Atai Life Sciences (Nasdaq:ATAI) recently announced positive results from a Phase 1 study testing KUR-101 for opioid use disorder. KUR-101 is an oral formulation of the kratom alkaloid mitragynine.
Atai subsidiary Kures is leading the effort to test the potential of mitragynine, which acts as a partial mu-opioid receptor agonist.
Kratom itself is a source of controversy. Proponents note that the supplement, which is native to Southeast Asia, is a safe treatment for everything from anxiety to chronic pain and opioid use disorder. Conversely, critics maintain that kratom is dangerous. The FDA was warned consumers against it. Similarly, calling kratom “unsafe and ineffective,” the Mayo Clinic recommended patients “work with your doctor to find other treatment options.” A number of states have either banned or restricted kratom. Meanwhile, Thailand, where the plant is native, recently decriminalized it.
Meanwhile, scientists continue to study kratom and its alkaloids. A 2018 study published in Addiction Biology concluded that the alkaloid mitragynine “does not have abuse potential,” adding that it had “desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal.”
Several years ago, researchers at Columbia University decided to investigate the potential of mitragynine for opioid use disorder. Andrew Krugel, a professor at the university until 2019, co-founded Kures in 2017. Atai acquired Kures three years later.
To learn more about Kures, we sat down with the company’s CEO, Chad Beyer, who discusses the potential of the company’s deuterated mitragynine to treat opioid use disorder and potentially other conditions.
Could you provide an overview of your background?
Chad Beyer [Image courtesy of Kures]
Beyer: I’m a PhD neuroscientist by training and have been in drug development. Started at Wyeth. I have been doing drug development and CNS disorders forever. I’ve had the privilege of working on some really cool projects — things that you’ve seen commercials for on TV like Effexor and Pristiq. I was on the bapineuzumab team before everyone else was making monoclonal antibodies to reduce amyloid beta.
After Pfizer bought Wyeth, I jumped out of working with 50,000 people and started working with companies with five people. I’m used to working with small companies, which is why Kures is so exciting. It’s one plus one equals seven. You get to do a lot of cool things quickly. It’s my second time being a CEO. I enjoy being at the cutting edge of bringing these molecules to people. And that translation of making the world a healthier place is what it’s all about.
I also do a lot of other things — professional jury duty is what I’d call it. I co-wrote a book on antidepressants. I have taught entrepreneurship. I sit on a couple of study sections to review grants. If you were to submit a grant to the NIH about anything related to CNS drug development, I would be on that panel. I work with the ALS Association and Michael J. Fox Foundation.
Can you share more about Kures kratom-derived drug KUR-101?
Beyer: People have been taking kratom for at least 100 plus years for everything from anxiety to low back pain and as a tool to replace opiates.
The active alkaloid of kratom is mitragynine. There’s good rationale for its use to replace opiates. The folks out of Columbia University who stood up Kures knew that the problem with natural products is that you can’t patent them. So, they made a deuterated version of mitragynine. Deuteration is taking a hydrogen bond out and replacing it with deuterium. Deuterated mitragynine does a coupe of things. It adds stability and metabolic resistance. Deuterated mitragynine is a little bit heavier and stronger, and it also gives you intellectual property.
We’ve got composition of matter patent protection for KUR-101 to 2039. That’s the first expiry and there could be some extensions and things we can apply for.
You look at the opioid crisis that we’re in, and put two and two together pretty quickly and you realize this could be a very useful, viable, safe and effective treatment for opioid use disorder.
If you take any opiates, prescription or street, tolerance is a problem. You continue to need more and need to take higher and higher doses. Given the drugs’ effects on the respiratory system, your breaths get eventually shallower and then you don’t wake up.
That doesn’t appear to happen in people who take kratom every day for opioid use disorder. They do not have respiratory issues.
We’ve looked at KUR-101 in humans and we’ll continue to investigate it in our clinical work. We measured respiratory rates in humans and we see no evidence of respiratory changes in any of the doses that we looked at.
All of the preclinical work is translating to what we’re seeing in humans. That’s a good foundation for why KUR-101 is being positioned for opioid use disorder.
The opioid epidemic has worsened during the pandemic. How do you foresee KUR-101 addressing that?
Beyer: The problem has gotten worse and the medicines that people take to treat opioid use disorder are not getting any better. There’s still a tremendous unmet need. There’s some stigma associated with getting an injectable drug for opioid use disorder. KUR-101 is an oral capsule.
People are dying from opioid use disorder constantly. In our press release, we state that once every seven minutes, there’s an opioid-related death in the U.S.
We’re trying to generate as much data as we can to continue to build out the foundation of not only efficacy but, importantly, safety. We just completed our first entry into Phase 1.
Part 2 of the Phase 1 study will be a head-to-head comparative trial with KUR-101 versus placebo versus oxycodone. So a pretty high dose of oxy — 20 mg compared to the highest dose that we looked at in KUR-101. We are looking at safety and the analgesic response that we saw both in a cold pressor test. We’ll look at heat and see how we stack up to the standard of care.
