Harry Croft, M.D., psychiatrist and the chief of CNS Research at Clinical Trials of Texas, Inc. talks about a promising new medication for treating PTSD.
Interview conducted by Ivanhoe Broadcast News in June 2016.
Is there a shorter phrase or name of this drug beside TNX-102 SL?
Dr. Croft: No it’s an experimental drug but it’s a new formulation of a drug that people may know about: Flexeril. The chemical name is cyclobenzaprine. Flexeril has been around for years; it’s taken by pill and it’s taken three times a day, usually ten milligrams three times a day. If you’ve ever taken a muscle relaxant you know it makes you real sleepy and you don’t feel good. What Tonix Pharmaceuticals, Inc. did with this compound was they took the main compound and made it sublingual medication (under the tongue) formulation, of the medicine. What that does is it goes directly in to the bloodstream without going through the stomach and the gastrointestinal symptom and it doesn’t go through the liver to get metabolized. Because it doesn’t have an active metabolite that lasts a long time, the hope was a drug whose maximum blood level would occur after people fall asleep and it wouldn’t cause them to be drowsy the next day and it would have a much shorter half-life in the body. The metabolic breakdown product does something that actually may worsen PTSD, so we get away from all that with this sublingual preparation.
How often do they take it, just at bedtime?
Dr. Croft: Those in the study have taken it just at bedtime and Tonix Pharmaceuticals tested two doses: 2.8 milligrams and 5.6 milligrams. The 5.6 milligram dose worked, it showed a statistically significant positive effect, not just on sleep for PTSD but the major symptoms of PTSD as well. The population that was being studied was either combat veterans or first responders, all of whom had PTSD.
Besides sleep what are the other things this has impacted so positively?
Dr. Croft: The four clusters of symptoms of PTSD are these. The first is unwanted remembering of the traumatic event. To have PTSD you had to have experienced a traumatic event that either involved possible loss of life or health: that is, major traumatic event. Unwanted recall could come in the form of unwanted thoughts, nightmares, nightmare like events when veterans were awake, called flashbacks. Or triggering events, sights, smells and sounds that would bring back responses of the traumatic event. That’s cluster number one. Cluster number two is called avoidance. That is a conscious avoiding of talking about or thinking about or dealing with the traumatic event. Cluster number three has unwanted thoughts and emotions. The most common of which are mood problems, problems with socializing, not wanting to be out with others, not wanting to be in crowds, problems with guilt, and problems with experiencing positive emotions. Then the forth cluster is the one we usually think of with PTSD and that’s called the arousal cluster. That involves things like being easily startled by noises or being touched from behind when you don’t know somebody is there. Hyper vigilance: that is always looking around and worrying about who’s around you and that becomes problematic in veterans. In driving situations where there’s a lot of cars right around them. Or when they go to a restaurant and they have to sit with their back to the wall so they always can see who’s coming in. It also may involve at night being hyper vigilant. Sometimes sleeping with a weapon, a bat or stick or knife. Or checking the windows and doors at night to make sure everything is safe, and then anger and irritability. Those are the four clusters. We measure the impact of the PTSD by means of an instrument called the CAPS, the clinician administered PTSD survey. The CAPS involves questions about the presence and severity of all of those symptoms I just mentioned. The top score on the CAPS is eighty. To get in to this study you needed at least a moderate to moderate severe amount of PTSD: a number of at least mid-thirties. Most of the patients who got in to this study had a CAPS score of forty. What we measure over time is the reduction in the CAPS score. And the CAPS score deals with all these four clusters of symptoms. In other words it not only helps sleep, it not only helped anxiety, it helped with arousal symptoms, it helped with negative thoughts and emotions, it helped with avoidance, it helped with unwanted thoughts to a degree that was statistically significant. This was a twelve week study so the veterans or first responders with PTSD came in every week at the beginning and then every two weeks and we measured their CAP score and how they were doing and so forth. Then at the end of the twelve weeks they could join in an open label test which meant there was no placebo group. In the first group some patients got 2.8 milligrams some patients got 5.6 milligrams and some got placebo or sugar pills. In the open label they got the actual drug just to see the safety and how they would do for the next six months. Patients in our group on the open label, those that we knew were getting the drug did extremely well.
