380: A new top drug regulator and the future of psychedelics

Welcome to this week's episode of the Read Out Loud, a weekly biotech podcast from STAT. I'm Allison DeAngeles. I'm Adam Feuerstein. And I'm Elaine Chen. It's Thursday, December 4th, and here's what we're going to talk about this week. There's a growing interest in psychedelics from pharma investors and regulators. And with that, there's also growing debate about whether the psychedelic aspect of these drugs is actually needed to help treat depression, anxiety, and other psychiatric conditions. David Olson, a longtime psychedelics researcher, has co-founded a company focused on developing psychedelics without the hallucinogenic trip. He joins us this week to discuss. But first, a word from our sponsor and a roundup of this week's biotech news. In clinical trials, every day matters. For your team and for the patients waiting for a promising new treatment, metadata's AI helps you reclaim time by reducing delays and accelerating every step of your study. Built on the experience and insights from powering over 36,000 trials, reaching more than 11 million patients, metadata's purpose-built AI turns complexity into clear, confident decisions that move your trial forward faster. Imagine seeing risks earlier, enrolling patients 37% faster, and automating work that slows you down, with 75% faster study builds and 80% faster data-claiming. Don't just run a study. Accelerate a breakthrough. See how at metadata.com/ai. So you may have heard Adam there in the introduction, but it's just us in the studio right now, Elaine, right? Yeah, it's just you and me right now. We had recorded our interview that's going to come later in this episode with Adam a day earlier because Adam is now headed out to the American Society of Hematology Conference. But overnight news broke, so here we are, you and me, Allison, talking about the news. I do have to say I did jinx it because yesterday I said, oh, I hope there's not big news that comes overnight. It's okay. Elaine, I'm not going to hold that against you. And you know what the show must go on. Yes. So the big news we're talking about is Tracy Beth Hoag becoming the next leader of the FDA's drug center, CEDR. She'll replace Rick Pazder, who is leaving the FDA just less than a month after he agreed to take on this role of leading CEDR. Yeah, sources told Stat that Pazder was concerned about the legality of a new commissioner voucher program that offers expedited review to drugs that align with national priorities. He also took issue with Commissioner Marty McCurry and top biologics regulatory official Vinay Prasad, inserting themselves into drug review decisions, as well as efforts by McCurry to handpick hires for the drug center. Yeah, and as for Hoag, she's a sports medicine physician and epidemiologist who rose to prominence during the pandemic because she was challenging school closures, mass mandates, and the approval of booster shots for children. This comes soon after Vinay Prasad had sent out a memo to staff claiming that the COVID-19 vaccine was responsible for the deaths of 10 children, which many experts said we needed more data and evidence on. But it's just interesting to see how it seems like people aligned with RFK Jr., McCurry, and Prasad are consolidating power at the FDA. Yes, people within the drug industry had welcomed the appointment of Pazder as the top drug regulator about a month ago because they thought he would be a stabilizing influence after a year of real turmoil at the FDA and that he is someone who's been involved in many cancer drug approvals, knows this industry quite well, and they thought surely he will be there to counter some of what's happening and some of these concerns that we have about how the agency is approaching very common medications like vaccines. Clearly, that's not going to happen, but yeah, we are kind of seeing this consolidation of power, it seems right now, where people who are kind of close to Kennedy and Vinay Prasad's and the larger organization's view on vaccines are now going to be in charge. In other news, the UK announced an agreement with the US in which it will pay more for medicines and in exchange be spared from pharmaceutical tariffs being considered by the Trump administration. This deal is a critical element of Trump's most favorite nations plan to lower US drug prices and to get other rich nations to pay more for medicines. Also this week, Allison, you had an exclusive story on retro bio, which is a longevity startup that's backed by open AI CEO, Sam Altman. You reported that the company is close to raising what could be one of the drug industry's largest investment rounds, and it's chasing a $5 billion valuation. Yes, this was a really interesting story to dive into. We had heard at the start of the year that retro bio was looking to raise about a billion dollars for a series A round, it's kind of first big round with outside investors that had been reported by the Financial Times. As the year has gone on, it turns out that they have been very heavily pitching this round and looking to potentially get a $5 billion valuation for the company. The company is just about to start its first clinical trial. It has not yet started dosing any patients or doesn't have any clinical data. I obtained two slide decks and talked to some folks who have been hearing this pitch to kind of dissect what's behind it, what's driving this valuation that they're seeking. I think one of the great examples from the pitch deck is a slide that kind of forecasts retro bio's potential market cap, its potential value as surpassing that of Eli Lilly and Novo Nordisk and actually nearing the valuation of tech companies like Alphabet and Microsoft because it is not only working in this longevity