Current Series: Treatment Advances In Dravet And Lennox Gastaut Syndrome

Anup Patel, MD: I think these are important conversations and topics, and I really appreciate everybody’s insight. I want to shift the conversation to something that we’ve alluded to, which is this movement that we’ve had in newer treatment options for both kids and adults with Lennox-Gastaut and Dravet syndrome. But before we do, Ian, I want you to comment a little bit on medical cannabis as a broad topic and how that’s taken over a lot of our conversations.

Ian Miller, MD: Sure. Medical cannabis doesn’t have a legal definition or a medical definition, per se. It simply speaks to the intent behind giving a cannabis-derived product to a patient. And if you’re talking about medical cannabis, you have a medical intent. I think in my experience one very confusing point for patients is that there are multiple ways in which you can access something derived from cannabis. The way that I think about it is that there are 2 very different ways. Probably the first division of the ways to think about it is that you have a pharmaceutical product that comes from the cannabis plant, or you have a vernacular product, or a dispensary product, that has been made available through a state legalization process.

Those are very different because of the regulatory framework in which they are provided. Obviously, the pharmaceutical products are provided through the FDA framework and are medications just like all the other medications we’ve been talking about, like valproic acid or levetiracetam. Whereas the dispensary products are unregulated and are essentially sold as food supplements and don’t have as much regulation or batch-to-batch consistency. I worry personally a whole lot more about those products.

We all know how frustrating epilepsy is due to the variability of the disease—you can have a good day, you can have a bad day. You can have a good month, you can have a bad month, and it’s just up and down, and we get frustrated by how hard it is to predict and know what’s causing what. With the dispensary product that problem is magnified because now you have one of your treatment agents that has potentially some variability. So for that reason, it’s an important discussion to have with your doctor about, is there a pharmaceutical form of cannabis that is reasonable for my child’s epilepsy?

Anup Patel, MD: Speaking of the pharmaceutical formulations, products from compounds that come from cannabis, we have one now in a purified plant-based cannabidiol product. Elizabeth, let’s talk about that. How does it work? Why does it work? Where is it used and indicated now?

Elizabeth A. Thiele MD, PhD: I think that this is an incredibly important and very interesting story, the whole development of cannabidiol. Largely this whole story is driven by the epilepsy patient community, which I think is very powerful. Years ago I became involved, I think many of us did, because of the increasing anecdotal reports of cannabidiol being effective in the treatment of epilepsy. And my involvement with all this actually started with an anecdote as well.

A patient of mine from California who actually had come to us for dietary therapy, was the first child actually. The parents connected with this company GW Pharmaceuticals in the United Kingdom, who had a product in clinical trials, 50% tetrahydrocannabinol, 50% cannabidiol named Sativex for MS multiple sclerosis spasticity and pain. They contacted this company because they knew the company had some preclinical work looking at cannabidiol in the treatment of epilepsy.

So their son, Sam, was patient number 1 who tried Epidiolex in 2013, and that pretty much launched the expanded access program where a group of us got together with GW in a dark room in New York. Now in 2013 discussing was this an effective treatment option for our patients, was it safe and well tolerated. And at that point we started children on purified cannabidiol, or Epidiolex, and we started our first 25 patients, 5 years ago now.

What happened then, the development program, first expanded access program saw that it could be effective, was fairly well tolerated, and then the company filed INDs [investigational new drug applications] to do RCTs [randomized controlled trials] in both Dravet and LGS [Lennox-Gastaut syndrome]. And as you know, now all 4—2 trials in Dravet, 2 trials in LGS—have all reported very positive results, all showed pretty good tolerability. So it’s been an incredible story. I think we do know now with the FDA approval that this is an effective treatment for many of our patients.

Interestingly though, the conversation I was having my colleagues recently is we try very hard to use the generic name or chemical names of medications and not the brand name. This is one where I feel it’s important to use the brand name of Epidiolex because parents come in, you can see cannabidiol everywhere. And since cannabidiol is not regulated, to say I use cannabidiol without specifying what it is…I think it’s probably important here to acknowledge that this is a pharmaceutical product that’s purified cannabidiol, not an extract enriched in cannabidiol.

I think we’re still trying to figure out how it works. We know it has a different mechanism of action. It’s not a sodium channel modulator. I think the best hypotheses now is it modulates a G-protein receptor, GPR55, that we know plays a role in neuronal excitability. It also probably plays a role in TRPV1 ion channels. So like most of our effective medications it probably has a couple of different mechanisms of action. Importantly, it’s clear that it has a different mechanism of action, and it’s also clear that it has a favorable adverse effect profile when you compare it with some of our medications.

I agree with Eric. I use a lot of Felbatol. But to sit down and talk about relative adverse effect profiles of several of our existing anticonvulsant medications, cannabidiol I think is very favorable.

Anup Patel, MD: And you alluded to this, Ian also alluded to this, but Elaine, why is it important that you recommend FDA approved products when we’re treating kids with seizures?

Elaine C. Wirrell, MD: As Ian has already mentioned, the importance of consistency is essential for me. I need to know that what is being given to the child in this batch versus the batch they’re going to be using next month is the same. I’m also quite a strong believer that cannabidiol is very safe. I think it’s well tolerated. I have a lot of concern about using tetrahydrocannabinol in kids, particularly kids with cognitive issues already; I don’t think they need any more. And I think a lot of the artisanal products that are out there, you just don’t know how much tetrahydrocannabinol is in them. We know that the Epidiolex is essentially a purer cannabidiol.

I think the other issue is getting coverage for these families. I have had families that have obtained through the state supply in the state where I work, various medical marijuana products, and it is incredibly expensive for them. It is something that has not been covered by their insurance, and so now we actually have a medication that is FDA approved and can be covered by their insurance.

Anup Patel, MD: Eric, you wanted to comment.

Jesus Eric Pina-Garza, MD: Yes. One of the things that makes this product very attractive is the community sense that it’s a natural treatment. And people always think about natural treatments that they don’t have adverse effects. I always share with them that the only reason the natural treatments offered don’t have adverse effects is because they were never looked for. If you don’t do a strict trial to look for that, you will never know.

So the importance of cannabidiol, which is Epidiolex, a very good product and safe product, is that we studied it. We know the only thing that we have to watch would be the interaction with clobazam because we can make someone toxic on that co-medication. And we have to look at the liver enzymes, because in a small percentage of people that can be elevated. That’s something that if you were just trying cannabidiol wildly, you would never know. So under the FDA and in our hands, you can make something that comes from nature safer.