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October 5, 2009


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OPERATOR:  Good afternoon, ladies and gentlemen, and welcome to today's conference. For further remarks, I'd like to turn the floor over to Jeff Levine of the National Institute on Drug Abuse. Sir, the floor is yours.

JEFF LEVINE, PRESS OFFICER, NATIONAL INSTITUTE ON DRUG ABUSE:  Good afternoon and welcome to this teleconference sponsored by NIDA, the National Institute on Drug Abuse. I'm NIDA Press Officer, Jeff Levine.

Today we're pleased to share with you the results of the first successful trial of a vaccine to treat cocaine addiction. To explain the significance of the findings, we have with us NIDA Director, Dr. Nora Volkow, and Dr. Thomas Kosten, the lead investigator of the study from the Baylor College of Medicine in Houston. The research has just been published in the Archives of General Psychiatry. After our presentations, all of you on the call will have a chance to ask follow-up questions.

Dr. Volkow, let's start with you. Why has NIDA chosen to support this study?

DR. NORA VOLKOW, DIRECTOR, NATIONAL INSTITUTE ON DRUG ABUSE:  For several reasons. First of all, welcome, everybody. It's a pleasure to be here and have you here.

The reason why NIDA supported this study is, number one, it's — cocaine abuse is a serious public health problem. Indeed, one out of three drug-related emergency room visits can be associated with the abuse of cocaine. It's also a frequent drug of abuse and it is estimated that in the United States, approximately — there approximately 1.4 million users of cocaine and these numbers are particularly problematic among those that are 18 to 25, where the abuse of the this substance is the most frequent.

Despite the importance of this drug, there are no currently FDA approved medications for cocaine addiction and the findings from Dr. Kosten are transformative, vis-à-vis their ability to demonstrate for the first time an intervention that shows positive results in the cocaine addiction, number one. And it's also of importance because they show that this may be a promising approach as a strategy to address other types of drug addictions. So we welcome very much the results from Dr. Kosten. They open a series of new opportunities, including the first positive trial of a successful intervention for cocaine addiction.

LEVINE:  Thank you, Dr. Volkow. Dr. Kosten, would you give us some background on the development of your vaccine and the key findings of your new study?

DR. THOMAS KOSTEN, PROFESSOR OF PSYCHIATRY AND NEUROSCIENCE, BAYLOR COLLEGE OF MEDICINE:  Thank you very much for the introduction and certainly I do want to say thank you to the National Institute on Drug Abuse, who has stood with us for now almost 15 years of supporting what seemed initially an idea that really wasn't going to work and now has in fact shown great promise.

The vaccine itself, like other vaccines, it works by stimulating the body's immune system to produce antibodies. In this case the antibodies are targeting cocaine molecules while they're still in the blood stream, thereby preventing the cocaine from entering the brain and exerting their psychoactive effects.

Unlike other vaccines, though, such as those from measles and influenza, the antibodies do not destroy or really neutralize the disease causing agents. They simply bind the cocaine molecules and then prevent them from crossing the blood-brain barrier. The other part that's particularly important with cocaine is that there's an enzyme in the bloodstream called cholinesterase that will break down the cocaine as long as we hold it in the bloodstream.

So cocaine is a particularly good target to start with, because with your other drugs of abuse the antibodies will be needing to carry the nicotine or opiates or methamphetamine to deliver to the kidney, where they will eventually be excreted. But the process of these holding the drug in the bloodstream and out of the brain and out of the heart and out of these other organs is the key way that it works.

The study itself is published in the Archives of General Psychiatry and it was done in part while I was still at Yale University and was finished here at Baylor College of Medicine in Houston and has been very strongly supported by the Veteran's Administration, both at the Connecticut Healthcare System and the Michael E. DeBakey VA Medical Center. I do want to acknowledge them that I worked with the VA and they have been very helpful in this.

