Vaccine candidate to treat nicotine addiction shows promise

May 16 2005

Cytos Biotechnology AG has announced that its vaccine candidate CYT002-NicQb to treat nicotine addiction has achieved proof of efficacy.

The phase II clinical trial results were presented by Prof. Dr. Jacques Cornuz (CHUV Lausanne), principal investigator, at the Annual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, USA, on behalf of the three Swiss study centres.

The study included 341 smokers and assessed safety, tolerability and efficacy of the vaccine candidate. Efficacy of the vaccine was determined by continuous abstinence from smoking between week 8 and 24 after treatment start and was measured by self-reporting of the participating smokers and by independent biochemical validation.

Two thirds of the smokers received the vaccine, whereas one third received placebo. All smokers who received the vaccine mounted an anti-nicotine antibody response, which corresponds to an immunological response rate of 100%. Based on the measured levels of antibodies, the vaccine-treated smokers were grouped into a high, a medium, and a low responder group. All smokers who received placebo had no measurable anti-nicotine antibodies in their blood. The following table provides the continuous abstinence values of the analysis of all smokers from whom complete antibody measurements were available and who refrained from using nicotine replacement products (NRT) (NRT use was considered a major protocol violation):

The data show with a high statistical significance (p=0.014) a strong relationship between the induced antibody levels against nicotine (mechanism of action of the vaccine) and the desired clinical effect (continuous abstinence from smoking); and this was irrespective of the unexpected high placebo response observed. The difference of continuous abstinence between the high responder group and the placebo group was highly significant (p=0.004). Overall cigarette consumption in the high responder group was less than half of that seen in the placebo group (p=0.004). Moreover, the average cigarette consumption by those people who did not achieve continuous abstinence was also lower in the high responder group than in the placebo group (p=0.16). The vaccine was safe and generally well tolerated with common side effects being local injection site reactions and flu-like symptoms, which usually resolved within 24 hours.

Prof. Dr. Jacques Cornuz commented: "I am very excited about the outcome of this study, as the data clearly suggest that antibodies against nicotine are effective in helping people quit smoking. There is certainly no doubt that new approaches such as vaccination are urgently needed. Despite the fact that smoking causes 30% of all cancer deaths, including 87% of deaths from lung cancer, there are 1.3 billion smokers worldwide. And each smoker looses on average more than 10 years of lifetime as a result from this serious addiction. I believe that the vaccine approach has the potential to dramatically alter the way how we will treat smoking addiction in the future."

Dr. Wolfgang Renner, Chief Executive Officer of Cytos Biotechnology, added: "We are extremely pleased about the results as the data in the high responder group are better than anything we have seen so far. The clear correlation between antibody levels and clinical effect greatly supports us in the further development of this vaccine. It is now our goal to get everybody into this high antibody response range; and to achieve this we have several measures at hand: A) We will increase the dose of the vaccine, as we have already done with other clinical candidates in different indications, B) we can add more injections as even after the fourth injection there appeared to be no antibody plateau, and C) we will certainly use these findings in our ongoing formulation development. But most importantly, the data show elegantly that we can use the body's own defence, the immune system, to modulate even such complex conditions like addiction. This finding is extremely important with respect to our pipeline of 27 vaccine candidates in other major disease areas like high blood pressure, obesity or Alzheimer's disease where we use the same basic Immunodrug principle."

According to the World Health Organization, 1.3 billion people smoke. With 5 million tobacco-related deaths per year, tobacco use is the leading cause of preventable death in the world today. Smoking harms nearly every organ of the body and 30% of all cancer deaths, including 87% of deaths from lung cancer, are attributable to smoking (American Cancer Society, 2005). Nicotine, an alkaloid derived from tobacco leaves, has been shown to be the principal addictive component of tobacco. Upon inhalation of cigarette smoke, nicotine passes into the bloodstream and within seconds penetrates through the blood-brain barrier, where it stimulates specific neurons in the brain. Stimulation of these neurons leads to the release of messenger molecules, which give rise to an almost immediate reward and a feeling of pleasure. This sensory stimulus is critical to the addictive properties of nicotine and causes a high relapse rate after quitting attempts. Although nearly 75% of smokers in the U.S. report that they want to quit smoking, less than 5% of those who try quitting are able to stay tobacco-free for 3 to 12 months (Surgeon's General Report, USA, 2004).

CYT002-NicQb is a therapeutic vaccine in development for the treatment of nicotine addiction. Vaccination with CYT002-NicQb has been shown to induce high levels of nicotine-specific antibodies that bind nicotine in the blood. As the complex of nicotine attached to an antibody is too large to pass the blood-brain-barrier, nicotine uptake into the brain and the subsequent stimulation of nicotine-perceptive neurons in the brain is believed to be significantly reduced or even prevented. In this way the addiction- driving and satisfaction-inducing stimulus of nicotine is minimized.

The study, the largest ever performed with a vaccine to treat nicotine addiction, was a randomized, double blind, placebo-controlled, multicenter phase II clinical trial to assess safety, tolerability and efficacy of the vaccine candidate. It was carried out at the Kantonsspital St. Gallen, the Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, and the Lung Center Hirslanden Zurich, all in Switzerland. The study was conducted in 341 healthy male and female smokers, aged 18-70 who have been smoking between 10 and 40 cigarettes per day for at least 3 years and who were motivated to quit smoking. 5 injections of the vaccine or placebo were given at monthly intervals at month 0, 1, 2, 3, and 4. All participants received smoking cessation counselling by the study collaborators at each visit during three months. One month after the first injection, the participants were asked to make a serious attempt to quit smoking. Smoking behaviour was recorded by the participants in personal diaries, and independent biochemical validation was performed by measuring carbon monoxide in exhaled air (a by-product of cigarette burn that remains in the blood for up to 24 hours).

Out of 341 smokers enrolled in the study, all participants were included in the efficacy analysis from whom complete antibody measurements were available and who refrained from using nicotine replacement therapy (NRT) (n=239). NRT is believed to have a different effect on the two treatment groups (CYT002-NicQb and placebo). Based on the proposed mechanism of action, NRT products and the vaccine are expected to neutralize each other, whereas in smokers on placebo NRT has a documented positive effect. An intent-to-treat analysis of the entire study population has not achieved statistical significance; therefore, the sub-group analysis based on antibody levels was performed. In this analysis, NRT users were excluded, then, the vaccinated smokers with complete antibody measurements were divided into three groups of increasing antibody levels (low, medium, and high responder group), and efficacy analysis was performed on each group. The placebo group was treated identically: NRT users were excluded and all participants with complete antibody measurements were included. Study participants were counted as continuously abstinent only when at all visits between week 8 and 24 the carbon monoxide concentration in their exhaled air was below 10 ppm and when throughout the entire period between week 8 and 24 they declared themselves as being non-smokers.

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