Phase 2 Trial Results Show Efficacy, Safety for Treatment of Acute Cannabinoid Intoxication in the Emergency Department Setting

Pharmacy Times® interviewed Simon Allen, MBA, CEO of Anebulo Pharmaceuticals and Kenneth Cundy, PhD, chief scientific officer of Anebulo Pharmaceuticals, shared the results from the randomized, double-blind, placebo-controlled phase 2 clinical trial (NCT05282797) evaluating ANEB-001 as a potential treatment for acute cannabinoid intoxication (ACI) in healthy volunteers challenged with oral delta-9-tetrahydrocannabinol (THC). In this trial, ANEB-001 was able to reduce VAS Feeling High statistically significantly in all cohorts (p=<0.0001 at the 30 mg THC dose level). Additionally, delayed dosing of ANEB-001 was able to rapidly reverse pre-existing THC effects.

Pharmacy Times: What is ACI, and what are the symptoms?

Simon Allen, MBA: Acute cannabinoid intoxication or as sometimes I like to refer to it as just too much cannabis. It is the circumstance an individual finds themselves in, inadvertently or advertently, when taking essentially too much marijuana or cannabinoids and it overloads the system, specifically the CB1 receptor in your brain, which is responsible for the psychotropic effects of cannabinoids. That receptor, when it gets overloaded with cannabinoids, actually turns out to be quite a serious issue. And drives, believe it or not, thousands of people a day to the emergency department with some form of cannabinoid intoxication.

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This is from the NED's data, this is a government number, where close to 1.7 million people every year present at an emergency department around the United States with some form of cannabinoid intoxication. So it is a very serious circumstance, and right now there are no FDA approved therapies to treat this condition.

Pharmacy Times: What was the impetus for investigating novel solutions for people suffering from ACI?

Allen: So several years ago, the founder of our company, Dr. Joseph Lalo, realized that the deregulation and legalization of cannabis around the United States, especially high potency edibles was likely going to cause an issue in society with acute cannabinoid intoxication. And so the impetus really was understanding that there are no FDA approved therapies for acute cannabinoid intoxication. Doctors right now can really only treat the symptoms of the disease.

So we talked about psychosis, anxiety, elevated heart rate—you can have a whole bunch of stuff associated with ACI that doctors really need to intervene, the patient is not in a good place, they're in pain, and in distress, and often psychotic. And so while they're able to treat certain symptoms, like benzodiazepine for anxiety, or a beta blocker for elevated heart rate, keep in mind that those therapies are truly treating the symptoms, not the root cause. So the impetus was to understand what is the root cause of ACI, and how could we best address it? And that's really what ANEB-001, our lead program, is all about. It is a small molecule that binds to the CB1 receptor as an antagonist. It is a receptor blockade. It essentially displaces THC off the CB1 receptor, and we believe solves the root cause of ACI by relieving the pressure on the CB1 receptor, essentially. If successful, we believe it will be the first FDA approved therapy to treat acute cannabinoid intoxication.

Pharmacy Times: Is there a certain patient population in particular these treatments would be suitable for, eg, patients with cancer who need support around ACI for treatment-related reasons or patients who use cannabis to manage other health disorders?

Allen: There's many different circumstances as to how cannabinoids can cause an issue, not only in society, but for the patient. And you've mentioned several of them right there. What we are focused on, to begin with, we've got the other opportunities on our radar, but we are a focused biotech that has a single mission today, and that is to deliver the first FDA approved therapy for treating ACI in the emergency department.

Now the other areas that you mentioned, using cannabinoids as potential therapy, cancer, pain, appetite, it is knowing that sometimes those individuals take too much of that drug and might even become intoxicated in the therapy. So yeah, its potential to use our molecule to rescue that patient in that event, and that's something that we've considered. We've also considered things like cannabis use disorder, addiction, and the long-term hyperemesis—there's a whole bunch of stuff that we believe is available as a potential therapy for 001. But as I said, our first strategic gateway, laser focused today, is purely on the emergency department setting, where we think the patients have the highest unmet medical need at present.

Pharmacy Times: Could you discuss the results of the phase 2 trial evaluating a potential treatment for ACI?

Kenneth Cundy, PhD: So the phase 2 study was really our proof-of-concept study. So once we have this molecule in development, the intention of course, is that it will ultimately be used in emergency department when people turn up with acute cannabinoid intoxication, but in order to test whether that is going to work, the easiest way to do that is actually to create a very similar situation in healthy subjects by giving them a challenge dose, is what we call it, a challenge those of THC, which is the primary component of cannabis that causes the psychotropic effects and the unwanted effects of intoxication. So the study was designed so that we could go into a set of patients who are healthy subjects, they have some experience with cannabis, and they were given a specific fixed oral dose, single dose of THC, and then treated with either our drug, ANEB-001, or with placebo. And during the course of that study, we investigated not just the doses of THC that we could reverse or treat, but also the doses of our drug that would actually work in that setting. And then we looked also at what happens if you don't get to treat right away, and you have to wait a while before you can give ANEB-001. So that was the kind of high-level design of the study.

We did that in 2 parts. The first part was a very initial trial comparing 3 arms. So we took 60 people, and we gave all of them a single dose of THC. So this is the primary component of cannabis, we gave them 10.5 milligrams, which is a relatively high dose for someone who might just be using cannabis for the first time. And those people did get symptoms related to THC, if they were given placebo. In most cases, they would get high very quickly, and then stay high for quite a while. So by the end of the observation, which was 8 hours of close observation, most of the patients that got high were still coming down from that high and recovering.

