Nicvax Failure Casts Shadow Over Nabi's GSK Partnership and Nicotine Vaccines

July 19, 2011 NicVax failure casts shadow over Nabi's GSK partnership and nicotine vaccines

Jonathan Gardner

NicVax’s failure in the first of two pivotal trials is a huge blow for Nabi Biopharmaceuticals as well as the immunotherapeutic approach to smoking cessation. The Maryland biotech lost two-thirds of its value yesterday following the news that patients taking the vaccine quit smoking at rates similar to those on placebo.

The failure raises the prospects that partner GlaxoSmithKline will walk away from its option to license the candidate, leaving the smaller partner without hoped-for milestone payments and holding the bag for remaining development costs (Event - Nabi’s phase III NicVax data could be decider on whether or not Glaxo quits, July 11, 2011). Moreover, it does not augur well for the remaining nicotine immunotherapeutic pipeline, which has been notable more for failure than success.

No difference

Nabi announced that the first trial in 1,000 smokers produced a quit rate of 11% among those treated with NicVax, similar to the rate among smokers randomised to a placebo arm. Investigators considered those who had abstained over the last 16 weeks of the 52-week trial as successful quitters, using both self-reporting and exhaled carbon monoxide as measures.

Executives acknowledged that a high placebo response may have contributed to the trial’s failure, given that counselling was included for smokers in both arms. However, there was little explanation for the setback beyond that; the executives said analyses will be conducted to determine whether those with a greater antibody response had a higher quit rate, along with secondary endpoints such as number of cigarettes consumed.

A second trial in 1,000 patients is still underway, with topline results expected at the end of 2011 or early 2012. Given the design of the second trial is identical to the first, expectations must be low for a more positive outcome - analysts from Leerink Swann have lowered their chances of success from 70% to 15%.

Failure in the first trial alone has cost the group a $20m milestone from GSK, due only if both phase III trials are successful. The Leerink Swann analysts write that Nabi, which had $100m in cash on March 26, will soon announce cost reductions to conserve cash.

Innovative strategy

NicVax is designed to work by stimulating the immune system to produce antibodies that attach themselves to nicotine molecules in the bloodstream. That in turn makes the nicotine molecules too large to cross the blood- brain barrier, preventing them from attaching to nicotine receptors in the brain, This would otherwise release dopamine and other stimulants associated with the pleasurable sensations of smoking.

Using the immune system to disrupt those pleasurable sensations would seem to be an innovative strategy. The chief prescription drugs for smoking cessation, Chantix and bupropion, also disrupt the pleasure-reward system using small molecules, but both have serious safety concerns surrounding them, both for neuropsychiatric effects and Chantix with cardiovascular effects. Thus a safer alternative is clearly needed.

Yet progress in immunotherapeutics for smoking cessation has been patchy at best. NicVax’s trials paused for nearly a year as Nabi put itself up for sale, before pursuing the phase III trials and sealing the GSK option (After giving up Nabi starts again with nicotine vaccine, November 5, 2009).

Behind NicVax in the pipeline is Novartis’ and Cytos Biotechnologies’ NIC002. That vaccine works in a slightly different way, by creating a complex nicotine molecule that presents itself as a virus and in so doing stimulates a stronger immune response to the presence of nicotine in the bloodstream.

No progress NIC002, too, has failed in the clinic, but at phase II (Cytos has much to prove after second pipeline setback, October 16, 2009). Clinicaltrials.gov shows only one active trial, another phase II test, this time headed up by the US National Institute on Drug Abuse and Duke and Wake Forest universities, which will measure how the vaccine redistributes nicotine in the tissues of 65 smokers.

Meanwhile, a third nicotine vaccine, TA-NIC from Celtic Pharma, was announced to have completed phase IIb enrolment in late 2007 to great fanfare and that it would be a phase III-ready product to be auctioned in mid- 2008. The lack of any news on the immunotherapy in four years suggests the privately held Bermuda based group has stopped further development.

Given the need for a safer alternative to assist smokers who want to quit, using immunotherapy looked like a hopeful treatment strategy. Repeated clinical setbacks suggest, however, raise doubts that this appproach is viable.