FDA Talks Help Cybin Advance Two Psychedelic Drugs Toward Approval

A conversation with Cybin CEO Doug Drysdale

Psilocybin and DMT (dimethyltryptamine) are both considered Schedule I drugs by the DEA. Yet, clinical-stage biopharmaceutical company Cybin is looking to develop drugs in both categories with its CYB003 and CYB004 clinical programs. That hurdle is one CEO Doug Drysdale and his team are willing to overcome — for the millions of patients in the U.S. dealing with depression and anxiety.

Cybin’s CYB003 program is a deuterated psilocybin analog delivered via oral capsule and has been granted FDA Breakthrough Therapy designation for the adjunctive treatment of major depressive disorder (MDD). As a deuterated version of psilocybin, CYB003 is expected to reduce some interpatient variability and provide rapid onset of effect. The second program is CYB004, a deuterated version of DMT. Short-acting and dosed intramuscularly, it delivers a 90-minute experience. CYB004 is in development for treating generalized anxiety disorder (GAD).

Given the drug scheduling challenges and in the context of a pessimistic opinion of an MDMA-assisted therapy clinical trial by an FDA advisory committee, Drysdale sat down with Clinical Leader to discuss regulatory considerations and trends in the psychedelic drug development space.

Understanding that psilocybin (and also DMT) is a Schedule I drug in the U.S., do you have to make certain accommodations to study them, and how does that influence your pipeline?

Every aspect of the supply chain — anyone who handles the drug substance — has to have a DEA license, whether that's in manufacturing, in testing, or at a clinical center. That adds administrative hurdles and time. But obviously, it's not stopping us from progressing clinical trials. There's been plenty of data to show that psilocybin is not habit-forming. Our goal is to show through our studies that it is safe and effective. Upon potential FDA approval the DEA would then be forced to reschedule it because, once approved, it no longer meets the criteria for a Schedule I drug.

And there's been many examples of this, where Schedule I compounds are being developed for clinical use and then being rescheduled. And so far we're seeing promising results with CYB003, our proprietary deuterated psilocybin analog in development for the treatment of major depressive disorder. In our Phase 2 CYB003 study, 75% of patients with depression were in remission after just two doses of CYB003. That's a 75% remission rate sustained through four months so far after just two doses. We believe there's a clinical benefit here and we're seeing a very clean side effect profile so far. Although there are challenges with handling Schedule I substances in clinical trials, we don't expect the scheduling to be an issue for approval.

How do you find partners licensed by the DEA?

We have a very experienced team that has collectively managed more than 60 INDs through the FDA. We have a CMC (chemistry, manufacturing, and controls) team that has a lot of relationships with manufacturers, as well as a clinical operations team and CRO that have broad relationships with clinical sites. For our upcoming Phase 3 program, we've recruited 30 sites so far that are all experienced with psychedelics.

Working with psychedelics must require increased communication with the FDA. What do your conversations with the FDA look like?

The FDA's position toward psychedelics has been very positive. They've granted us Breakthrough Therapy designation for CYB003, suggesting that they recognize the clinical potential of CYB003 and the significant unmet need in treating depression. They've also issued draft guidance on how to run clinical trials with psychedelics. And from our discussions with them, they seem quite excited and positive about the potential.

Think about how we treat depression today with SSRIs. The majority of patients are not in remission, their symptoms are just blunted, they have to take medicine every day, and they're dealing with chronic daily side effects. Current treatments are woefully inadequate for many people. The potential for putting the majority of patients in remission after a couple of doses yielding very rapid, large, and long-lasting effects is quite an exciting concept for the FDA.

We had our end-of-Phase 2 meeting with the FDA in February. We were aligned with them on our Phase 3 study design. Our Breakthrough Therapy designation allows for regular consultation with the FDA, which we will definitely leverage, and we'll meet multiple times as we run through the Phase 3 program. It is a great opportunity to be able to ask the FDA questions and get alignment up front and not have to do things at risk. The Breakthrough Therapy designation also gives us access to Fast Track tools — rolling review, prior review, and accelerated approval.

Was there anything monumental that came out of these conversations or were they just affirming that you’re heading in the right direction?

We are very, very well prepared and have run through many scenarios to make sure that there aren't any surprises. That's the goal of meeting with the agencies, to make sure you're aligned.

When we presented our Phase 3 plan to the FDA, we presented two studies each with a primary endpoint at 12 weeks after dosing and the FDA guided us to reduce that to six weeks. So that's very positive for the study in terms of timelines and cost, but also good for patients because depressed patients receiving a placebo for 12 weeks are more likely to drop out of a study. Having the primary endpoint just six weeks out means we're more likely to retain patients throughout that time frame. And then, after six weeks, the patients get the chance to have a dose of the active drug if they have not responded or if they relapse. That was quite a positive suggestion from the FDA.

