Novartis Gives Up On Nicotine Vaccine

Another one bites the dust.

Novartis, a leading health care products company, called it quits on its NIC002 nicotine vaccine project, which failed badly three years ago in Phase II studies undertaken with an eye toward government approval. Novartis said it would terminate the license it has for the NIC002 vaccine with Cytos Biotechnology, for which it paid $38 million in 2007. The Phase II study “showed formation of nicotine-specific antibodies in patients but did not meet its primary endpoint of increased smoking cessation,” according to Genetic Engineering and Biotechnology News

Much the same arc was followed by Nabi Biopharmaceuticals, which announced in 2011 that its vaccine, NicVax, had failed to outdo placebos in Phase III clinical trials—the only addiction vaccine to advance that far in the approval process. The company’s own studies had shown happier results in 2007. In regulatory filings, the company claimed that the NicVax vaccine triggered a reliable antibody response, thus preventing nicotine molecules from reaching the brain. The antibodies bind with the nicotine molecules, making nicotine too large to cross the exceedingly fine blood-brain barrier of the brain. Roughly 15 per cent of smokers who received injections of NicVax were nicotine-free after one year in company-funded studies. For comparison, early studies of Chantix as an anti-smoking medication show a quit response rate in the range of 20 per cent for heavy smokers.

As I have previously written, the idea of vaccinating for addictions is not new. If you want the body to recognize a nicotine molecule as a foe rather than a friend, one strategy is to attach nicotine molecules to a foreign body--commonly a protein that the body ordinarily rejects--in order to switch on the body’s immune responses against the invader. A strong advantage to this approach, say researchers, is that the vaccinated compound does not enter the brain and therefore is free of neurological side effects.

There remain a wealth of questions related to the effects of long-lasting antibodies. And it is sometimes possible to “swamp” the vaccine by ingesting four or five times as much cocaine or nicotine as usual.

Drugs that substantially reduce a smoker’s craving for nicotine, like Chantix, may yet prove to be a more fruitful avenue of investigation. While several anti-craving medications have been approved for use by the Food and Drug Administration (FDA), no vaccines have made it onto the approved list. However, as the Genetic Engineering article reminds us, “all is not lost for the vaccine yet: in November of 2010, Duke University, in collaboration with Wake Forest University, commenced a Phase II clinical study with NIC002 performed with 65 smokers that aims to assess how nicotine antibodies, induced by vaccination, affect the pharmacokinetics of nicotine during cigarette smoking. The study is being conducted in the United States with funding from the NIH.”

Photo: Creative Commons / juliealicea1947

NIDA’s Volkow Defends New Medications for Addiction

On Big Data, Big Vaccines, and a Big New Agency.

In her Director’s Report to the 2011 meeting of the College on Problems of Drug Dependence in San Diego last week, Dr. Nora Volkow, director of the National Institute on Drug Abuse, sought to refute allegations that NIDA lately has been too focused on pharmacological approaches to treating addiction—“magic bullets” in the form of pills or vaccines. Dr. Volkow presented figures showing, as the CPDD Community Website reported, that “NIDA funding allocation for new medication development has remained stable at about 12% for some time, despite concerns expressed by some researchers that funding in other areas is being sacrificed to support the medication development portfolio.” Basic and clinical neuroscience research accounts for 45% of expenditures, she said.

In other news, Volkow expressed her avid interest in the possibilities presented by so-called “big dataset science”—the act of pooling together huge amounts of data in order to generate greater statistical power. She traced a set of disciplines—genetics, epigenetics, proteomics, brain imaging, clinical data, and systems biology—and said that the NIH’s Working Group on Data and Informatics  was seeking systematic ways of integrating and analyzing large biomedical datasets in these crucial areas.

As for treatment, the current emphasis is on stimulants. Volkow said that work continues on finding reliable antagonist drugs to combat the dopamine disruptions promoted by active drug abuse. She suggested that work on buspirone, the D3 receptor antagonist and partial serotonin 5HT agonist used to treat generalized anxiety disorder, has shown that it may reduce cocaine self-administration in rhesus monkeys. This would be of considerable clinical interest, since addiction medicine presently has no effective drug treatments to offer for stimulants like cocaine and methamphetamine. A large clinical study now underway is showing that buspirone blocked D3 receptors in monkey brains in a way that reduced their interest in cocaine.