This is the first successful placebo controlled demonstration of a vaccine, which targets an illicit drug of abuse. It involved 115 patients who were both men and women between 18 and 55 years old. They were on a methadone maintenance program and met DSM IV criteria for cocaine and opiate dependence.

These methadone-maintained patients were studied because retention in methadone is substantially better than in primary cocaine treatment programs and this study really required volunteers who'd be retained for at least the 12 weeks to complete the vaccination and then another 10 weeks of follow-up that we were doing with them.

Participants, again, randomly assigned to receive either this anti-cocaine vaccine or a placebo with 55 of the vaccinated completing the study and 47 of the placebo patients completing. Both groups received five vaccinations at the baseline and then two, four, eight, and 12 weeks over this 12-week period and were then followed for an additional 12 weeks.

The efficacy assessments began at week eight, when most of the vaccine responders should have reached significant blood antibody levels and all participated in weekly relapse prevention therapy with a trained substance abuse counselor. They had their blood tested for cocaine antibodies and underwent urine toxicology three times a week for both opiate and cocaine use.

What did we find? Well we found that those who achieved sufficient antibody levels of what was 40 micrograms per milliliter, a fairly high level of antibodies, and this was 38 percent of the participants or 21 of them. But at this level, it really blocked cocaine's euphoric effects and that it corresponded to an increase in cocaine for urines during weeks nine to 16, compared to those who got placebo or those who did not achieve these higher levels of antibodies.

The participants with the highest antibody levels had the greatest reductions in cocaine use. There was a dose response relationship in that way and the antibody levels fell significantly in weeks 16 to 24, with a corresponding decrease in the cocaine for urines, that is people began to override the antibodies as the antibody levels fell.

There were no serious adverse effects associated with the vaccine and the immunization did not achieve complete abstinence from cocaine use in most of the people, however the reduction in use can still be associated with meaningful improvement in cocaine users' social functioning and of course in therapeutic outcomes. And a lot of the cocaine use that continued was testing the blockade, some of which was testing to what appeared to be up to ten times the amount of cocaine that people had used in the past and yet they were describing that they were not getting any high from it and they eventually just ran out of money.

So the optimal treatment will likely require repeated booster vaccinations in order to maintain these appropriate antibody levels. Probably about every two to three months they would need a booster and for most of these patients, usually you're going to have to have two years or so of treatment. In some patients it may take longer than that, since they've usually had six to eight years of cocaine abuse and dependence before they show up for treatment.

We will be making efforts and they are certainly needed to maintain patients during the initial series of injection, since the antibody levels do rise slowly over the first three months when the patients are immunized under this protocol and it's only at about week eight that you're getting substantial levels of these blocking antibodies present.

So that I think would cover most of the findings. I think in the future we see this as a very promising step towards an effective medication for cocaine addiction. And we are planning on a follow-up study in a larger population of users in a multisite study to start in January of '10 and the goals for our future vaccine development is to increase the proportion of subjects who can really attain these higher antibody levels and extend the period of decreased use and abstinence through longer term maintenance of these adequate antibody levels.

In the animals we have in fact already developed some second generation vaccines, including one that uses a Neisseria meningitides protein complex that was provided by Merck Pharmaceuticals called Po-MPC (ph), in which we are getting four to five times higher antibody levels. They are rising within two rather than four injections of the vaccine and they are being sustained for almost twice long at these high levels. So we already have significant improvements over this, but I do want to emphasize that 40 percent of the patients got really blocking levels of antibodies that they did not appear to be able to overcome while those antibody levels were there.

Another 40 percent of the patients got sufficient levels of antibodies that we had studied this in a previous study with Meg Haney at Columbia University and found that at half of these antibody levels, that is at 20 micrograms per milliliter rather than at 40, we could block the effects of one to two dosages of cocaine, smoked cocaine, so that as a relapse prevention measure, as many as 70 to 75 percent of these patients would have sufficient antibody levels that if they were already abstinent it could help them remain abstinent.