field, but it's also using AI applications, has a collaboration with OpenAI to do drug development. There are clearly very large ambitions here. Just all the buzzwords, all crams together. I was going to say I think that kind of a projection is seen as pretty bold and very ambitious in the biotech worlds, but that I assume is probably just something you see every day in the tech world. Yeah. I've kind of heard that commentary as I've been asking around about retro bio in the day since my story went out because basically the sentiment is that for a biotech company that's an extremely high valuation, for an AI company or a tech company maybe not as lofty of a valuation kind of based on where the market is right now, but we'll see what they actually end up raising and hopefully I'll get to hear a little bit more about what valuation they actually reach ultimately. So lastly in our news roundup, Capricor Therapeutics said that in a phase three trial, its cell therapy significantly improved muscle and heart function among patients with Duchenne muscular dystrophy. If you recall, the FDA had earlier rejected this treatment in July, saying that Capricor's application, which was based on mixed results from an earlier study, lacked "substantial evidence of effectiveness," but Capricor now thinks these new results could convince the FDA to reverse its decision. This is great. I mean, this is a much needed win for the Duchenne population, I would say, Elaine. And exciting to see how the FDA will respond to this additional data given that they earlier rejected the application. And it will be really interesting to see the position that Vinay Prasad takes because he was the one reportedly who decided to reject Capricor's therapy overruling staffers who actually had supported the therapy's approval. And now, back to our previously recorded episode. The psychedelics field is rapidly advancing. Biotechs are testing versions of psilocybin and LSD for depression and anxiety that are close to regulatory review. But there's also a new crop of companies that are trying to develop drugs that are similar to psychedelics in that they exert strong and rapid therapeutic benefits, but they don't have the so-called "trip," as in they don't alter people's perception or sensory experiences. David Olson co-founded a company, Delix Therapeutics, that is developing such drugs. He's also long studied psychedelics as an academic researcher and is director of the UC Davis Institute for Psychedelics and Neurotherapeutics. David joins us now to chat about the science behind these drugs and his thoughts about the growing psychedelics landscape. David, welcome to the podcast. Great to be here. So, David, can you explain to us a little bit about the understanding of how psychedelics actually may work in the brain to address conditions like depression or PTSD? So psychedelics activate a particular serotonin receptor in the brain that has some pretty interesting effects. The first thing that they do is they produce these mystical-type experiences, these profound subjective experiences that many people call "the trip." In addition to that, they actually promote structural and functional neuroplasticity, which is actually the physical rewiring of the brain. So depression, PTSD, substance use disorders, many, many neuropsychiatric diseases are characterized by physical changes in the structure of the brain, a part of the brain called the prefrontal cortex that is really important in regulating mood, motivation, fear, reward. It actually atrophies in many of these conditions. So there is physical damage that needs to be repaired, and every single antidepressant intervention that we know of promote the growth of those critical neurons. So the field believes that changes in neuronal structure are really at the heart of these diseases. And one of the reasons that psychedelics might be so effective for treating these conditions is because they promote the growth of these cortical neurons very rapidly and very robustly. So instead of having to wait weeks to months after taking an SSRI daily, if you take a psychedelic or ketamine or one of these types of cycloplastogen drugs, you'll start to notice the effects within 24 hours. And something that's really interesting about them is that the effect seems to last long after the drug has been cleared from the body, really suggesting that there is some repair going on. So based on your research, you believe it's possible to separate the therapeutic effects from the psychedelic effects, the so-called trip, as you had explained. Tell us a little bit more about that. So right now, in order for psychedelics to be administered safely and effectively, you need to give them in the clinic, usually under the supervision of multiple healthcare professionals, that drastically increases the cost and the complexity of the treatment and limits the number of people that can benefit from them. And so we realized that if it was possible to separate the hallucinogenic effects of the drugs from their beneficial effects on neuroplasticity, we would have compounds that are much more scalable that could help a larger number of people. So when we started looking into this, we took a few different approaches. The very first one that we did was simply dose. In preclinical tests, we started giving subhalusinogenic doses of psychedelics, and we found that we could still induce these neuroplasticity effects. So it seemed that the neuroplasticity turns on before the hallucinogenic effects turns on in terms of dose. But of course, that's not an ideal solution because people could simply take a whole bunch of pills simultaneously, even if they're a low dose, to achieve a hallucinogenic effects. And so there's diversion issues. It's still not going to be something