We are fully engaged in the pivotal NicVAX Phase III clinical trials. Both trials are double-blinded, placebo-controlled studies comprised of approximately 1,000 subjects each. The primary endpoint of each study is smoking abstinence rate at 12 months. The first trial began in November 2009 with final data expected in the second half of 2011. We initiated the second trial in March 2010 with final dated expected in early 2012. Among the features of the Phase III trials:

 ·  Participants will receive six injections over a six-month period 

 ·  The target quit date is at week 14 to better align with high  antibody levels

 ·  Standard-of-care counseling aligned with the target quit date will be employed

 ·  Participants must be smoking a minimum of 10 cigarettes per day

The revised dose regimen and target quit date were determined based on the results of our 2008 Phase II schedule optimization immunogenicity study that is described in more detail below.

We are also participating in an investigator-initiated Phase IIb study to evaluate the safety and efficacy of NicVAX when co-administered with varenicline as an aid to smoking cessation and relapse prevention. This study, initiated in October 2009, is being conducted by The Research School CAPHRI of the Maastricht University Medical Center in Maastricht, The Netherlands and is funded primarily by The Netherlands Organization for Health Research and Development and Maastricht University with Nabi providing some additional support. This Phase IIb study for NicVAX is a double-blinded, placebo-controlled parallel-arm study comprised of approximately 600 subjects randomized in a 1:1 ratio to one of two treatment groups. One group will receive NicVAX and varenicline and the other group will receive placebo and varenicline. The primary endpoint of the study is the long-term smoking abstinence rate at one year. Abstinence will be evaluated by self-reported cigarette consumption and measurement of exhaled carbon monoxide. Secondary endpoints include the abstinence rate at various interim periods, smoking lapse and relapse, safety, immunogenicity and withdrawal symptoms. The study will also involve behavioral counseling as with other smoking cessation programs which likely will enhance efficacy rates in this study. 

In 2008, we conducted a Phase II schedule optimization immunogenicity study to assess the antibody response and safety of a 400 microgram, six-dose immunization schedule. The vaccine lot used in the first cohort of this study was from the same lot used in the Phase IIb proof-of-concept trial whose results were announced in November 2007, while the lot used in the second cohort was the same lot being used in the Phase III trials. Final results from the study confirmed the positive interim results announced in July that significantly higher anti-nicotine antibody levels can be generated three months earlier and in a much higher percentage of subjects for sustained periods of time than observed in previous NicVAX studies. Antibody levels achieved at 14 weeks were more than 2-fold higher than those achieved at the same time point in the Phase IIb proof-of-concept study as a result of the added injection. Moreover, greater than 80% of subjects who completed the six- dose 400 µg NicVAX regimen had anti-nicotine antibody levels above the target threshold at the planned week 14 “quit date”. The revised six-dose schedule continued to be well tolerated with an adverse event profile comparable to previous NicVAX clinical studies.

The results from both cohorts are virtually identical to those of the first cohort described above. This indicates that the quality of the vaccine is nearly identical between the vaccine lot used in the Phase IIb proof-of-concept trial and the vaccine lot manufactured for our planned Phase III trial. In addition, to confirm that the anti-nicotine antibodies generated in response to these two lots are functional, the lots were tested in animal models. Data from these functional animal models indicated that both vaccine lots effectively blocked nicotine from entering the brain of rats, confirming the quality, specificity and effectiveness of those lots.  

Previously five Phase I/II clinical studies completed to date involved more than 475 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 Phase IIb proof-of-concept study showed a correlation between antibody concentration and the ability of subjects 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 subjects 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 IIb 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 III 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.

A statistically significant number of subjects 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.High anti-nicotine response was defined as the top 30% of antibody responders (61 of the total 201 subjects receiving drug). Subjects having the highest serum anti-nicotine antibody (Ab) levels achieved higher rates of 8 weeks of continuous abstinence compared with subjects who received placebo. Nearly a quarter of these subjects, (24.6%; p=0.024) showed continuous abstinence between weeks 19-26 compared to only 12.0% for the 100 subjects receiving placebo. In contrast, the quit rate of those subjects who did not have a high antibody response was not statistically different 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 subjects 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.

A statistically significant number of subjects treated with the NicVAX optimal dose (400 micrograms [μg]) and schedule (Schedule 2, consisting of 5 injections) 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)

The rate of smoking cessation and ability to achieve long-term abstinence in treated subjects 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 = 18% (11/61) vs. Placebo= 6% (6/100), p<0.01. 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.

Subjects with high antibody response in the NicVAX group who continued to smoke 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.

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