This was a much more difficult population and all these patients were using cocaine quite heavily. Many of them daily users of cocaine and we were trying to get them to stop with a blocking agent, which is a more substantial and difficult population than the population in which you're having, working with them to provide — to provide them a opportunity to not relapse too.

So we're very enthusiastic about this. We think there's great promise for all the other drugs that we can vaccinate against, with the only exception being alcohol. The molecule itself is too small to make an antibody. And I'm happy to address any questions that people might have about the details of the study or the promise for the future or what some of the implications might be for how these types of vaccines might be useful.

LEVINE:  OK, Dr. Kosten. Thank you very much for your presentation. Now let's go to our listeners online for questions. Go ahead.

OPERATOR:  Thank you. The floor is now open for questions. If you do have a question, please press star one on your telephone keypad at this time. Questions will be taken in the order they were received. If you're using a speakerphone, we ask that while posing your question you pick up your handset to provide favorable sound quality. If at any time you question has been answered, you can remove yourself from the queue by pressing one. Again, ladies and gentlemen, if you do have a question or a comment, please press star one on your telephone keypad at this time. Please hold while we poll for questions.

Thank you. Our first question comes from Joyce Rudanne (ph) of the Clinical Psychiatric News. Please state your question.

JOYCE RUDANNE (ph), CLINICAL PSYCHIATRIC NEWS:  Yes, hi. This is a question for Dr. Kosten. You said you got a 38 percent response. Is there you know do you think you'd need to get it up higher? Is there more of something you'd have to put into the vaccine?

KOSTEN:  Yes. We think we could get more than 38 percent of our people getting these very high antibody levels with a different carrier or different adjuvant. We used a very primitive carrier, which was the cholera toxin, and the simplest of adjuvants, which is aluminum. And this is technology that's really from about 20 years ago.

The current technology that's developed in the large pharma companies for their vaccines, including the one that Merck Pharmaceuticals very generously let us use for the animal studies, produced substantially higher levels of antibodies, so that in the animals we were producing five times the levels of antibodies. If we did that in the humans, we would effectively have 80 percent of these people producing antibody levels above the threshold that we needed.

So I think that it's — the vaccine components that we need to do this are certainly available, but they're available in big pharma and the challenge right now is to try to get big pharma interested in not only nicotine vaccines, which there's already three of them that are moving along and Merck may have one also, based on the results we've gotten. But to somehow indemnify them or somehow make it in their interest to do this public health service to provide the vaccine for all these other drugs of abuse, which just don't have the profit margin that nicotine has.

RUDANNE (ph):  Thank you.

OPERATOR:  Our next question comes from Robert Boyd of McClatchy Newspapers. Please state your question.

ROBERT BOYD, MCCLATCHY NEWSPAPERS:  Yes, Dr. Kosten, how is it that the cocaine now passes the blood-brain barrier?

KOSTEN:  It's a very small molecule, so it just diffuses across. And you have receptors called the dopamine transporter on the other side that attract it. So it's driven across by the binding potential that exists on the other side of the blood-brain barrier.

BOYD:  Does dopamine transport — have any — be affected at all by your — by your antibodies?

KOSTEN:  No. These antibodies, they can't get across the blood-brain barrier and so it's holding it on the other side.

BOYD:  Yes, OK. OK, good, thank you.

KOSTEN:  You're welcome.

OPERATOR:  Our next question comes from June Nguyen (ph) of the American Psychiatric Association. Please state your question.

JUNE NGUYEN (ph), AMERICAN PSYCHIATRIC ASSOCIATION:  Hi. My question is in addiction treatment trials, attrition is a problem. Did you see that problem and do you anticipate problems in larger trials? Thanks.

