The five Phase 1/2 clinical studies completed to date involved over 480 subjects and demonstrated that NicVAX was well-tolerated, highly immunogenic, gave a dose-dependent increase in antibody concentrations, and showed a clinical proof-of-concept for efficacy in smoking cessation in that clinical response rates were highly correlated with antibody concentration.  Significantly, the data in the most recent study showed a correlation between antibody concentration and the ability of patients not only to quit smoking but also to remain abstinent up to 12 months.

On November 7, 2007, we announced the successful completion of our Phase IIb trial of NicVAX® (Nicotine Conjugate Vaccine), the company’s innovative and proprietary investigational vaccine being developed to treat nicotine addiction and prevent smoking relapse.  At the 6 month primary end point we observed a statistically significant number of patients in the high anti-nicotine antibody responder group who met the trial's primary endpoint of eight weeks of continuous abstinence between weeks 19-26. The final 12-month data confirmed the highly significant trends seen in the previous data at six months and nine months for both smoking cessation and long-term smoking abstinence.

The Phase 2b study was a double-blind, placebo-controlled, dose-ranging study designed to establish proof of concept and the optimal dose and regimen for the Phase 3 program. This study was designed in collaboration with the U.S. National Institute on Drug Abuse (NIDA), the U.S. Food and Drug Administration and other global regulatory agencies. The trial enrolled a total of 301 heavy smokers who smoked an average of 24 cigarettes per day prior to enrollment. In no case did any patient smoke less than 15 cigarettes per day prior to enrollment. The trial's primary endpoint was the rate of carbon monoxide-confirmed, continuous abstinence from smoking after 6 months (during weeks 19-26 after first vaccination). Secondary endpoints include the abstinence rate at 12 months, daily cigarette consumption, antibody levels, safety and nicotine dependency.

6 Month Primary Results: Proof of Concept

A statistically significant number of patients with a high anti-nicotine antibody response met the Phase IIb study’s primary endpoint of eight weeks of continuous abstinence between weeks 19-26.

Data from the drug-treated population was divided into those who quit and those who continued to smoke and then analyzed for antibody levels throughout the trial. In an analysis of the intent to treat population, patients who quit smoking had a median total antibody level that was significantly greater than patients who continued smoking (p=0.002). To further examine the relationship between antibody and quit rate, the top 30% of antibody responders (61 of the total 201 patients receiving drug) were examined in detail. A statistically significant number of these patients, (24.6%; p=0.04) showed continuous abstinence between weeks 19-26 compared to only 13.0% for the 100 patients receiving placebo. The quit rate of those patients who did not have a high antibody response was not statistically significant from placebo.

The efficacy data trends were both vaccine dose-proportional and antibody level-dependent. In the responder group, antibody levels increased with time and number of doses. Individual patients were tracked on a continual basis and were seen to be more likely to abstain from smoking as their antibody levels rose after vaccination; thus definitively providing proof of concept.

12 Month Results

A statistically significant number of patients treated with the NicVAX optimal dose (400 micrograms [μg]) and schedule (Schedule 2) were able to quit smoking and remain abstinent over the long-term:

• 12-Month continuous abstinence: NicVAX 400 μg, Schedule 2 = 16% (8/51), Placebo=6% (6/100), p<0.038 (intent to treat population)
• 12-Month continuous abstinence: NicVAX 200 μg, Schedule 2 = 14% (7/50), Placebo=6% (6/100), p<0.056 (intent to treat population)

Anti-Nicotine Antibody Levels Drive Long-Term Smoking Abstinence

• The rate of smoking cessation and ability to achieve long-term abstinence in treated patients was correlated with level of anti-nicotine antibodies at critical time points: The high antibody responder group (top 30% of antibody responders) showed continuous abstinence rates almost three times those of placebo at 12 months.
• These high antibody responders continued to show statistically significant abstinence at 12 months:
• NicVAX = 16% (10/61) vs. Placebo= 6% (6/100), p<0.032
• Subjects in the therapeutic effect window show a >30% likelihood of achieving at least four months of smoking abstinence and remaining entirely abstinent through 12 months following the first administration of NicVAX.

Overall Health Benefit - High Antibody Responders Smoked Fewer Cigarettes

Those patients in the NicVAX group who continued to smoke and also showed a high antibody response (top third) showed a statistically significant reduction in cigarettes smoked over the full 12 months compared to placebo (p<0.022):

Using a repeated measures model, vaccinated smokers who failed to quit but showed a high antibody response smoked a median of only 10 cigarettes per day while in the study, compared to their own baseline value of 20 cigarettes per day before treatment.

