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 The Lycaeum Forums » Integrate » Science (Moderator: farmerjack)Topic:
 Nicotine Vaccine Reaching Phase III Testing

[2a]

http://www.cnn.com/2009/HEALTH/11/09/anti.nicotine.vaccine/index.html

(CNN) -- When Katherine Frazier was a teenager in Silver Spring, Maryland, back in the '60s, smoking was the "in" thing to do. She thought it was glamorous. She thought it was cool. Her friends smoked, her parents smoked, and at the time, no one knew that smoking tobacco could kill you.

Fast-forward 40 years. Frazier, 57, still smokes, but she wants to quit. She knows that the longer she puffs, the higher her risk for developing certain health problems, including heart disease and certain cancers.

In her battle against the butt, Frazier has stuck on patches, chewed gum and even tried going cold turkey. Sometimes it worked, but never for long. "I am desperate to quit smoking for good," she said.

Soon, she might have another tool at her disposal.

The National Institute on Drug Abuse, a division of the National Institutes of Health, gave Nabi BioPharmaceuticals a $10 million grant to take its anti-nicotine vaccine, NicVAX, to Phase III clinical trials.

According to the National Institutes of Health, in Phase III trials, the treatment is "given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely." It's also the last step before the drug can go before the FDA for approval.
Video: Vaccine trial underway
Nicotine addiction causes nearly a half-million deaths annually in the United States alone.
--Dr. Francis Collins

NicVAX is designed to stimulate the immune system to generate antibodies that latch on to nicotine in a smoker's body and actually prevent nicotine from ever entering the brain. The testing began last week.

"Nicotine addiction causes nearly a half-million deaths annually in the United States alone. Finding effective treatments that can help people stay off cigarettes has been a real challenge," NIH Director Dr. Francis Collins said. "This Phase III trial of a nicotine vaccine offers tremendous hope towards solving this immense public health problem."

Drug experts say nicotine is more difficult to kick than heroin. The American Cancer Society reports that of the 44 million smokers in the United States, 70 percent say they want to quit. About 40 percent do quit each year, but only 4 to 7 percent manage to give up smoking, without help, for good.

"We hope the Phase III trials will get stronger results so that a large percentage of our population can benefit from it," said Dr. Nora Volkow, director of the National Institute on Drug Abuse. "Ideally, we'd like to see 100 percent of those taking the vaccine stop smoking for good."

Volkow says that what makes NicVAX different from existing anti-smoking therapies is that it helps smokers quit permanently. Relapse is a significant challenge facing smokers, and relapse rates with currently available smoking cessation therapies can be as high as 90 percent in the first year after a smoker quits, Volkow says.

When a smoker inhales cigarette smoke, nicotine is absorbed through the lung tissue and into the bloodstream and carried through the body. Because nicotine is a small molecule, it easily crosses the blood-brain barrier and binds to receptors that release dopamine. The release of dopamine generates the pleasurable sensation known as a "smoker's high."

The whole process occurs very rapidly -- less than one minute after tobacco smoke is inhaled -- so the nicotine fix is quick, reinforcing the addiction.

The NicVAX vaccine prompts the immune system to create antibodies that bind to the nicotine molecules in the blood. The now-larger molecules are prevented by their size from crossing the blood-brain barrier. Trapped outside the brain, the bound nicotine can't reach the receptors that trigger the release of dopamine. No dopamine, no pleasure.

It's believed that a smoker's addiction to nicotine will diminish over time because, as the antibodies created by NicVAX continue to bind to the nicotine, the amount of nicotine reaching the brain will gradually decrease. This lack of feel-good reinforcement reduces the urge to continue smoking.

According to NicVAX maker Nabi, the results of prior trials have been promising, with few side effects. In the Phase II trials, Nabi reported that 30 percent to 35 percent of those given NicVAX were able to remain smoke-free over the long term, compared with only 10 percent of those receiving the placebo.

"In addition, those participants that continued to smoke but showed a high antibody response to NicVAX significantly reduced the number of cigarettes smoked over the full 12-month period from a baseline of 20 cigarettes per day to 10 cigarettes per day," Nabi reported.

The initial Phase III study for NicVAX will enroll approximately 1,000 patients. The primary reason for the study is to see what the abstinence rate is at 12 months: in other words, how many people are actually quitting for good? Study results are anticipated in the third quarter of 2011. According to Volkow, that's when "we can get the vaccine in front of the Food and Drug Administration for approval."

Frazier is thinking about joining the trial. But for now, she's relying on her own willpower to cut down on the number of cigarettes she smokes per day. Eventually, she knows she's gong to need some help.

"If I could quit, it would be a huge goal in getting my health in order. This could change my life," she said.

[yandosan]

"Because nicotine is a small molecule, it easily crosses the blood-brain barrier and binds to receptors that release dopamine."