KOSTEN:  We certainly did anticipate that problem and in primary cocaine abusers at the time that we undertook this study, now about five years ago, we were quite cognizant that we didn't — we weren't going to be able to retain the 85 percent that we were hoping to retain by conducting this in primary cocaine abusers, which is the reason we chose a population of both opiate and cocaine dependent patients.

We took those patients and we put them on methadone maintenance, which has extremely good retention and it's a treatment, though only for opiate dependence, not for cocaine dependence. And the combination of us seeing them every day in the methadone maintenance program, providing them with the methadone and giving them really first class treatment for their opiate dependence helped a great deal in the 85 percent retention that we had at the end of the study.

In a primary cocaine dependent population, in the last five years we've been able to come up with strategies that involve contingency management. That is we provide essentially prized for people or opportunities to get those prizes based on how regularly they attend the treatment programs and how regularly we can get them to come in over an extended period of time. In a small study that we just finished with this, we found we could retain the primary cocaine abusers actually out to six months.

This was for a different — for a vaccine study with a hepatitis vaccine, rather than a cocaine vaccine. And for the hepatitis you have to get injections over a six month period and we found that 90 percent of the patients were able to do that and it was a management strategy that involved essentially giving the rewards for showing up. The rewards were — they were like lottery tickets that they would get that they could in fact get more lottery tickets if they showed up more consistently. So it's called contingency management and it looks like it would be very effective for our next outpatient clinical trial where we're, again, trying to keep people in treatment for about six months.

OPERATOR:  And does that complete your question?

NGUYEN (ph):  Yes. Thanks very much.

OPERATOR:  Again, ladies and gentlemen, if you do have a question or comment, please press star one on your telephone keypad at this time. Thank you. Our next question comes from Andy Pollack of the New York Times. Please state your question.

ANDY POLLACK, NEW YORK TIMES:  Yes. I apologize; I haven't seen the paper. But I was just curious, what is the actual endpoint of this trial and did you achieve the endpoint?

KOSTEN:  Well the endpoint is reduction in cocaine use or increase in cocaine-free urines. And the cocaine-free urines is the essential endpoint that's the hard endpoint. And so what we did is we measured the urine toxicologies three times a week, since the half-life of the urine metabolite benzoylecgonine is such that by three days it's significantly washed out of your system. So we could then tell if people were using cocaine during this period.

And we compared the rates of cocaine-free urines for three groups. One group was the placebo group. Another group was those that were vaccinated but didn't reach the 40 micrograms per kilograms — actually 43 micrograms per milliliter of antibody concentration and those who met that criteria or went over it. And what we found was that the group that had the high levels of antibodies did significantly better than the placebo and the group that had the low levels of antibodies. And the people with the lower levels of antibodies, though, could not be distinguished from the placebo group.

So the outcome measured was weekly cocaine use and that is weekly cocaine-free urines is the way to put it. We also looked at self-reported cocaine use, which had a similar outcome, but the urines were the main outcome measure and we were looking for a difference during the period from when we felt — when the antibody levels were going to be sufficiently high, which is about week eight, through week 16, when we expected the antibody levels to start to fall off.

They stay fairly high for about eight weeks and then antibody levels tend to just drop because it's a protein that doesn't last that long and while with an infectious disease, each time you get another infection, it will stimulate the production of more antibodies, the cocaine itself does not stimulate the production of more antibodies. It's only cocaine attached to cholera that will do it. So even if they're using cocaine that will not push their antibodies up. It won't push them down either; it just won't change them.

And so we need to give this booster after about two months to — so that would be about week you know two months after week 12, so that would be around week 16. I think that got that — no. Do I have that right? No, week 20 — sorry; around week 20 we would give a booster that would then push the antibody levels back up. A single booster will push it up as much as we got from the initial five injections. And we've done some studies to actually show that already.

There's no way of telling in advance who will respond to this, so everyone would have to take this for about eight weeks to see if you're getting the proper levels of antibodies. That's the simplest way. We actually do have some predictors right now. One of the more intriguing predictors is the finding that we and others have had, which is there appear to be some people that make antibodies to cocaine, but have never been vaccinated against it.