NicVAX was well-tolerated with the placebo and NicVAX dose groups showing comparable adverse event profiles at each stage of the clinical study. The most common local reactogenicity events were minor ache and tenderness. Systemic reactogenicity events – such as general discomfort, headache and muscle ache – were mild to moderate in severity, resolved quickly and did not increase with number of injections. Fever and nausea were seen in less than 10% of all subjects.

Importantly, there was no evidence of compensatory smoking or increase in withdrawal symptoms observed in NicVAX patients at any stage of the 12- month trial.

Summary of Previous NicVAX Trials

In July 2005, The Company completed enrollment for its European-based NicVAX Phase II dose-ranging study in smokers. The study, designed to evaluate NicVAX's safety, anti-nicotine antibody response, and measure smoking behavior and nicotine dependency, was a randomized dose-ranging study in smokers.  The study was comprised of 50 healthy smokers, who were randomized to receive one of four dose levels (100, 200, 300 and 400 μg), with either of 2 alum adjuvant formulations, administered as five injections over a 6 month period. A total of 20 patients received the 200 μg dose, with 10 patients receiving each of the other dose levels. The study was undertaken to assess the tolerability and antibody response at higher doses (300 and 400 μg), recognizing that the top dose used in previous studies (200 μg) was well tolerated.

This study was completed in August 2006 and the results showed that all formulations of NicVAX were well tolerated and immunogenic. Antibody concentrations increased with each dose administration, and the lower adjuvant formulations did not appear to compromise the antibody response. Nicotine dependency exhibited a trend downward from the baseline, and tended to be better sustained in the higher dose formulations.  

In September 2004, the Company reported positive results from its U.S. Phase II trial. The trial was a double-blinded, placebo-controlled, randomized study in 63 smokers who wanted to quit smoking, designed to assess safety and antibody response. In addition, standard measures of smoking behavior were included. The results showed that, at the 200 μg dose, 33 percent of smokers in the treated group quit smoking (defined as no smoking for at least 30 consecutive days) versus 9 percent in the placebo group. Additionally, results showed a substantial reduction in average cigarette consumption in smokers who received the highest dose of NicVAX versus lower doses or placebo. Smoking cessation was confirmed by cotinine and carbon monoxide levels, which are biochemical markers of smoking. Nicotine dependency was measured by a questionnaire and also showed a substantial reduction at the top dose of NicVAX as compared to placebo or the lower dose levels. NicVAX was very well tolerated, and side effects were similar between the active dose levels and the placebo group. The outside clinical costs for the trial were funded by a grant from the National Institute on Drug Abuse (NIDA).

In February 2004, the Company announced the successful findings from its double-blinded, placebo controlled Phase I / II trial with NicVAX. The purpose of this study was to assess safety and the ability of NicVAX to generate specific antibodies against nicotine following multiple injections of the vaccine. A total of 30 subjects comprised of 21 healthy smoking and 9 healthy non-smoking volunteers each received a series of four injections containing either NicVAX or a placebo (an inactive substance) over a six month period. The results from this study revealed that NicVAX was well tolerated and was able to generate high levels of nicotine specific antibodies. Three doses of NicVAX produced significant levels of antibodies, which declined slowly over the next several months. A fourth dose (given on day 182) boosted nicotine specific antibody to even higher levels, which then declined more slowly over time.  Reactions to the vaccine were consistent with those seen with other intramuscular vaccines, and tended to be mild, self limiting and resolved within a few days.  The most common reactions associated with NicVAX use were localized reactions such as tenderness, aching and redness at the injection site.  The most frequent systemic reactions were myalgia (muscle pain), headache and malaise (weakness).  The study was conducted at the University of Maastricht, the Netherlands.

In 2002, a placebo-controlled, double-blind Phase I clinical trial of a single dose of NicVAX in healthy, non-smoker volunteers was completed with the assistance of funding from NIDA. Analysis of blood samples from the participants showed that a single dose of vaccine resulted in a rapid immune response and generated nicotine-specific antibodies. Local reactions to vaccination were generally mild to moderate, temporary and required no therapeutic intervention. Antibody levels were detected within 7-14 days of vaccination and were either maintained or continued to increase through at least 60 days post-vaccination.