Hmmm...
Actually, the nicotinic ACh receptors allow for  Ca++ or Na+ influx. Depolarization.
The muscarinic ACh receptors are  GPCRs.
I think they ought to change that to "binds to receptors in neurons that release dopamine."

Also, there's a stoichiometry issue. An antibody for every nicotine molecule? It  seems  far-fetched.

[foreward]

^^ perhaps why it has such a low success rate of 30-35% in Phase II...

[whateveryouwantmetobe]

Their success rate could be bolstered by placebo effect, definitely for something like this.

Also what do you do about second hand smoke?  I believe it would bypass the circulation & antibodies and get into the brain pretty quickly.  

Finally is nicotine the only psychoactive in tobacco?

[foreward]

If 10% of the test subjects were also experiencing placebo benifit, then this vaccine is only 20-25% effective.

Don't drugs generally need to be 30% more effective than placebo to be approved?

[whateveryouwantmetobe]

I'm not sure there is an official percent it needs to have, although clearly there should be a cut-off range, probably right around ~30% as you suggest.  Then again I wonder why not at least make it to where a final study has to demonstrate something like 50%-75% (if not higher) effectiveness in an afflicted population to get approval.  You would think that would be more along the lines of what gets something approved.  That is, there needs to be a "knock out" study where the result is in your face screaming "Yeah this stuff works."

http://www.essortment.com/all/fdadrugapprova_rrgy.htm

[farmerjack]

if the new drug is not otherwise harmful would it be such a bad thing that 20% could quit? I'll bet an actuary would say it would save the "countrys' health system" billions.

also, if I understand this correctly the drug simply stops the nicotine from attaching to the brain which means from the moment one starts taking the drug the smoker is effectively quitting cold turkey even if he keeps lighting up. That's going to make for some crazzzzzzzy people for awhile. Maybe a step up dosing program will be in order.

[pylkko]

Also, there's a stoichiometry issue. An antibody for every nicotine molecule? It  seems  far-fetched.

No, it has been found to be maximally 65% decreasing in rats.
http://dx.doi.org/10.1159/000063617

^^ perhaps why it has such a low success rate of 30-35% in Phase II...

Low? Higher than anything before.

If 10% of the test subjects were also experiencing placebo benifit, then this vaccine is only 20-25% effective.

No. You can't just subtract placebo group from test group like that. You don't know the extent of the placebo effect within the test group. All you know is that more people managed to keep of nicotine with the treatment than with just placebo. Furthermore, even in the group that gets no treatment there are some that manage to quit.

Don't drugs generally need to be 30% more effective than placebo to be approved?

Where did you get this from?

I'm not sure there is an official percent it needs to have, although clearly there should be a cut-off range, probably right around ~30% as you suggest.  Then again I wonder why not at least make it to where a final study has to demonstrate something like 50%-75% (if not higher) effectiveness in an afflicted population to get approval.  You would think that would be more along the lines of what gets something approved.  That is, there needs to be a "knock out" study where the result is in your face screaming "Yeah this stuff works."

http://www.essortment.com/all/fdadrugapprova_rrgy.htm

No. A drug just needs to be therepeutically valuable, that is better than the previous best treatment. It could also be just less toxic, or easier to use or something like that which gives it a therapeutical value. And there are very few drugs that would pass your high criteria!

if the new drug is not otherwise harmful would it be such a bad thing that 20% could quit? I'll bet an actuary would say it would save the "countrys' health system" billions.

also, if I understand this correctly the drug simply stops the nicotine from attaching to the brain which means from the moment one starts taking the drug the smoker is effectively quitting cold turkey even if he keeps lighting up. That's going to make for some crazzzzzzzy people for awhile. Maybe a step up dosing program will be in order.

You are right, though you get it a little wrong. If with medicin A 30 percent manage to quit and with medicine B 10% manage to quit it does not mean that medicine a is really only 20% effective. But you are right that if even only a fraction manage to quit, and there is no better way, then it is important.

Yes. this drug does not lessen the cravings, and people can smoke just more to get more nicotine. But as it lowers the dopamine rush it lowers addiction potential. It has been demonstrated that it is still more efficient.

Their success rate could be bolstered by placebo effect, definitely for something like this.

Also what do you do about second hand smoke?  I believe it would bypass the circulation & antibodies and get into the brain pretty quickly.  

Finally is nicotine the only psychoactive in tobacco?

Why would second hand smoke be different? Bypass circulation? You mean as in somehow not go to the lungs but still go to the brain?

Nicotine is not the only psychoactive in tobacco. However the measure of effectiveness was smoking cessation, remember. And it has been demonstrated that nicotine patches a gum can be used to kick tobacco. So nicotine is central to the addiction.