For those that got a dose of ANEB-001, that was done at 2 different dose levels, at a 50 milligram and 100 milligram dose level. And in all cases, we saw blocking of that occurrence of THC-related symptoms. So there was a decrease in the feeling high, which is a visual or what we call a visual analogue scale, where people record how high they are on a scale between 0 and 100. We saw that very significantly reduced, extremely statistically significant reduction in that. And we saw an improvement in alertness, which is another measure of how you're impacted by THC.

Then, in the second part of the study, we went a little deeper, and we tried higher doses of THC and lower doses of our drug. And what we were able to show in that setting was that even with subjects given an oral dose of 30 milligrams of THC, which is a substantially high dose of THC, even if you waited for an hour, and then treated them with an of 001 and just a 10-milligram dose, we could see very rapid reversal of the effects of THC—so people who were high, people who had diminished alertness, people who had body sway, which is a measure of their ability to maintain their balance, and also their heart rate. One of the things that THC does is increase the heart rate in people as well. So we were able to reverse all of those with our dose of ANEB-001, even when given an hour after the THC had already been on board. So that's the real takeaway from this study is we had the proof of concept here, we were able to both block and reverse the primary effects of THC. And our drug in that setting was actually safe and well tolerated, so bodes very well for this being used in the setting of subjects who turn up at the emergency department after being exposed to an unexpected amount of cannabis or other cannabinoids.

I mean, one key thing about this mechanism is it doesn't matter if it was cannabis, or a synthetic cannabinoid. And there are now many of those around, alternative synthetic versions of THC, that have been made and circulated, and those are much more potent and have more significant consequences if you have overdose on those.

Pharmacy Times: In cases where a patient has taken cannabis by accident, such as by consuming an edible by accident, would this treatment help address those symptoms for all age groups, such as among children?

Cundy: Yeah, absolutely. That's the intent here is that this becomes an emergency use antidote to the overdose, and whether that's from edibles or from smoking or inhalation or other forms of exposure, it would still work because you're all going through the CB1 receptor, which is the only way that cannabis, or other cannabinoids, have these effects on the brain.

Now, when we get to initial trials right now, we're of course in adults. But our plan in the long term, of course is to be able to treat all age groups that are exposed. And as you mentioned, there have been instances where people at parties say how have inadvertently consumed gummies that look like regular gummies, and that's included children. So yes, there are subjects turning up in the emergency department, both adults and children that are inadvertently exposed as well as those that are more routine cannabis users who have perhaps mistakenly expected higher dose to be okay. And it was too much for them. So all of those are potential uses for this antidote.

Pharmacy Times: With an end of phase 2 meeting with the FDA approaching in the middle of 2023, what are potential next steps for this treatment?

Cundy: Great. Yeah, so obviously, for us, that's a key meeting to discuss with FDA the findings of the phase 2 study that we just completed, and also to talk about the steps forward as far as what's required for registration of the drug. In other words, what studies would be needed to achieve approval for marketing in the US.

So that's what we want to get out of this discussion is a clear understanding of the pathway forward, I can't say too much about what our expectations are for that, which is obviously highly dependent on the discussion. But one could imagine that we move forward with studies where we are then looking at how this would work in a larger number of subjects so that we can obviously achieve sufficient evidence of effectiveness and safety to meet the requirement for FDA to approve the drug in the US—that would be the goal.

Pharmacy Times: Any closing thoughts?

Allen: I think there's one observation that I'd love to share with your audience, Alana, and that is, we love to ask a question: How many people do you think turn up at the emergency departments around the United States with some form of cannabis intoxication? And I would say roughly a third of those individuals, we ask, say, ‘None, like, what do you mean, cannabis is a safe drug?’ Which is really fascinating to me, because when you think about the number being 5000, that is a long way away from none.

I would never want to say that cannabis is as dangerous as fentanyl or opioids because, clearly, fentanyl can kill very rapidly. That's not to say that cannabis can't kill either. In fact, it's even possible to be charged with murder. Because in Virginia, a mother unfortunately left her edibles out and her 4-year-old son ate them and died, and she got charged with murder, because apparently, she wasn't forthcoming in the emergency department when they could have intervened.

Now, that is an isolated incident. But here's where it really gets tricky. The pharmacoeconomic impact of ACI is what very few people are talking about. So when we consider an individual that does present at the emergency department with ACI, we believe that the cost of the health care system is between $5000 and $8000. That's what it costs to take that individual through the emergency department, sometimes requiring an overnight stay. And in the extreme cases, other than death, individuals actually get escalated to the psychiatric ward. Their anxiety and psychosis is so acute, that the doctor in the emergency department probably just washes their hands and says this is way too much for me to handle right now, off to the psychiatric ward.

Once that happens, the cost of the health care system, we believe, can easily exceed $15,000 or $20,000 once that happens. So, yes, there is an unmet medical need for the patient that really does need to be addressed. And that's clearly a focus of ours. But the other key benefit of a rapid reversal of ACI would be to reduce the burden on the health care system, both in cost, because we believe people would be discharged several hours earlier, if ANEB-001 was made available to that individual, meaning a decent cost saving to the health care system.

On resources, a lot of the emergency departments are overwhelmed. And a lot of doctors will see an ACI and basically say, ‘Yeah, here's a benzo, here's a beta blocker, and go sit on that emergency department bed for 7 hours and then we'll let you go.’ And that's not really an effective therapy, not for the patient and not for the health care system. And so we really do believe that the introduction of ANEB-001 would not only drive substantial improvements in patient outcome and address that unmet medical need. But moreover, to the health care system, we're talking about saving billions—that's with a ‘B’—billions of dollars if we're able to effectively treat ACI at the root cause that being the CB1 receptor, versus having thousands of people a day basically sit in emergency departments until the THC essentially washes out of their system. So we really do believe that tackling those 2 things will drive substantial value for the company.