There’s been no other drug that’s effective, allowed sleep and address these four clusters?
Dr. Croft: Yes. The drugs that have been FDA approved for PTSD actually came about from the studies of civilians and PTSD. PTSD can be caused by combat but it also can be caused by single incident trauma. A rape, hurricane, fire, flood, car wrecks and so forth. The drugs were originally tested mostly on single incident in civilians and the only two drugs that have been approved for PTSD are Zoloft® (sertraline) or Paxil® (paroxetine). Those drugs were improved in the early nineteen nineties. We haven’t had another new drug that’s been FDA approved since those two drugs.
And we’ve had so much happen since 2003 in terms of PTSD. So those drugs even if you were to take them they still aren’t addressing these four clusters?
Dr. Croft: They don’t address them as effectively as this drug appears to do.
This to me sounds promising, is it really a big deal, is this huge?
Dr. Croft: The way we study new compounds for the FDA: we do Phase I studies which is the first time you’ve used the drug in human beings, those are normal volunteers usually a few, less than a hundred. The Phase II is where we first study a compound in people who have the disorder. The Phase I are normal volunteers. Phase II are the people with the disorder and in Phase II we try to find out does the drug work and in what doses does it work best and what are its side effects. This was a Phase II trial, it was positive for the 5.6 milligram dose and what then will occur hopefully will be the Phase III study and in Phase III you give it to an a lot bigger group of people. This study involved about 240 patients, the next study is planned to involve 400 or more patients. The next step is Phase III, if it works in Phase III then the answer to your question is yes, this would be a big deal. Patients with PTSD, especially combat PTSD, are suffering tremendously, many of them. And anything we can do to help will be of value. We do use some medications now off label that is that are not FDA approved for that use. For example, we have a drug for nightmares, it was a medication that used to be used for high blood pressure called minipress® or prazosin and then they found out by accident, wow, it reduces the frequency and intensity of nightmares but it didn’t work for the other symptoms.
Tell me the difference between those kinds of drugs you’re talking about too and even Paxil and Zoloft those go through the liver. That’s that whole metabolizing thing?
Dr. Croft: Yes but they’re not metabolized in quite the same way. The metabolic breakdown is important for TNX-102 SL but is not as important for those drugs.
Tell me again what the name of this drug is.
Dr. Croft: TNX-102 SL is the name of the sub-lingual formulation of cyclobenzaprine that Tonix Pharmaceuticals is studying. It is similar to Flexeril, which is used orally in pill form and for a different reason and in a different way. It’s the same basic compound that’s given in a totally new form.
So the metabolism of that isn’t as big the way the other things are?
Dr. Croft: Yes.
What about other drugs used to treat depression?
Dr. Croft: These other drugs most people will realize are called SSRI’s, they’re usually used for depression or anxiety, they seem to help those symptoms better than some of the other symptoms for PTSD. Many of the veterans find they don’t work all that well for PTSD.
They’re not addressing all those clusters and those things you’re talking about. When is Phase III going to start?
Dr. Croft: We don’t know because I don’t work for the company that is developing the drug, Tonix Pharmaceuticals; I’m an independent investigator. Tonix has announced that the company plans to start a Phase 3 trial in the first quarter of next year. But a lot of that depends on negotiations with the FDA in advance.
They have to have FDA approval for Phase III? I didn’t know that. So does that make it faster to get it approved if Phase III goes as planned and it’s as positive as this has been?
Dr. Croft: We don’t know, there are some other “ifs” in there.
I guess the way I would word this is if it continues to show the promise it does now it’s likely it will be on the market in a couple of years.