[whateveryouwantmetobe]

I just figure if you breathe 2nd hand in through your nose that some is going to diffuse through the nose right into the brain/CNS.  I mean it's not like it would warrant the stuff useless, just that people on the antibody might not want to be around 2nd hand because of it.

Regarding my "high criteria" I guess I am just too optimistic... I should know by now the world is lousy.

[foreward]

While perhaps not "scientific" I think that it is a pretty good estimate to say that a drug's biological effectiveness is proportional to the placebo effect. If the test and control were not subject to the same experimental circumstances, then the test would not correlate with the control, and you could say that the reason why the test group performed better is because they had pink sheets rather than yellow sheets, or that because the research facility that monitored the test group was on the sunny side of the building. It should be assumed that with such low successes of 30-35%, and placebo as high as 10% a significant number the test group experienced placebo effects. I'll admit though, maybe 10% was a bit high.

As far as 30-35% effective being the most success we've had so far, I'd REALLY be concerned of any side effect. Patients should know when a drug has such a low success rate. Unfortunately this isn't the case, and doctors often reply to questions regarding a drug's efficacy as "it's really effective!" and other vague and intimidating responses.

While this drug might have a promising side effect profile now, at 30-35% I'd expect that no side effects be present at all, and if there are minor side effects that they be reversible. I would also be reserved to accept a drug with such a low success rate as we won't truly know long-term effects until they occur. For example, if 2% of people who use this vaccine later develop schizophrenia, that would mean potentially thousands of people develop the disease, thousands more will before a correlation is discovered, and thousands more will while the drug is evaluated and eventually withdrawn - and many, in fact the majority, would still be smoking.

This has happened. Like most ssri's, Paxil was not supposed to have significant side effects when it was approved. However, it is now shown to be highly dangerous in undiagnosed bipolar disorder, supposedly induces suicidal ideation in some children, and has a painful withdrawal symptoms. Paxil specifically, like this vaccine, only had a 39% success rate (15% placebo) in the treatment of depression. Today, many SSRI's have proven to be even less successful outside the laboratory.

I am not saying that this nor any other drug should not have been or be approved. However, with success rates significantly lower than 50% I think that extra scrutiny should be placed on drug approval, and educating the patient about it's success rate and it's side effects.

[pylkko]

That's definetely not scientific as you say. In drug trials you set the null hypothesis to that your new therapy group will have as many quiters as the placebo group or less. Then you try to prove with a certain level of probability that that hypothesis is wrong. When you manage to do this, you can claim that it is more rational to use your therapy than placebo in the treatment. These are the integrals of two separate probability density functions, you cannot normalize the data by subtracting the placebo probability. In our example: if you had 100 people, and in the placebo 10 of them to stop, and your drug group 35, how would you know many of those 35 stopped because of 1) placebo 2)drug 3) placebo and drug?

Can you name even one indication in which one therapy, and only one threrapy cures more than 50% of the cases?

EDIT: "cure" is a little dubious of a word to use with medicine, as many mant medicines only allevate symptoms or something else, and don't actually cure...

[foreward]

I dare say that for many benign to moderate infections, modern antibiotics are more than 50% effective...

I agree that my logic when it comes to placebo-control was wrong. Still, some portion of the test group will have experienced placebo, and with success rates as low as 30%, this doesn't give a lot of wiggle room. If even it was 5% then only one quarter of those who use this vaccine will truly benefit from it. This is important because find it highly unlikely that those who benefit due to placebo will remain off tobacco indefinitely.

Still, I don't think that there was anything wrong with what I said. If the majority of drugs are not more than 50% effective, then the patient should be made aware of this when they are prescribed the majority of drugs. How can we possibly evaluate risk v. benefit if we don't even know what the likelihood of benefit is?

If you were prescribed a drug that might or might not save your life, but there is also a fairly good, albeit rare, chance you might die from some serious side effect, wouldn't you want to know exactly what the odds are?

[pylkko]

If you read the article, it said "30 percent to 35 percent of those given NicVAX were able to remain smoke-free over the long term, compared with only 10 percent of those receiving the placebo", meaning that the placebo only group quiters remained smoke free for as long as the vaccine group ones. I think that it is more correct to say in your example that 30% will truely benefit from the care with the vaccine, and 10% will truely benefit from care with only placebo (the placebo effect within the vaccine is feature of the vaccine, and not the same as the placebo of the placebo only) and an unkown amount will truely benefit from no care.