that you can take home and put on the medicine shelf. So then we wanted to know if it would be possible to separate the neural circuits that mediate the beneficial behavioral effects from the hallucinogenic effects. And for that, we used some novel chemical and molecular tools and some nice work that we did with my colleague Tina Kim demonstrated that the circuitry seems to be distinct. And so what my lab did very early on was we took every major psychedelic scaffold that we could think of, urgalines like LSD, tryptomines like psilocybin, you name it. We took those compounds and we just made small structural tweaks. We didn't change them drastically. We just moved an atom there, added a group here to try to make psychedelics better versions of themselves. Now, everyone thinks about the issues with the hallucinogenic effects and removing the hallucinogenic effects, but every single psychedelic or psychedelic related compound, they all have their own unique inherent challenges associated with them. What I like to say often is that psychedelics might have therapeutic properties. They were never engineered to be CNS medicines. And that's really where chemists can make an impact is we can optimize these compounds. So in addition to their profound subjective effects, many of these compounds have cardiotoxicity issues, something like Ibogaine binds to an ion channel in the heart and can cause cardiac arrhythmias. Others have psychostimulant properties. Obviously, some of them have abuse potential. So when we're designing new drugs, we're trying to eliminate all of these issues to make something that is so safe that you can just go to your local pharmacy, pick it up and bring it home. And really quickly, David, just for our listeners, can you define what this term you're using, neuroplasticity, and you call these drugs that are similar to psychedelics, but don't have the hallucinogenic effects. You call them neuroplastogens, but can you just define that really quickly? Yeah. So all of our work started with ketamine. So maybe I should go back to talk a little bit about ketamine. So ketamine is not a psychedelic, but ketamine has this ability to promote the growth of cortical neurons very, very rapidly. We started calling ketamine-like compounds, cycloplastogens, and a cycloplastogen is just a molecule that can promote cortical neuron growth rapidly to produce a therapeutic behavioral effect that is sustained long after the drug has been cleared from the body. Way back in 2018, we reported that psychedelics could do the same thing that ketamine could do. And so that kind of broadened this class of cycloplastogens. In 2020, we published on the first what many people call neuroplastogens. At the time, we were calling them non-halusinogenic cycloplastogens, but that became a mouthful. So some people started calling these non-halusinogenic analogs neuroplastogens to differentiate them from the hallucinogenic molecules. Yeah. That's definitely much easier, David, to kind of get out there quickly. I wanted to ask, so you co-founded a company, Delix Therapeutics, that's working on these types of treatments, the benefits without necessarily the psychedelic effects. And you're in the clinic. How is that going so far? What kind of data have you gathered? Yeah. So Delix has licensed a lot of technology from the University of California Davis, and they've also developed a lot of their own compounds. They have a broad pipeline of assets to address a large number of different conditions. And something I want to emphasize is that cortical atrophy is at the heart of many different brain diseases, neuropsychiatric diseases like depression, but also things like schizophrenia and even neurodegenerative conditions. And so where Delix, where they are now is they've taken one compound called Zalzupendol through phase one clinical trials, and that includes phase one A trials, which looks at safety and phase one B trials that is still looking at safety, but is in a patient population with major depressive disorder. Now a big question with all of these neuroplastogens was all of our original work was done in pre-clinical species. And we felt really good that these were going to have the kind of desired properties because we had really good control compounds to compare them to. So there are a lot of tests that you can do to predict whether or not a compound is likely to produce hallucinogenic effects in people. And so with Zalzupendol, we were very confident that it was going to be non-halusinogenic in people, but you can never know for certain until people take the drug. Now we have, you know, over 100 people have taken the drug and it is definitively non-halusinogenic. This is not micro dosing. You cannot take a high enough dose of this drug to produce a hallucination ever. If you go to the really, really extremely high doses, you might get a little nauseous, but you're not producing anything that resembles a trick. So that was really, really important proof of concept to just demonstrate that we could engineer out the trip. Now the next question is, if you've engineered out the trip, how can you be certain that you haven't just, you know, lost your efficacy? Maybe you've just created the world's, you know, most expensive placebo. And so we needed to make sure that the drug was doing something in the brain that was relevant to neuroplasticity. And so for that, we looked at a particular biomarker using quantitative EEG. So basically you can hook electrodes up to the scalp and you can measure electrical signatures that are related to the same types of neuroplasticity that you see with ketamine and psychedelics. And we saw the exact same response. And so that gave us hope that the drug was getting into the brain, engaging relevant targets and producing