Trip Or No Trip: Pharmas Are Taking Psychedelic Trials To Australia

A conversation with Enveric Biosciences CEO Joseph Tucker, Ph.D.

Two themes have arisen as of late in the clinical trials space, and both collide in this Q&A for an interesting perspective on pursuing regulatory approval of hallucinogenic and non-hallucinogenic psychedelic therapies in the U.S. and abroad, namely in Australia. Herein, Enveric Biosciences CEO Joseph Tucker, Ph.D., chronicles Enveric’s quest for regulatory approval by first heading down under, as well as addresses both the confusion and excitement experienced by those navigating the unknowns of developing psychedelics for therapeutic use. Enveric’s pipeline includes both hallucinogenic and non-hallucinogenic small molecule therapeutics for the treatment of anxiety, depression, and addiction disorders. EB-373, its leading candidate and next-generation synthetic prodrug of the active metabolite, psilocin, is on track for a Phase 1 clinical trial in early 2024.

Enveric Biosciences created a subsidy to oversee its preclinical clinical and regulatory activities for pipeline programs in Australia. What attracted Enveric to the country as its initial market?

The Australian government has really been very proactive in creating an opportunity for small companies who have to be very capital focused. The biggest attraction is a 43.5% tax rebate on dollars spent in the country. By way of creating an Australian subsidiary, an American company like ours can conduct preclinical and clinical studies in Australia at a significant tax rebate.

The Therapeutics Goods Administration (TGA), Australia’s regulator, has also ensured that the data that's generated there is accepted by regulators in the United States, Canada, and Europe when planning for future clinical trials in those jurisdictions. It’s a low-risk way to conduct a Phase 1 trial because you can come back to the U.S. with no nasty surprises.

And the third thing is a slightly simpler process to get approved to begin a clinical trial in the first place. In Australia, it's only the local review board that has to approve a Phase 1 trial. Once the review board has approved the trial, the sponsor then informs the TGA, but the TGA itself doesn’t conduct a formal approval process. So, that saves some time and cost.

Are there any hesitancies when choosing to conduct early-stage clinical trials in Australia? What have you heard from your peers who have already gone ahead of you?

I would call out two things to watch for. One, the industry in Australia has had to grow very quickly to absorb all of this new business. In any rapid growth industry, you run into situations where there are new folks popping up who don't have a great depth of expertise, even though they may sound good. If you make too quick of a choice, you may end up finding yourself working with a CRO that doesn't have as much experience as you’d like, and then you may run into mistakes as they are developing their own experience set.

Two, sometimes there's not enough capacity in Australia to run all the different preclinical studies that you need. You may find yourself coming back to Europe or North America to get all of your preclinical studies done in a timely fashion. So it's not a panacea. But luckily, clinical development is really a global enterprise. And so, you can solve resource shortages by running something over here in Europe, running something over here in Canada. You can put it all together at the end of the day.

What has the regulatory reception been to psychedelic therapies? Are there any regulatory markets that are more accommodating than others or nuances sponsors must understand?

On the non-hallucinogenic side (we do both), the receptiveness we’ve experienced is very, very large even though it's early in the demonstration and the validation of the mechanism. Paradigmatically, it's a new idea that inducing neuroplasticity in the brain can translate into recovery or repair of regions that control anxiety, depression, and post-traumatic stress disorder (PTSD). While new from a regulatory standpoint, and frankly from a Big Pharma standpoint, everyone is arms wide open, really excited about that potential, in part, because there’s less concern than on the psychedelic side.

On the hallucinogenic side, jurisdictions seem to have a different comfort level. We’ve seen going back a couple of years ago in Canada, for example, there were Ministry of Health exemptions being granted to allow people who had end-stage cancer to use psilocybin as part of treating their anxiety. And then you had doctors being given exemptions, because how can the doctor prescribe it if they don't know what their patient is experiencing? And then you have Australia, which recently has permitted the use of psilocybin and MDMA. This is for the naturally occurring, or extant, compounds. And then you see the U.S., which is not quite so open.

But I will say the regulators in the U.S. are very reasonable. My experience with dealing with the FDA and the DEA, who are the ones that put the scheduling on these drugs, has been very open. Historically, as a scientific community we don’t yet have sufficient data that confirms these psychedelic compounds are viable pharmaceuticals. There's no true clinical data that's gone through peer review, that’s passed the FDA bar, that's compellingly proven that these molecules have benefit. It seems as though the FDA is saying, “We're happy to do what needs to be done to get this to patients, just prove it.” I think that what's happened in Australia, where they’ve moved ahead in the absence of “proving it,” is they have opened the doors in the absence of regulatory hurdles that every other drug has to go through before it gets approved is kind of surprising.

The FDA came out recently with guidance on clinical trials for psychedelic drugs. How does that affect Enveric’s journey toward commercialization, at least in the U.S.?