I was thinking about my own dare, and thought about insulin in diabetes 1, but then I came to the conclusion that that is not a fair example because insulin is not an exogenous crafted drug. Even so, there are people for whom certain insulins suite them better than other ones, mainly because of non pharmacodynamical reasons (kinetics, practical reasons, whatever). Some antibiotics might work in more cases than 50% for specific microbe infections, this is not always the case with resistence, variance in tissue morphology and penetration and other individual factores, about 10% of people can't use betalactam antibiotics because of allergies and all, but there might be cases where it is true... I'm not sure about that. But anyway, my point was that having such high therapeutic success rates (50-75%) would be a little too much. Discarding drugs that help smaller portions of the population would not be sane, especially since they could help those few very very much. The success rates of competing nicotine addiction therapies are pretty low also AFAIK. Like nicotine maintenece with gum and patches.

Usually it's not a problem for patients, because if the drug has a low success rate, there are other ones that can be tried, sometimes in combo. In this case, your physician would probably say that it has been shown that even those that fail using this vaccine will lessen the amount that they smoke per day, and hence it is still worth it.

Any rational patient always asks (or finds them independently) the risks in various cures. Usually, however, when you are seriously ill there are few options. And usually drugs don't cure.

[foreward]

I agree with what you are saying, mostly, and I didn't mean to imply that drugs with less than 50% success should be discarded, only that patients should be given better access to information, that drugs of particularly low success rates and particularly high placebo success should be considered with greatest scrutiny - which is of course the case. I'd just like to see more balances put into place here to prevent SSRI-type problems in the future.

As for what "most patients do" there is some truth to that. However, many patients are under informed, I think. My doctor for instance told me that Lunesta "isn't addictive" and that Prozac "won't cause mania", keeping in mind that I am DX'd bipolar. Many patients would take this on face value, and if they hear otherwise then they would assume that their trusted doctor should know better than they do and that they must be misunderstanding something.

[pylkko]

You need to get a new doctor, seriously. And never trust the opinion of only one in big questions.

[foreward]

yeah, dude. the guy is a joke. doesn't know jack shit about BP. I kind of doubt he's going to last long at the clinic I go to. My therspist says of all the people she referred him to, I'm the only one that still goes. My therapist said that he prescribed a girl with anxiety disorder dextroamphetamine. That'll help. Offered me benzos before inquiring if I have had problems with substance abuse (which I don't, but still very irresponsible). Wanted to increase my medication from depakote to like three or four other drugs, including one blood pressure medicine.

He's a lousy doctor, but, I know the condition well enough. He respects my rights, he's not going to rediagnose me for no reasons, and he's not going to ask a lot of questions if I need ativan or lunesta - some docs just won't prescribe these kinds of drugs at all, so it's nice to know that if I really need them they will be made available. But the best part is he is an addictionologist!

Like I said, I'm pretty sure this guy is going to be fired in a matter of weeks. But it's not so bad for me. I just know there are a lot of scared/desperate people in the mental health  community who he could really fuck up. I've voiced my position on him to the clinic, so i'll just let things take it's course.

[Gnome]

Who here manages to smoke once in a while and not develop a need for nicotine on a daily basis?

I do.

Not that it is directly related to the topic, but I think it's interesting to see how people who have a cigarette almost expect themselves to "have to" smoke every day, and also people around them who think along the same lines. Hell, I often go for a week or two without ever craving a cigarette. It puzzles me how the addiction seems to be something people expect to happen, and therefore willingly make it happen, instead of setting realistic boundries for their smoking.

If memory serves me correctly, physical addiction can take over a year to develop when smoking on a daily basis.

This is not a bash directed at people who are smokers. I'm simply wondering about what psychological mechanisms are in the works when addiction to nicotine develops.

[pylkko]

The neurochemical reasons for addiction are pretty well known and documented. Some people are just more prone to addictive behavior than others.

[whateveryouwantmetobe]

Can you name even one indication in which one therapy, and only one threrapy cures more than 50% of the cases?

Do you mean cures outright or just treats?  If treats, insulin.

We could also stretch to say glucagon is damn near 100% effective at "curing" hypoglycemia. 

[2a]

what about pain meds?  again, this is dependent on what is meant by "cure," and those too may not be all that efficacious, I don't know.

[pylkko]

Do you mean cures outright or just treats?  If treats, insulin.

We could also stretch to say glucagon is damn near 100% effective at "curing" hypoglycemia. 

Lol apparently you missed a part of the thread.

what about pain meds?  again, this is dependent on what is meant by "cure," and those too may not be all that efficacious, I don't know.

Well you can specify the question/dare by asking whether there is one indication as in medical norms like ICD 10 or DSM or something like that, in which more than 50% of the patients can be efficiently treated with one and only one pharmaceutical therapy.

[Gnome]

The neurochemical reasons for addiction are pretty well known and documented. Some people are just more prone to addictive behavior than others.

Not what I was asking. I'm curious as to the psychological and social mechanisms for nicotine addiction.

[whateveryouwantmetobe]

Ah, well in that case...

Insulin cures type 1 diabetics from having to die.