Dr. Croft: If it shows positive results and you know medication trials for FDA approval generally take a couple of years to finish, to enroll, to do it, to finish, to analyze the data and then the FDA itself may take six months to a year to actually approve the drug. We’re probably looking at another couple three years or more. But it’s exciting that at least we’re looking in to something that has promise.
PTSD is a horrible thing isn’t it?
Dr. Croft: Yes. I have evaluated over the last twenty two years some eight thousand veterans for PTSD and traumatic brain injury. Some of the things I explain to those veterans, one is PTSD it is not something you’re born with it’s something you develop in response to a trauma. It doesn’t mean you’re weak or you couldn’t handle it. It’s something that happens. Number two PTSD invades many areas of your life. It doesn’t just affect your emotions or your sleep it affects your relationships, it affects your ability to parent, it affects your job ability, your employability, your ability to go back to school. It affects lots of areas of your life. Number three, time alone does not seem to cure combat related PTSD. I wish all we needed to say is give it enough time and it will get better. We know from dealing with Vietnam vets– and remember Vietnam has been over for decades already– many of the Vietnam vets are still suffering from it. The fourth thing about PTSD is it is treatable but the treatment involves both the talking therapy and medication. The medication makes it easier to fully utilize the talking therapy or psychotherapy.
This particular medication as you said helps with that because it’s one of the clusters. Can someone who’s had PTSD for four decades be treated possibly with this drug? Is it working?
Dr. Croft: I don’t know about this drug but with treatment yes, even people who have suffered from it for many years. Now it may well be that they don’t get cured of PTSD, in the same way that they don’t get cured of diabetes. But people with diabetes who get effective treatment can live meaningful and satisfying and often symptom free lives. That’s our hope with treatment of PTSD.
So this medicine is not going to be a cure?
Dr. Croft: No. I’m afraid no medicine will be a cure but it will be part if it gets approved and remember that’s down the road, but if it gets approved it might be an important part of the treatment process for treating PTSD.
That’s exciting.
Dr. Croft: Yes it is exciting and you know I was in the Army in 1973 I was in charge of the Army’s drug and alcohol program in this area. That was at the end of Vietnam and we never had an empty bed, tragically, in our drug and alcohol program. All of the soldiers who came back from Vietnam with drug and alcohol problems also had PTSD. But it was a disorder in 1973 that didn’t even have a name. It didn’t get its name until 1980 and more importantly we didn’t know what to do for these poor souls that had the disorder. That’s where my interest in PTSD started, twenty two years ago when I got a call from a company that works with the VA to evaluate disability in veterans I jumped at the chance because by that time we better understood PTSD. That’s where I became really interested. When we started doing this study at our site, and by the way there were twenty four sites in the United States that did this study: two academic sites, two VA sites and twenty private sites like ours here at Clinical Trials in Texas. When we got the chance to do this study I jumped at it because I hoped that this would be a product that would help veterans. Because even though we have certain medications we don’t have the full package yet to help these vets. Treatment is difficult, even the talk therapy. Remember I told you one of the clusters is called avoidance. Avoidance means you go out of your way not to talk about it. Well guess what, part of the therapy, especially prolonged exposure or cognitive processing therapy, demand that you think about it and talk about it. Do the very thing that you’ve been avoiding all these years and many vets even who have great therapists say, “I ain’t doing that. You know when I talked about it and thought about it my nightmares went up and my flashbacks got worse and my thoughts came more frequent.” It became very difficult for them to even engage in the talking therapy. Hopefully medications like this one if its approved might make it easier. We can’t say that for certain yet because this was only a Phase II study.
But in the Phase II did it help them talk?
Dr. Croft: Yeah, it helped them in terms of their avoidance symptoms. They were able to deal with it, think about it, and talk about it better.
So how many people in the study, six hundred and forty?
Dr. Croft: Two hundred and forty in this one. The next Phase will be 400—
Okay and so 240 was that all at this clinic?
