efficacy of TA-CD in addicts seeking treatment for cocaine abuse, and to determine appropriate end-points for a Phase III study.

Up to 132 subjects, all of whom are methadone-dependent cocaine addicts being treated for drug dependency are being recruited into this clinical study. Half the subjects will be treated with active TA-CD and half will be given a placebo. Subjects will be monitored three times a week to assess cocaine usage, including testing for cocaine metabolites in urine, for a period of 20 weeks. Patients will also undergo medical examinations and blood tests for anti-cocaine antibodies to assess the immunogenicity of the dosing schedule. The trial is expected to last up to two years (depending upon the rate of recruitment) and will allow an objective assessment of the efficacy of the TA-CD vaccine against placebo.

The TA-CD investigations are being funded in part by the National Institute on Drug Abuse (NIDA) which recognises cocaine abuse to be a major problem in the U.S. NIDA has also supported earlier clinical work as part of this program.

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