Wyeth’s Dr. Phil Ninan on Pristiq

Dr. Grohol: Did Wyeth’s clinical trials on Prestiq show any increased risk of suicidality or suicidal ideation for people taking the drug?

Dr. Ninan: That again is a very good question, and let me just give you a little bit of background. One, when we look at the rating scales. So, for example, we look at the item of suicidality that might be in the Hamilton Depression or the Montgomery-Asberg Depression Rating Scale, we see significant improvements in those groups over the group that got placebo.

What happened in 2004 was the FDA looked at this issue beyond just these rating scales, and looked at what caused suicidal behaviors. And this is where the details become really relevant. So, you might have somebody who has taken the pill in the morning, doesn’t realize that they’ve taken it, and then therefore they go back and take the pill again later in the day. Some charts would code that as an overdose, even though there was no intent to harm themselves.

There were situations where somebody would get frustrated and bang their head against the wall. And that was coded as being a suicidal gesture versus somebody who had a very serious intent to harm themselves, and actually completed suicide.

So, what the FDA did to try and balance this out… And so we have this variability when we have 30 or 40 sites that are assessing patients coming into studies. You can see a wide variety of things that are put into the case report form. And so what the FDA did was they came up with a comprehensive list of words that might be associated with suicidality.

And then if those words came in a case report form, then narratives of that event was written up. And then blindly, three raters would rate those on a scale that was agreed on by the FDA to decide whether a suicidal attempt had been made, what was the intent of that, how serious was it, and those kinds of issues.

And the idea of having three raters was: you would start with two and if there was a disagreement then the third one, his or her work, would be the one that would be made to use to make a decision like that. So, that technique, and the rating is done at Columbia University.

So, if you ask the question: Have you looked at the studies with Prestiq along those kinds of lines that were done by the FDA? No, we have not. But, we’ve looked at trying to understand whether there is an increase in suidicality during the acute phase of treatment, which is what the FDA has added the black box warning for.

And these numbers are pretty small. And so it’s hard to be able to make a statistical significance to it. There is a greater number in the people who are treated with Prestiq compared to placebo. And we don’t know how exactly to code some of what has been termed suicidality, so I can’t give you exact numbers.

But we do have a black box warning like all of the new generation antidepressants do. And we would expect that the risk associated with Prestiq would be no different compared with the risks associated with other antidepressants.

I should also point out that suicide ideation, suicidal gestures, behaviors, and completed suicides are often possible with the illness. And so it’s one of those things where you’re trying to distinguish what is the underlying illness versus what are the effects of treatment.

I should also, to completely transcend, we did have one patient who did commit suicide, who completed suicide. That patient had been randomized to Pristiq and completed suicide about four or five days after they had been randomized. But, it’s not clear whether that person took even a single dose of Pristiq. And that was part of the information that we gave to the FDA.

Dr. Grohol: Does Wyeth have plans to publish all the clinical research data, including any negative trials related to Pristiq?

Dr. Ninan: Yes, we do. And in fact, information about each and every trial that had been conducted with Pristiq is already available. These are called the phase three or the conformatory trials. These are actually available on a website called clinicalstudyresults.org.

And if you go into that site and you put in the word Pristiq, you’ll come up with, I believe it’s about 14 studies that have been reported in there. And that is the complete portfolio of the phase three studies that was submitted to the FDA.

These are synopses of the case reports. And each synopsis is anywhere from three to seven pages long. So, there are over 100 pages of information that if somebody wants to go through the details, those are available on the web.

We are in the process of writing up these studies and publishing them. These take time, because we have to make sure that we’ve got all the details down. And we have to submit them, reviewers have to go through these 10 to 20 times. And then there’s a delay before they finally get published.

But the pivotal papers are being published. We have, I believe, around five or six of these studies that are already available. And the others will be available fairly soon.

Dr. Grohol: Companies seem to be increasingly tweaking existing drug compounds. What are the challenges faced with trying to come up with a completely new or novel antidepressant?

Dr. Ninan: Well, that’s a huge question. One is that as we have been on the search of the human genome, we are amazed by the tremendous variability that exists between us as individuals. And so when you take the human brain, which is the most complicated organ.

It’s actually the most complicated structure in the known universe. And it’s the only organ that has about 80 percent of all of our genome expressed in it. And it has this incredible phenomenon, which is the brain is the organ, but you have the mind that is emerging from the activities of the brain.

And what we have are the challenges that when we are using medications to try and treat abnormalities in brain function that are expressed as mental phenomenon. We are using medicines that go to the brain, but we are measuring outputs that are coming through the mind.

And so you can understand that this is one of the most complicated areas in terms of drug development. It’s much easier if you have, say, a cancer cell that you can make into a cell line, and you can throw a bunch of things at it in the lab, and get an idea of how you would be able to treat it.

So, the complexity of this is extraordinarily difficult and complex. Additionally, what we find is that the way that, with our current state of knowledge, we’re making the diagnosis of depression as a very… It’s a global kind of a label that is based on the presence of a minimum of five symptoms out of nine that are present most of the time for at least two weeks.

And so you can see that within that smorgasbord approach, you’re going to have a tremendous number of different types of depression that exists. We have not been able to distinguish those different types yet from a biological standpoint. And that has been a big challenge.

So, we might have had medicines that were effective in a subgroup of patients with major depressive disorder. But, within our current capacity to be able to demonstrate efficacy, we might have difficulty demonstrating that because it’s not a broad spectrum medication that would affect it.

So, these are some of the challenges that I think, we, as well as other companies, are struggling with in terms of being able to come up with revolutionary answers that you would want. But, in the meantime, what I would say is coming back to Pristiq, we are proud that we are able to come up with, because we are able to demonstrate efficacy and safety with this medication.

And we tweaked it so that, by and large, people seem to be more tolerant of this medication, such that a number of people stopping it are no different from the number of people stopping placebo. I didn’t tell you right at the beginning in answer to your first question, this is a medicine that doesn’t have to go through complicated metabolizing enzyme systems that break down medicines, because there’s genetic variability in those enzyme systems.

So, not having that makes it also a medicine that goes through simpler systems in the liver. And therefore, it’s a little bit more predictable in terms of plasma levels that would have when you take a particular dose. And that might actually also give it some advantages in terms of having this simple starting dose being the effective dose, and helping a substantial number of patients with depression.

Dr. Grohol: Just one last question… On Monday Eli Lilly won expanded approval from the FDA for Cymbalta in the treatment of fibromyalgia. Is this a concern that you think maybe that Pristiq may be good for? Or are there other concerns that Wyeth might be looking for Pristiq further down the road?

Dr. Ninan: We do have studies that we want to see whether it’s efficacious and safe for, so we’ve done a number of studies in the area for vasomotor symptoms associated with menopause in women.

We are also doing studies in fibromyalgia. And we are also doing studies in pain conditions, to see whether Pristiq would demonstrate benefits.

Dr. Grohol: Thank you very much for your time.