And she referred to the failed promise of NicVax, the short-lived vaccine for cigarette addiction. The treatment “failed to meet the primary endpoint in Phase II trials.” In other words, it flunked out. Only 30% of addicted smokers developed sufficient antibodies from NicVax to do them any good. But she cited new research on an alternative approach to vaccines, including a new cocaine vaccine (dAd5GNE) shown to be effective in reducing cocaine addiction-related behaviors in rats through the long-term blockade of dopamine transporters.

In a related approach to producing a reliable anti-cocaine antibody, researchers in the Department of Genetic Medicine at Weill Cornell Medical College went to work on “an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain.” An AAV is a small virus that is infectious but not pathogenic in humans. You might have it right now, but wouldn’t know it, since AAV doesn’t cause disease. So, the researchers used an AAV to build a transporter mechanism for their monoclonal antibody, GNC92H2. In mice, the result was “persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood.”

And finally, while the name is still up in the air, a new national institute combining the study of alcohol and the study of all other addictive drugs will follow after final recommendations submitted to NIH Director by year’s end. Volkow briefly laid out the timeline of the merger for the assembled scientists. Call it the Institute for Substance Use Disorders, or the Institute for Addiction Disorders, or the National Institute of Substance Abuse, but whatever the eventual name, it will be fully operational by late 2013, or at least that’s the plan—and Nora Volkow, the current director of the NIDA, which will merge with, or rather absorb, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), won’t be its director (See "NIH Turf Wars"). Whether that’s good or bad is the subject of much debate, but the project marches on, and seems sensible in the end.

A Shot for Cigarette Addiction?

NIDA’s Nora Volkow on addiction vaccines.

Nora Volkow, director of the National Institute on Drug Abuse (NIDA), predicted in a telephone interview on Friday that a vaccine for cigarettes could be available in as little as three years, if two large ongoing Phase 3 trials—the last major FDA hurdle—prove as successful as earlier studies.

NicVax (Nicotine Conjugate Vaccine) from Nabi Biopharmaceuticals, with a boost from a $40 million up-front cash infusion from GlaxoSmithKline Biologicals SA, is poised to become the first of a new kind of science-based addiction treatment—an avenue of approach that brings with it great promise, and a significant number of problems.

I asked Dr. Volkow if the NicVax studies had shown evidence that the effects could be overcome with greater levels of smoking. This is a hurdle that has plagued early research on a promising cocaine vaccine, as reported in the Archives of General Psychiatry (See my post "Cocaine Vaccine Hits Snag").  In the cocaine studies, researchers found that users could overcome the blunting effects of cocaine antibodies by ingesting as much as ten times their normal level of cocaine—clearly a dangerous outcome that could enhance the possibility of lethal overdose.  (See discussions at Neurotopia  and DrugMonkey).

“I am very sensitive to that issue,” Volkow said during a conference call from NIDA's Eighth Annual Blending Conference in Albuquerque, NM, where she was a featured speaker. “But the data we have give no evidence that smokers increase their cigarettes to overcome the antibodies. It was that piece of the data that led me to approve funding.”

In fact, said Volkow, “craving decreased after these vaccinations, so we would not necessarily expect smokers to try to overcome the effects. We’ve also seen a dramatic decrease in cocaine administration in animal models.” The matter of defeating a vaccine by overindulging remains a theoretical rather than an established risk, Volkow believes. 

Vaccines may operate somewhat differently that we think, she explained, by helping to extinguish the conditioned responses to craving cues as well. “We did not expect to see [anti-craving effects],” she said. “Craving is a product of memory, associated stimuli, the anticipation of a pleasant response. With cigarettes, if you feel nothing, the brain mechanism of conditioning that drives craving starts to weaken.”

The vaccine itself “is not totally stopping all of the drug from getting into the brain. But it affects the pharmacological properties, so users don’t get the expected outcome.  Nobody knows exactly how this might accelerate the extinction process—we haven’t done the studies. It’s going to be intriguing to have a product that has the capacity to make extinction much more universal.”