We've characterized those antibodies. We haven't published this yet, but the people who have those antibodies did not seem to — they seem to be immune to immunization against cocaine. We could not produce an immune — another response to this cholera toxin vaccine. Why they have it is an intriguing question, but there have been three groups all showing it's particularly — it seems to occur in people who smoke cocaine.

A mechanism may be that it's like when the doctor — when you get allergy desensitization, where the doctor scratches you with the allergen on your hand and keeps doing that for months. Eventually you become — you're no longer allergic to that substance. That substance is viewed as something should be normally in your body.

There are people who appear to have self-immunized themselves, so that your body considers cocaine a natural part of it and doesn't — and you can't develop an antibody response to it, cause it's — that it's viewed as part of you. We think it occurs — well we've seen it in smoked cocaine users. It doesn't occur in others. We think it's a damage to the lung that occurs in cocaine reacting with proteins in the lung that are damaged, producing a self-immunization and a tolerance.

It's a — it's a fascinating phenomena opening up a whole new area of immunobiology that we're quite excited about, but it doesn't help us with the vaccine, unfortunately.

POLLACK:  Thank you.

KOSTEN:  You're welcome.

OPERATOR:  Our next question comes from Shari Roan of the Lost Angeles Times. Please state your question. Hello, Shari, are you on the line?

SHARI ROAN, LOS ANGELES TIMES:  Yes, yes. Can you hear me?


ROAN:  Hello?


ROAN:  OK. I'm sorry. Could you tell me, Dr. Kosten, if you'll have a different endpoint with your next study? For example, will you be looking at cocaine abstinence over a certain period of time?

KOSTEN:  It's a very good question. We certainly will look at that as one of the outcomes and we may do better than we did in this very heavy cocaine-using population because we will be taking primary cocaine abuses who tend to have lower levels of cocaine. That is they don't tend to use cocaine every day, but more like you know every couple of times a week or something like that, so getting — attaining abstinence might be easier with them.

But one of the things that is characteristic of giving any agent that's a blocker is that, like rats when you give them a blocker, they keep testing it out. And there's a couple of reasons that occurs in humans. First off, we do tell them in the consent form you have a 50 percent chance you're getting a placebo, so that has them test it out.

The other is we tell them in the consent form two other things. One is that this is a blockade that will help you, but you probably can overcome it and we wish you wouldn't try. And I think that the fact that we say we wish you wouldn't try probably makes them try. And then the third thing is the consent form does say some place during the course of this study you know probably near the end, even if you've been vaccinated, these antibodies are going to wear off and you have to be very careful not to use too much cocaine to try to override it because you might overdose.

So once again, I'm afraid that while we think of it as a safety issue, they think of it as an interesting challenge and so every other week or so they try how much cocaine can I afford and can I override this. And as I said, some people appear to be getting up to ten times as much cocaine as they'd usually take in an attempt to override it and it's just deconditioning this behavior, even though you would think it would be pretty obvious that you know why waste your money.

It's just as hard as it is in the rats, where they just you know they don't just immediately stop hitting the lever when we vaccinated them. They continue to hit it for about a day or so, although I do have to admit that the rats do seem to be smarter. Once they figure it out they don't hit it anymore. The people aren't quite the same. They keep hitting it.

ROAN:  Thank you.


OPERATOR:  Once again, ladies and gentlemen, if you do have a question or comment, please press star one on your telephone keypad at this time.

Sir, there appear to be no further questions at this time.

LEVINE:  All right then, thank you for joining our NIDA teleconference today. If you do have any additional questions, please call our press office at 301-443-6245. That's 301-443-6245. Thank you all for joining us again and have a very good evening.

OPERATOR:  Thank you. This does conclude today's teleconference. We thank you for your participation. You may disconnect your lines at this time and have a great day.