Dr. Croft: No, no.
That’s across the country?
Dr. Croft: That’s across the country. I think there were about forty patients on the bigger dose, the 5.6 milligrams.
Were there any side effects that you guys found?
Dr. Croft: Sedation was one of the side effects; dry mouth was a side effect. There were some other side effects: headaches and other things, it worked. The good news about the sedation was it generally came while they were trying to sleep and since sleep is a problem it can help.
That actually helped them sleep better?
Dr. Croft: Right.
Is there anything that I didn’t ask you about you can think of?
Dr. Croft: No. I think it’s important in the piece to emphasize this drug is not available yet. It’s not FDA approved yet, all the usual things. This was very early in its development but Tonix was so excited and the benefit frankly of this kind of piece will be that it will help with enrollment of the Phase III studies. I personally believe that combat PTSD may be a little different than other causes of PTSD although they’re going to study this for both. But combat PTSD is not a single event; if you’re in a combat zone, every day is a potential for an explosion of an IED, an incursion by enemy troops or things to happen. So that it’s not just the battle that causes the PTSD it’s the whole picture, the whole gestalt of being in the combat zone.
Yeah, you’re just sitting there waiting.
Dr. Croft: Exactly and you never know when the sirens will go off or the explosions will go off. I’ve had veterans that I’ve evaluated, one guy told me I’ll never forget, he said “doc I was a cook, I was a cook, I didn’t even carry a weapon I was a cook. But you know that IED that came over the wall that exploded not more than fifty yards from us it didn’t know I was a cook.” Everybody can be in danger whether you’re a typist or a cook or whatever you are. That’s different and being in combat is different. Another difference is this is the first war in the history of modern warfare where combatants have gone back to the same combat zone over and over and over again. In World War II you were there for three or four years maybe. But once it was over it was over, you came home and it’s done. In Vietnam you were there for twelve months, thirteen months if you were a marine because you were tougher, but at the end of twelve or thirteen months you came home, it’s done. In this war I’ve seen veterans who have gone back five, eight, nine times to the combat zone.
What does that do for their—-
Dr. Croft: We don’t even understand, just the impact of that. Forget the fact that they’re in combat just the fact of going back to the combat zone over and over and over again. We don’t know. But it’s got to have an impact.
I imagine that’s your worst nightmare if you have PTSD, I’ve got to go back.
Dr. Croft: There’s an interesting part of it; many veterans come back, they hated it where they were but they understood it and they got comfortable with it. They came home and felt like a fish out of water. Many of them volunteered to go back as private contractors sometimes because culturally they couldn’t deal with the- the civilian world.
Really it can be a short so called tour over there to change you. All you know is civilian world and you can go over there for six months and be a changed person.
Dr. Croft: Yeah, I said of all the things you saw and heard about in Vietnam, now this was Vietnam many years ago, what’s the one that affected you most? He said “well we were on a convoy, we were in a truck and I was sitting next to this guy and a shot came through the window and killed the man, my soldier buddy right next to me.” Imagine the impact of that. Or the impact of seeing civilians, women, children hurt in war. Or having to hurt them in war. There’s a lot that goes into it and this PTSD can affect lives greatly. It can affect marriages, it can affect children. You know one of the symptoms is you don’t want to go where there’s a lot of people. What if your ten year old child has a football game and you want to go to it; you want to see your kid but here’s all these people. How do you do it, often veterans don’t, or often if they go they have to get way in the back or way on the side so they can leave if it gets too bad. Or if they don’t go their children often wonder what’s wrong with dad. He must not love me enough, he don’t come to my stuff, or the anger and irritability, simple stuff. You leave your toys out and the veteran with PTSD goes absolutely angry and then feels so guilty about what he or she just did.
And you can’t help.
Dr. Croft: You can’t help. They won’t even talk to you about it and that’s a problem.
END OF INTERVIEW
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