Torsten Falk, PhD, Associate Professor for Neurology and Pharmacology at the University of Arizona talks about using Ketamine with Parkinson’s patients.
Interview conducted by Ivanhoe Broadcast News in August 2018.
Tell us how you came upon the idea of treating Parkinson’s with Ketamine.
Dr. Falk: How I would actually get into that is to go one step further because what we want to do is treat the symptoms that occur with treatment of Parkinson’s. The side effects that result from levodopa are what we think that we can actually treat. So I was thinking to just introduce these side effects real quick.
Let’s talk about the side effects of levodopa.
Dr. Falk: Levodopa has been since the early 60s the gold standard treatment for Parkinson’s disease. It works well in replacing that missing dopamine that’s so central to regulation of movement. The problem is after five to seven years, a lot of patients start developing these side effects that can be just as debilitating as or worse than the disease itself. They’re called levodopa-induced dyskinesia and they’re the opposite of the motor symptoms of Parkinson’s disease. Parkinson’s disease is characterized by slowness of movement and levodopa-induced dyskinesia is actually over excited, over exaggerated movements. It’s more like a Chorea where people actually flail their limbs and have no control over their limbs. That can be very devastating and the effects increase the longer people get treated with levodopa, so often times they need to reduce their dose, despite the disease itself progressing. Finding an adjunct therapy that would blunt this side effect would be a great advance for patients because the patients that never develop levodopa-induced dyskinesia can be treated with levodopa quite well for a long period of time. We started thinking about this seven or eight years ago when my colleague Dr. Sherman, the head of the movement disorder clinic, and I were discussing Ketamine with a physician who uses that approach to treat migraine headaches. There are some similarities in brain activities between headaches of that kind and what happens during levodopa-induced dyskinesia. Activities in different brain areas are overly synchronized in both disorders. We thought if it works for migraines, maybe it could work for levodopa-induced dyskinesia as well. Dr. Sherman looked retrospectively at data from some Parkinson’s disease patients who were treated for pain with Ketamine and he actually saw some of these people had improvements in their dyskinesia. So we went back to the lab and with my graduate student Mitchell Bartlett we tested in our rodent model if that actually really holds up under controlled conditions. Indeed, we could show in our rodent model of levodopa-induced dyskinesia that with low dose sub-anesthetic Ketamine we were able to reduce established dyskinesia and we were able to suppress the development of dyskinesia. Based on that, we recently got some funding from an Arizona State agency to conduct clinical trials to see if we can translate that into the clinic. That is one big advantage of using a drug like Ketamine that actually has been used as an anesthetic for over 50 years. There’s a lot of safety data in much higher doses around. That makes it a much quicker translation where you can test it for efficacy in patient populations much earlier because a lot of safety testing has been done already.
It kind of shortens the time between. We’ve actually done a few stories on repurposed drugs and that’s the biggest advantage, isn’t it?
Dr. Falk: Absolutely. If you start with a new drug, it can be 5 to 10 years of safety testing before you can really do a proper trial to look for efficacy, and most drugs that fail, fail not for problems in efficacy, but rather in safety.
You said that the trial is coming up. Describe for us when that is and what the trial is going to consist of.
Dr. Falk: We’re currently working on the regulatory aspect and we’re hoping to start enrolling people in the fall. The first trial is going to be very small with 9 or 10 people to just look for the proper dosing paradigm. That way we actually take the dosing that we have used in animals and we translate the animal dose for human use. There will be some safety measures as well that will be evaluated. Then, next year we’re planning to do a proper placebo controlled trial. Because in the end, all the other preclinical work is all fine and dandy, but you need the controlled clinical trial to be really sure that the effects translate from the animal model to human patients.
If your trial proves successful and you’re right, how long until patients could actually take advantage?
Dr. Falk: Within about two and a half years, we’re hoping to actually have the results for the placebo controlled Phase II trial. In order for FDA to approve this there would have to be a larger scale Phase III trial. Phase II usually has about 20 to 25 patients and Phase III trials are big multi- institution trials that look all over the United States for effects. It is interesting to note that in recent years sub-anesthetic Ketamine has been used off label to treat depression and there are very encouraging results from the depression literature where there was recently a successful Phase III trial announced that actually showed efficacy against suicidality.
A patient who’s starting to have these conditions from the levodopa so you have to drop the levodopa to control the side effects, what then happens? Does their Parkinson’s get worse?
Dr. Falk: Yes. That’s the problematic thing. The Parkinson’s gets worse and the only really effective treatment we currently have for these patients is a brain surgery called deep brain stimulation where you put a stimulator in the brain. It’s an invasive procedure and a lot of patients due to their age are not candidates for such surgery any more. But that’s the only really effective treatment that’s out there currently.
For Parkinson’s, not for fighting levodopa side effects?
Dr. Falk: Let’s backtrack here. Deep brain stimulation is done for people that exhibit levodopa-induced dyskinesia so that they can reduce their levodopa dose. In the combination of deep brain stimulation and levodopa, people can continue to function quite well. It’s an invasive brain surgery, but it’s the only way you can actually avoid having substantial times both in the Parkinsonian or the dyskinetic state. The problems with patients is that later in the treatment of levodopa, they oscillate between their Parkinsonian state, then they take their medication, then they become dyskinetic, then they’re controlled for a while, then they need the drug again. So it’s a cycle.
So the tremors are not coming from the Parkinson’s, they’re coming from the drug?
Dr. Falk: The tremor comes from the Parkinson’s disease.
But Levodopa side effects would be a different kind of movement?
Dr. Falk: Yes. The levodopa side effects are rather like Huntington’s disease or a Chorea so people flail their limbs. Sometimes, in extreme cases, people have to lie down because they can’t sit in a chair anymore.
So Ketamine, what exactly is it?
Dr. Falk: Ketamine is a drug that has been used for over 50 years as an anesthetic. It’s still used in the emergency room for small procedures with children. It blocks a number of different targets so it has more than one mechanism of action. In the last decade, it has been increasingly used in a much lower dose, the sub-anesthetic low dose, to treat symptoms of pain and depression. We’re trying to show if levodopa-induced dyskinesia can actually be another disorder that can be treated by Ketamine. The way we’re looking at it is that, in a way, it’s almost like a reset button. You receive treatment and you have weeks to months long benefits. That is the really interesting, exciting part, that there’s no need for daily treatment. People get an infusion and then weeks to months long benefits get reported.
What haven’t I asked you about your upcoming trial and your research that you think is important to stick in the story?
Dr. Falk: One thing that would be good to mention is the sponsor. We received funding from the Arizona Biomedical Research Commission, which is Arizona State money, to conduct our clinical trials and investigate if the experiments with the animals translate to humans.
END OF INTERVIEW
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