Volkow admitted that “we need to get a wider response,” since a significant number of smokers and cocaine users do not form antibodies from the vaccines. In addition, “we need longer-lasting responses so we don’t have to re-vaccinate.” The cocaine vaccine under study is in Phase 2 trials, and it will be several years before more definitive results are in.

The Blending Conference Volkow was attending was titled “Blending Addiction Science and Practice: Evidence-Based Treatment and Prevention in Diverse Populations and Settings.” Despite her emphasis on science-based treatments, Volkow stated firmly that social intervention and psychological treatment can be equally important, and characterized the supposed line between physical addiction and psychological addiction as an “obsolete distinction.” It is important to remember, she said, that “psychosocial interventions make biological changes in the brain” as well.

“People are desperate, and vaccines will be very helpful to those who develop antibodies. People want these magic bullets, but we don’t yet know how these vaccines will effect the therapeutic landscape.”

Graphics Credit: http://www.attcnetwork.org/

Nicotine Vaccine Doubles Quit Rate in Human Trials

NicVax still showing promise against cigarette addiction

Nabi Biopharmaceutical announced this week that an experimental vaccine it has been testing against nicotine addiction had shown itself to be effective in human trials. Volunteers were more than twice as likely to quit, compared to a control group whose members were injected with a placebo.

The company-funded study gave volunteers five injections of NicVax, Nabi’s proprietary drug, or else a placebo. In regulatory filings, the company claims that the vaccine triggers an antibody response, which prevents nicotine molecules from reaching the brain. The antibodies bind with the nicotine molecules, making nicotine too large to cross the exceedingly fine blood-brain barrier of the brain. Roughly 15 per cent of smokers who received injections of NicVax were nicotine-free after one year. For comparison, early studies of Chantix as an anti-smoking medication show a quit response rate in the range of 20 per cent for heavy smokers. Studies of NicVax undertaken last year were also positive. It is one of several nicotine vaccines currently under development, and while it is farthest along in the FDA pipeline, it is still a year or two away from any possible commercial introduction.

Vaccines for specific addictive drugs represent one of two different approaches to developing pharmaceuticals for addiction treatment. The other approach, represented by Chantix and Zyban, decreases drug craving by altering the neuroregulation of dopamine and other substances in the brain. In this respect, these two drugs, which are non-addictive, are related to nicotine gums and patches, which also attempt to diminish cravings for cigarettes.

A vaccine like NicVax, however, does not attack the craving for nicotine. It contains no nicotine and is non-addictive. Rather, the vaccine makes the attempt to assuage nicotine cravings an impossible task. And in this respect, NicVax resembles Antabuse for alcoholism--except that the vaccine does not cause the smoker to become seriously ill when he or she takes a puff. . (The company reported that side effects were “well tolerated.”) It simply (or not so simply) cancels out the nicotine high altogether, or at least that is the idea. It is unclear to what extent the antibody reaction prevents nicotine binding in other areas of the body where nicotine-type receptors are found, such as acetylcholine receptors in muscle tissue.

In addition, NicVax must be injected, while Chantix and Zyban or taken orally. “Some people prefer a shot and some people will do anything to avoid one,” Rennard said. “It’s important to have options.”

Stephen Rennard of the University of Nebraska Medical Center, one of the authors of the company’s study, which is funded by a grant from the National Institute on Drug Abuse (NIDA) and is now in midstage, said that when smokers “don’t get the hit they would normally get, it makes it easier for them to quit because smoking doesn’t really do it for them any more.”

The results were presented at the American Heart Association Scientific Sessions in Orlando, Florida. “This double-blind, placebo-controlled trial has demonstrated [that] there is a correlation between antibody level and the ability of patients to quit smoking and remain abstinent over long periods of time,” Rennard told the group. Leslie Hudson, CEO and Interim President of the company, said he was “excited and encouraged.” Nabi Biopharmaceutical, headquartered in Boca Raton, Florida, is traded on the NASDAQ stock market [NABI].