Greg Mayes, the new CEO of Reunion Neuroscience (TSX:REUN, Nasdaq:REUN), has a more traditional drug development background than many executives in the psychedelic space. He had a successful foray into epilepsy at a company known as Engage Therapeutics. Founded in 2017, Engage was picked up by UCB in 2020.
While Mayes’ background in pharma dates back to 2001 when he was senior counsel at AstraZeneca, his interest in Engage was more personal. “The whole reason I founded that company was because of my son’s epilepsy diagnosis,” Mayes said in a recent interview. “The most common comorbidity associated with epilepsy is depression and anxiety.”
In a recent conversation, Mayes and his colleague, Reunion’s Chief Scientific Officer Nathan Bryson, open up about the company’s strategy and how they foresee the psychedelic market evolving in the coming years.
Could you share more about what inspired you to join Reunion?
Mayes: Because of my son’s epilepsy diagnosis, I’m extremely passionate about the CNS area. As I reflect upon that successful venture into epilepsy with Engage, it’s not surprising that the number one comorbidity of an epilepsy diagnosis is depression and anxiety.
So, at this stage of my career, after being in biotech for 25 years, I saw the opportunity to dive into depression and anxiety, which are just at epidemic proportions in our society, unfortunately. Many people feel the COVID pandemic did nothing to help those numbers.
I feel that I am most successful and am at my best when I’m passionate about something. And clearly, there’s an opportunity for depression and anxiety. And the item that is the hottest and has the most momentum in the depression and anxiety area in the past 35 years is psychedelics.
How do you see the psychedelic industry now?
Mayes: When you look at the basket of psychedelics companies, you realize that there are differences. Some companies don’t have intellectual property. Reunion has a substantial intellectual property estate.
There are products that, quite frankly, have very long psychedelic experiences, which could cause issues for patient adaptability to the therapy or cost more.
And lastly, you want to look at the chances for success. I think that many psychedelics will be able to show that they are safe and effective, but are they able to do it in the near timeframe? The plan is to go into postpartum depression (PPD) with an episodic indication that could be one dose. It’s a niche treatment population with a high need for a new product that could help with postpartum depression.
A recent CDC study summarized in USA Today found that more than 80% of U.S. maternal deaths are preventable. Mental health conditions were one of the top reasons for those deaths. So there’s a huge unmet medical need.
When you look at depression and mental health, unfortunately, there’s a dearth of innovative new tools for the disease. So you’re left with traditional antidepressants, which aren’t working for enough people.
What distinguishes Reunion Neuroscience from competitors in the space?
Bryson: When we started the company, we wanted to have a couple of things. We wanted a molecule that had intellectual property because it’s the best way to get partners and the best way to own your future. The other thing we wanted was a known psychedelic substance because then you can look at the anecdotal safety information, and subjects who have used illicitly recreationally would say it’s a positive experience.
We based RE-104 on a molecule called 4-hydroxy-diisopropyltryptamine (4-HO-DiPT), which comes from the work of the chemist Sasha Shulgin. It was included in his book TiHKAL.
4-HO-DiPT is a molecule that he identified as a short-acting drug that causes a positive, intense, brief experience. So if we could build a molecule based on 4-HO-DiPT, we take the risk out of the program.
We look for a market where there’s a high unmet need — where there are very few molecules where you could get good pricing and maybe good reimbursement for your drug. And we wanted a short development pathway.
All those things come together when you look at the science. So postpartum depression (PPD) makes a lot of sense for this drug:
- It has a fast washout, so women can get back to breastfeeding fairly quickly.
- PPD is episodic, so you’re not trying to treat a treatment-resistant chronic person.
- You’re trying to treat somebody for a short period of time, so your endpoints are shorter because you don’t have to demonstrate long-term safety.
- Clinical studies tend to be relatively small, and you can get fairly good powering out of them.
PPD turns out to be one of the fastest, shortest, least expensive pathways to the market for the drug that gets you the biggest bang for the buck in terms of price and is still a sizable market.
If it is all the things we expect, it should still compete with the psilocybins of this world. For other companies developing psilocybin, we can offer a shorter, more convenient molecule and still treat TRT patients. And that would be the second leg of our development.
How does Reunion envision that its psychedelics would be administered to patients post-FDA approval?
Bryson: I was not part of this psychedelic world in the past. I worked in traditional pharma — from early stage to product development and marketing.
But I understand through my experience over the last two years with Field Trip Health the importance of surrounding a patient in a sort of safety cocoon as you administer a drug like this that can be anxiety-generating. So it is important to put a patient in a very comfortable mood. If you can do that, you allow someone to have an introspective experience that can be one of the most meaningful experiences a patient can have. And then you can do it once, and it lasts a very long time.
Look at Field Trip Health’s experience with ketamine, offering a one-hour trip to patients six times. Under those conditions, patients sometimes go four to six months without returning. And I think it’s augmented by the psychotherapy component.
I think the optimal outcomes will be in a setting with an entourage around the patient. But I still believe there are some outcomes that you can get in a minimalist setting with digital tools to help you through the experience.
We’re trying to figure out exactly how we combine these things as we go through our development.
Can you share more about the limitations of traditional antidepressants such as SSRIs?
Bryson: SSRIs often don’t kick in for several weeks. And there’s often less than a 30% response. So the other 70% are trying a second SSRI and maybe trying a combination of drugs. So they could spend a lot of time in their depressive state while trying drugs, becoming disappointed in the whole pathway, dropping out and then becoming severely depressed.