As people have been running these clinical trials, which initially were mostly done by academics with the existing molecules, they didn't create new molecules, they just used, for example, psilocybin or MDMA. Findings from some of these early studies showed that the number one variable that indicated a successful outcome was whether the patient believed they had received the psychedelic agent. If you go in to take a clinical trial and psychedelics are being administered, you’ve got a pretty good idea whether you were given an active psychedelic agent. And so, your classic double-blind control is hard to do, and yet it's the most important criteria for whether you're going to have a good outcome that you can trust. That's one area where the FDA acknowledged that it's confusing in terms of trial design. And so, I’ve interpreted their stance to suggest that they are supportive of using an active control. Meaning, let's take a low-dose psychedelic agent at a dose that you think is not effective but will still make the person think they got it.

Secondly, the FDA has recognized that people have been using psilocybin and MDMA for a long time, though not in clinical trials. There's a lot of evidence out in the public domain in terms of their safety. You can make the case that you shouldn't have to do extensive preclinical work because there's evidence that's already out there. The U.K., for example, had already been proactive about that. This is providing good strategic fodder so that as a drug developer, we can look at, for example, one of our two molecules that gives rise to an active ingredient that's the same active ingredient that psilocybin yields. And as a result of that, perhaps we don't have to do quite as an extensive preclinical workup as you would with a completely novel molecule. And that can save us time and money without adding any additional risk to the patient.

More specific to embarking on what will be your first clinical trial, what were some of the challenges you faced in development?

With EB-373, the hallucination-inducing molecule, its intention is to be like psilocybin in terms of mechanism and benefit to the patient, but different from psilocybin as it's designed to solve for what are expected to be the commercial weaknesses in psilocybin, like taking longer to “kick in” and having a quite lengthy overall hallucinatory experience, and also causing vomiting which is a direct result of oral administration and gut absorption. So, we had to design our molecule very specifically to administer through a more direct route to the brain. That was one of the challenges that we had to solve on top of the initial technical issue, which was make a drug that's better than psilocybin, but works the same way. And then the third thing is navigating the “who’s on first” of regulatory and governmental permissions.

We’ve got a molecule that is novel and intended to be psychedelic, but it's not yet demonstrated in humans whether it's actually psychedelic. And so, the DEAs (U.S. Drug Enforcement Agency) of the world are not sure what to do about that. One country says, “That's no problem. You can ship that.” And the other country says, “I can't accept that unless you give me a letter from the DEA that says what they think of this.” And the DEA says, “Well, that's a novel molecule. It never existed before, so we can't say it's automatically hallucinogenic because there's no proof one way or the other.” It's an interesting little rat's nest to untangle.

What do you anticipate might be the most challenging part of the trial design process?

For the most part, it won't be too challenging because this is going to be a Phase 1. But the biggest challenge will be designing the Phase 1 to lead into the Phase 2, thinking about dosing up and repeat dosing. Again, this is the psilocybin-like approach. How many doses are you going to need to get the benefit? Those folks that are trying to advance psilocybin itself have the advantage of academics testing it for years, and though we presume something similar with ours, we don't know.

What are some of the things that you have learned in your past experience that are helping to drive or shape your decisions within Enveric?

One of the things that's become very clear to me is the receptivity of Big Pharma and their acknowledgement that this thing you're trying to advance can be commercialized. And there's a lot of factors that go into that. Neuropsychiatric markets have a history for the last 20 or more years wherein a drug comes along and it’s barely any better than what’s already out there. So, a new paradigm in the neuropsychiatric world would be a big, big deal. Our non-hallucination molecule has lots of inbound interest, even though it’s at an early stage. So that tells me Big Pharma’s going to really like this as well.

And then here at Enveric we said, let’s make sure that we have the intellectual property covered. And so, we started here at the very beginning using the Big Pharma approach of creating a thousand novel molecules and screening them to get one that checks all the boxes and has novel composition of matter.

And even though this feels very personal to me, it's probably also very personal for most people. I have people in my nuclear family who have struggled with depression and anxiety. Pretty much everybody can find somebody very close to them that this impacts and so you say, I really wish there was something so much better, something transformative. It becomes a passion project, too.

The answer might seem obvious, but I think it’s worth talking through: Why is there an uptick in interest or comfort from Big Pharma with the non-hallucinogenic option?

Number one is how it’s going to be administered. The hallucination-inducing molecules are going to require oversight of a couple of healthcare providers, so that treatment paradigm eliminates most of the appetite from Big Pharma. Administration a couple of times in a doctor’s office, at 10 hours each, for the most part they just don't want to have anything to do with it. On the other hand, with a non-hallucinogenic therapy, you go home, take a pill in the morning, and go about your day.  With hallucination-inducing molecules, there’s also concerns about the risk of inducing psychosis, the amount of money that can be made, and the accessibility for patients.

About The Expert:

Joseph Tucker, Ph.D., is a seasoned executive who has built several publicly traded biotechnology companies. Tucker was a founder and CEO of Stem Cell Therapeutics, which he took public on the TSX; Trillium Therapeutics acquired Stem Cell Therapeutics in 2013. Tucker has also held the position of co-founder and CEO of Epimeron Inc., a University of Calgary start-up acquired in the creation of Willow Biosciences Inc. At Willow, Tucker served as executive chairman and COO. Prior to founding companies, Tucker was a healthcare analyst with two investment banks and has also worked in technology commercialization for a university technology transfer office. Tucker received his Ph.D. in biochemistry and molecular biology from the University of Calgary.