the biological response that we cared about related to neuroplasticity. So that was all done in the phase one A. Then in the phase one B, we started looking at hints of efficacy. So the first thing we did is we verified safety. We wanted to make sure that the safety of the drug was the same in patients with MDD as in healthy individuals. And it was, there's still no increase or sorry, there's no hallucinogenic effects. And the biomarker that we had observed previously, we saw it again. So all that's like looking very, very similar to the first study. But now we had the opportunity to look at the antidepressant effects using a scale called the modris. So a very standard scale used in depression trials. It's used for the psychedelics and SSRIs and many other antidepressant interventions. Yeah, I'm sure that a good chunk of our listeners are familiar with that. But tell us what you found. So we found a few things that were very important. The first was we found a rapid response. And that is really what differentiates cycloplastogens and neuroplastogens from SSRIs is that the response happened very, very quickly. And so we only did a week of treatment. And then the first time we looked at a modris score, we saw there was a rapid reduction in depressive symptoms. And it was a fairly large effect size. The effect size actually was very comparable to that seen in many psychedelic trials. The second thing that was very important is that the effect was sustained. It was a durable response. And remember, if we're talking about a mechanism that involves the repair of neural circuitry, we would expect to have a durable response. You don't need to have the drug in the system in order to produce a therapeutic effect. It needs to go in, act as a chemical catalyst for repairing the damaged neural circuitry, and then you should have some lasting benefit. And we followed the patients out four weeks after they stopped treatment, and they didn't get any worse. They stayed better. And that is very consistent with what you see in psychedelic trials, too. So now we have the same rapid, robust, and sustained therapeutic effects that people have observed with psychedelic trials. But now we have a non-holucinogenic compound that the FDA has given us to go ahead to dose it at home in phase two trials. Now, I want to just throw a caveat on this, and that is that this is a phase one clinical trial. It was not placebo-controlled. It's not powered to detect efficacy. And so this is all going to have to be confirmed in a larger phase two trial, but it's very encouraging. What does the development path for this compound, for this drug, look like? I mean, I think a lot of our listeners are very familiar with companies that develop drugs, let's say for major depressive disorder and the kind of clinical trials that they run. I mean, is that the path that you are going down? That's what these clinical trials are going to look like? I mean, this compound is very vanilla flavor in terms of CNS drug discovery. We don't have a lot of the issues that have plagued some of the psychedelic companies, because we don't have to worry about unblinding. No one's having a trip on this drug, so we don't have to come up with clever ways to address that. The patient populations that we're going after are a little different, too. Because this medicine can be taken at home, we don't have to reserve it for treatment-resistant patients. So, a lot of the psychedelics are being used, third, fourth, fifth line treatments after patients have failed a lot of other options. We're really thinking of Zalzupendol as being kind of a first switch from generics. So you're never going to go ahead of generics. They cost pennies a day. They're super cheap. And so people are usually going to try a generic first. But imagine that if you don't get a response after that generic, you could switch to something like Zalzupendol and then know in just a few days whether or not you're going to respond to that. Now you're talking about getting people well very, very rapidly rather than going through the months and months of trying a whole bunch of different treatments before you're eventually deemed treatment-resistant and then have to try, you know, less scalable options like psychedelics. I'm curious, David, about dosing. Like, have you found an optimal dose to move forward with? And also, what are the side effects? This is actually a really fascinating question. So I'll start with the side effects. So this drug is extremely well tolerated. The only, you know, side effects that we are really noticing are nausea when you go to very, very high dose, well above what you would use for treating depression and maybe some headaches. And so that's not uncommon. These are kind of like very standard side effects that you see with all antidepressant treatments and the nausea that we see is actually less than what you see with things like SSRIs. We think the nausea really comes from, you know, local stimulation of serotonin receptors in the gut. There's a lot of serotonin receptors in the gut, so you're likely to get nausea. The other thing that's really interesting about, you know, this drug in particular and neuroplastogens in general is that the effects seem to be concentration dependent. So the more drug you can get to the target, the bigger the therapeutic effect. And that's true preclinically, and it also seems to be true with our clinical data as well. And so we basically are going to be giving patients the maximal dose that we can give them where they have minimal to no side effects. That will be tested in phase two. So figuring out the dose is not the real trick here. The real trick is figuring out the dosing frequency. This is a completely novel class of compounds, you know, all the other