We’re looking at things that sometimes have as high as 70% response rates within 24 hours. So you can drop depressive symptoms really precipitously in a very short period of time and bring people back. It’s another impetus for PPD because you’re not only treating the mother, but you have to get the mother in a safe space for the baby. A baby with a PPD mother could have a long-term development impact from that experience.
What are your plans for what is next at Reunion?
Mayes: Number one will be strengthening the C suite at the company.
Number two, we want to raise the visibility and let people know about our psilocybin prodrug. The company recently spun out of Field Trip Health on August 11. We anticipate our Phase 1 data will be available early next year. Then, we plan on starting our PPD Phase 2 study in 2023.
The company has a very well-laid-out playbook. We will now separate ourselves from other psychedelic companies based on our inherent differences and a well-established clinical pathway. We plan on having Phase 1 by the beginning of 2023. Phase 2 data will come later in 2023. Sandwiched in between, I will guide the company through an investigational new drug application with the FDA.
Reunion has several executives with extensive pharma experience. Do you think that differentiates the company from other companies in the psychedelic space?
Bryson: I don’t want to criticize my colleagues, but my approach has always been an FDA-focused long-term strategy. The goal is to build a pharmaceutical company with the right basis to do clinical trials. We want to do everything right and get the right licenses. We would like to be in a position where you can attract partnerships from Big Pharma companies that can help you take these things forward if we don’t find a way to do it ourselves or choose to do it that way.
And so it’s always been my approach before Greg came here. I only hired people with real pharma experience — people in clinical trials, chemistry, and ops rather than those who come out of the cannabis industry. We want to build something solid and do our clinical trials and paperwork right. We want to do our quality systems right and be ready for audits and partners to come along.
Mayes: I totally agree with what Nathan said.
When the Reunion Neuroscience board of directors hired me, their number-one goal was to have a CEO lead the company beyond the period where the founders were leading it. And I had substantial biotech experience.
I don’t see this job as any different than when I was working in oncology or bringing my epilepsy company forward. You do not want to cut corners. I want to run a very highly ethical clinical and regulatory process. That’s what people should expect.
And that’s what’s actually ultimately, at the end of the day, going to bring additional partners and interest into the psychedelic space when they see that there’s a regulatory door being opened at the FDA for these types of new therapeutics that can treat a huge unmet medical need in areas like depression.
In the psychedelic sector, I think you will need companies with intellectual property protection and new chemical entities that are highly differentiated with a strong clinical/regulatory pathway. And then, of course, they can prove that they are safe and effective at the end of the day.
Where do you see the psychedelic field headed in the coming years?
Bryson: I think Compass Pathways and MAPS will make it to the end. Many of these drugs are being used so infrequently that the levels of efficacy we can produce outweigh any kind of risk you might see with the drug. They’re extremely safe. And so even if there are still some questions around placebo or other things, the FDA will ask if the benefits outweigh the risks? I think in a lot of cases, they’ll say ‘yes.’
These drugs will find their way to the market. Then it’s a matter of defining the right one — defining the right profile, the right convenience, payment schemes and teams to deliver.
There are many teams I don’t think will be able to deliver. Psilocybin has no intellectual property, so companies focused on it will be genericized within five years after Hatch-Waxman runs out. Or they won’t be able to get funding because they won’t be able to partner because they don’t have longevity. How they’re going to get their return on investment?
What is the RE-200 series, formerly known as the FT-200 series?
Bryson: With this series, we wanted to differentiate based on safety and efficacy measures. We have to build products that are better for patients. And the FT-200 series was initially started to address a single question. That question was: Can we make a drug that does not activate the cardiovascular side effects you see with classic psychedelics?
Remember fenfluramine, a drug from the 1990s with 5-HT(2B) serotonin receptor activity. In some patients, that caused cardiovascular valve hardening. A handful of other products have come along and had some positive activity around 2B that have been pulled off the market, just like fenfluramine was.
Our idea was to dial that out through structural changes to the molecules. We wanted to make molecules that activate the serotonin 2A receptor and still produce the neuroplasticity that we think is part of the pathway to antidepressive effects without activating the serotonin 2B receptor. Most of the drugs in this class do activate the 2B receptor.
We have found at least three families that are fairly similar now — and we’re filing different patents to cover them — serotonin agonists at 2A and antagonists at 2B.
It’s still in the discovery phase. But we could develop a product that is as good as psilocybin in terms of its antidepressive effects but has no cardiovascular liability. So there’s an obvious commercial argument to go down this path regardless of how much classic psychedelics may induce cardiovascular problems.
But the more frequently these drugs get taken, the more likely that might occur.
Something like MDMA, with chronic use in recreational settings for five years, you can already measure cardiovascular changes in healthy subjects.
We’ve also have some candidates that look to be potentially less psychoactive. We may want to subset those out and have a couple of different pipelines. But the non-psychoactive ones could be take-home drugs with chronic administration if there’s no cardiovascular liability and no side psychoactivity. It comes back to a more traditional pharma model. And this looks like a novel serotonin agonist SSRI. It is different because it is a direct agonist, not a blocker of the transporter. It could have positive agonism of the serotonin 2A, but with no psychoactivity and no cardiovascular liability.
We still have to prove these things. These are works that are in progress, but there’s possibility there. When we started this program, that would have been the kind of thing I would love to do from the beginning. But I said we need a low-hanging fruit. We need to move fast. So let’s start with a molecule based on an existing psychedelic and build a low-risk program for depression. And that was FT-104, which is now RE-104. And in the background, let’s look for the long-term win that is better, safer and more effective. And that became the FT-200 series, which is now the RE-200 series.
Filed Under: Psychiatric/psychotropic drugs