Earlier this year an FDA advisory committee recommended against the approval of Lykos’ therapy-assisted MDMA for PTSD. How did that news impact Cybin or help you understand where the FDA stood on psychedelic drug development?

Several issues were raised, and all have been well-known for quite some time. However, the advisory committee spent a disproportionate amount of time talking about functional unblinding. And it was odd to me because, of course, there's functional unblinding with psychedelics.

Functional unblinding is very well known to the FDA. Every CNS drug has functional unblinding. Esketamine, which has been approved for depression, clearly has functional unblinding, and antipsychotics have functional unblinding. In reality, only about 10% of clinical trials are truly blinded. So functional unblinding is nothing new. I think it was overplayed in the meeting.

Importantly, as part of the draft guidance, the FDA has asked sponsors to run at least one of their Phase 3 studies as a dose-ranging study. So, we will be doing that with one of our studies. We'll have a therapeutic dose, a mid-dose that we expect to be subtherapeutic, and a placebo. The aim is to allow two-thirds of patients to get an active drug from the start. And then when they get an experience from the high dose or the mid-dose, they won't know which one they have received. They won't be able to guess, because these are psychedelic naive patients. That'll remove any expectancy bias that comes from the functional unblinding.

You remarked that so many patients who are on SSRIs just aren't getting the effect they need and are looking for. Does this patient need and desire for better treatment translate to patient recruitment and/or site selection?

There's been significant interest in the studies, and that creates a challenge in itself. We have a lot of demand and a limited number of slots in the studies. It puts quite a bit of a burden on the screening process to make sure that we are enrolling the right patients. Unfortunately, 21 million adults are suffering from depression, and over 40 million people in the U.S. are taking SSRIs. That’s about 11% of the population taking SSRIs.

It’s estimated that 20% to 30% of patients find remission from SSRIs, but the other 70% are still dealing with their depression in some form. It may be blunted, but then also many of them experience side effects such as insomnia, weight gain, and sexual dysfunction. If we can successfully create something that works more like an intervention after one or two doses and patients can have months of remission, then that really does change the treatment landscape.

Patients with depression are quite a burden on the healthcare system, too, and they visit their physician nine to 12 times a year. They're often on many other drugs to manage their side effects or other comorbidities. Treating their depression may take them out of the system in large part and free up resources for other patients. So, it's quite an exciting prospect.

If you had a chance to offer advice to your peers who are embarking on their first-in-human trials for psychedelic therapeutics, what would you say?

I'm afraid it's obvious. There are no cutting corners with the FDA.

I've seen some sponsors that have been developing generic forms of psychedelics that have been known for many decades and attempting to use publicly available data to support the submission. At the end of the day, you've got to do the work and the preclinical package has to align with how you intend to dose humans in clinical trials.

And there's always the opportunity to meet with the FDA in a pre-IND meeting and get alignment. I would highly recommend taking that opportunity and asking the hard questions and making sure you're aligned before submitting an IND.

Finally, are there any trends that you see in the world of psychedelic therapeutics?

We've seen significant consolidation in the sector. If you look back two or three years ago, there were allegedly 50 or 60 companies working on psychedelic compounds. Now there are closer to five or six companies that are in late-stage clinical development, all with very specific paths. It’s not a surprise that they're all U.S.-listed companies because that's what it takes to raise the capital necessary to do late-stage drug development.

The other trend is with investors. The investment community has had no doubt for quite some time that these treatments have the potential to work. I think it's quite clear in academia and in the psychiatric community. I think the big question with investors until recently has been the real commercial potential given the patients have to come into a clinical setting and be supervised while they're dosing. What's changed their minds or made them positive about the commercial potential is the success of esketamine or Spravato from J&J, which is now trending over $1 billion annually in revenue. It has a very similar administration model as supervised in the clinic. So, that framework and about 4,500 centers around the U.S. now exist, and it's easy to see how psychedelics might drop right into that infrastructure.

About The Expert:

Doug Drysdale is the chief executive officer of Cybin. During Doug’s tenure as CEO of Cybin, the company was taken public on the NYSE and now has two development programs in the clinic, with its lead depression program about to start Phase 3 trials. During Doug’s 30+ years of experience in the healthcare sector, he has built cohesive management teams, recruited board members, created multinational operations, and raised around $4 billion of both public and private capital. As founding CEO of Alvogen, Doug led the company from inception to around $500 million in revenues, across 35 countries. Previously, Doug was head of M&A at Actavis Group, leading 15 corporate acquisitions across three continents, between 2004 and 2008. In 2012, Doug was named E&Y Entrepreneur of the Year.