antidepressant agents that we use typically in the clinic, you give daily. But if you've got a compound that is a chemical catalyst of neural repair, how frequently should you dose it? Like, these are unanswered questions for not only Zalzupendol, but psychedelics in general. You know, David, it reminds me of, I know, like a company like Sage Therapeutics and they're developing the drug for MDD, you know, they were looking at or examining, you know, episodic treatments for depression, right? Instead of chronic use, you give it and, you know, you take it for like a week and you see these incredible effects. And then, you know, and then maybe there's a maintenance phase, but you're not taking it every day. I mean, is that something that you think is possible with your drug? Depression is an episodic disease. And so the ideal situation is you would take a drug and get them out of their depressive episode rapidly. If you can do that within 24 hours to a week, and then they can be depression free for a period of time, that would be incredible. Then you stop, you can stop treatment until, you know, their depression episode comes back and then maybe you re-challenge them. That is really kind of how we're thinking about all of these neuroplastogens being used for treating depression. Now, you know, we still are trying to answer this question is like, what is the most efficacious interval to be dosing? And so we've been taking a lot of inspiration from the psychedelic literature, but a lot of the ketamine literature, a lot of the ECT literature, so electroconvulsive therapy is the most effective antidepressant intervention that we know of. And that is basically you do it a few times a week for a few weeks, and then you don't have to do it very frequently anymore. And so when we did this phase one B trial, we actually had two different dosing paradigms. The first was we gave patients a dose of Zalzupendol every single day for seven days in a row, and then we measured the depression on day eight. The second group of patients received Zalzupendol on day one and day four, so just two doses. And again, measured their depression on day eight and then sustained effects, you know, four weeks later. We saw no difference between the treatment groups. Your drug is still very early in development. There are several biotechs working on more traditional psychedelics that do have hallucinogenic effects that are pretty advanced. They're close to regulatory review. The farthest along is probably Compass Pathways, and they're testing psilocybin in severe depression. How do you feel about those candidates, these more traditional psychedelics that are getting close to regulatory review, and how do you feel if they were to go in the market? Well, you know, I think that the world needs, you know, more solutions to treating brain conditions, not fewer. And so I'm very hopeful that a lot of these first generation compounds, you know, make it to the clinic. And I do think that some patients will be helped by them, but I do think that they are going to be replaced ultimately with better versions of them, but patients need help now. And so, and these are the furthest along. And so we should definitely, you know, pay very close attention to them. And if the data warrants it, we should absolutely approve them for the conditions where they can be useful and they can be used safely. David, we're in an era right now where several health officials have actually vocally supported the development of psychedelics, and they want to study them. They want to review them and potentially make them available to patients. This has said that the FDA has agreed to a rolling submission for its psilocybin treatment. As somebody who has been working in this field for several years, how do you feel about the regulatory environment that Delix is entering? Do you have any concerns about whether regulators are going to be rigorous enough in their review of these psychedelics? I sure hope so. I mean, we saw it with MDMA that, you know, the FDA did not allow that treatment to go forward because there wasn't sufficient data. It's important to keep in mind that, you know, psychedelics is not a monolith, like every compound is different. They all have their own unique advantages and disadvantages, challenges. In the case of MDMA, there's definitely the possibility for abuse potential with that molecule, and that needed to really be taken into account and considered. In the case of something like Ibogaine, there are major cardiotoxicity issues. People have died from taking Ibogaine, and so if appropriate guardrails are not in place, that drug could be potentially dangerous, even if it can help some people. And so I guess it really depends on the drug. So a compound like psilocybin, there's been a lot of clinical work on it. It does seem that you can administer psilocybin safely and effectively in the appropriate setting with the appropriate guardrails. And so I'm hopeful that those types of treatments will ultimately be approved, but they need to be approved with the appropriate rems. David, thank you for coming on and talking with us. Thanks for having me on the show. It does it for another episode of the Read Out Loud. Thank you to Hiacinth Empanado for producing this week's episode. Our senior producer is Alyssa Ambrose. Our executive producer is Rick Burke, and our theme music is by Brian Joel. We'd love to hear from you. Tell us what you like about this week's episode, what you didn't like, and whether you think Retrobio could reach the market valuation of the major tech companies. You can do all that by sending us an email at [email protected]. And if you like what we do, leave a review or rating on Apple podcasts or whichever platform you use to get your podcasts. See you next week.