Do you foresee KUR-101 as a potential replacement for opioids in some settings?
Beyer: That would be nice. If you go back to kratom and mitragynine, people take it for pain. Chronic lower back pain I think is one behind anxiety is one of the most widely cited reasons why people take kratom.
Chronic pain can be miserable. It hurts you physically and mentally. You don’t sleep. You don’t eat right. It can be a downward spiral pretty quickly. So if you could treat chronic pain, just imagine the impact you’re going to have on someone’s life. They can get out the front door, they can manage their life all of a sudden, you know the colors are brighter and then the sun is warmer and life’s better.
KUR-101 is safe because it’s a partial biased agonist. It’s a next-generation opiate.
We have the next generation of almost everything, but not opioids. We think that is what KUR-101 represents. It has a safer built-in design pharmacology.
But partial agonism might mean partial efficacy. And that’s why we’re doing this Part 2 of our Phase 1 trial. How does it stack up to standard of care? If you are going for knee surgery or knee replacement, and we come home for post-op with a prescription for oxy? Would we expect KUR-101 to produce the exact same amount of analgesia? I think the answer to that might be ‘no’ because it’s a partial agonist and oxy is a full agonist.
That’s why we look at pain as more of a pharmacodynamic marker. It’s a way to say, ‘it’s on target.’ It wouldn’t produce a pain signal without being on target. We’ll find out in the next couple of months to see how we compare to the standard of care.
The opioid system plays a hugely important role, obviously, in pain sensation and pain processing signaling. It also plays a role in mental health in general. There’s genetic evidence in a variety of places that the opioid system is dysregulated in things like mood disorder. The solution to restore that probably resides within the system itself.
A lot of companies are looking at things such as TRP channel drug discovery, and acid-sensing ion channels, sodium channels and a variety of other channels that are not opiates.
The hope is they’ll be pain relieving. So the hope will be that an indirect mechanism will have this powerful analgesic response. I think that the system is so important that the solution to fixing the system probably resides within it. And that’s what this KUR-101 approach does.
Can you talk more about the safety profile of KUR-101 in the Phase 1 study so far?
Beyer: We saw all mild side effects. You see mild side effects with placebo in the low to mid doses. It behaved very much like the placebo arm of the study.
As you get to the higher 90 mg dose, there were two subjects that moved into the moderate category. We do five doses: 10, 20, 40, 60 and 90 mg and placebo.
Can you talk about the next part of the Phase 1 study?
Beyer: Part 2 of the Phase 1 study is going to lead us to a more classic, more traditional Phase 2. We are doing this head-to-head arms with a three-way crossover. It’s a blinded, well-controlled trial. This work is being done outside the United States. All of this work is being done in New Zealand mainly because there’s tax incentives and financial incentives to do work there. A lot of small companies are doing this. It’s our drug at 90 mg versus placebo versus 20 mg of oxy standard of care. It’s all acute dosing. And we did our last patient just recently.
Results from Part 2 will come by the end of the year.
We expect results from Part 2 of the Phase 1 study to enable the Phase 2 trial in opiate use disorder. That’s a ways off. That would be designed to look at treating opiate users — getting them off opiates, getting them into a safe place, pharmacologically, versus sort of treating the withdrawal effects.
How does Kures fit into Atai?
Beyer: I am new to Atai and new to Kures obviously. Atai is heavily committed. They’re super passionate about treating mental illnesses. They know it’s not a one-size-fits-all approach.
Atai is taking multiple different approaches, Some of them are psilocybin based and derivatives of psilocybin to treat mental health. There’s ketamine approaches as well with Perception. There’s a lot of approaches that all click into place if you almost think of it as a kind of a bunch of spokes in a wheel. Atai is in the center, and you’ve got all these spokes out because some of these I hate to use the hockey analogy, I mean, some of these shots on goal will go in because the science makes sense and the team is committed and you got to find the right patients.
The thing I would mention related to Kures is the opioid stats. Every seven minutes, one person is dying, somehow related to opioid use. That’s like 190 some people dying every day, right? That is equivalent to a plane dropping out of the sky every day. If that were true, nobody would fly.
There are companies working on addressing the opioid crisis. Atai and Kures are.
The plane analogy amplifies the importance of the opioid problem. It’s complex. The patients are complex. Their biology is complex. Some people become addicted for different reasons, which makes them a bit unpredictable. But it’s not an insoluble problem. It may require a lot of things. It may require not just pharmacotherapy. It may require exercise. The best way to increase trophic factors and endogenous opioids in your brain is to exercise. That’s what the runner’s high is. The approach might be more than just pharmacological. It might be a variety of things. I’m not trying to tell you that we’re working in some exercise arms into our studies, but something so incredibly complex requires a holistic approach.