Dr. Husseini K. Manji reveals the groundbreaking journey of esketamine (SPRAVATO®) from lab to FDA approval. Discover how this rapid-acting antidepressant is reshaping depression treatment and paving the way for future psychedelic medicines.
Dr. Husseini K. Manji takes us behind the scenes of esketamine's development, from basic neuroscience research to FDA approval. Learn about the science of targeting NMDA receptors, the rigorous clinical trial process, and the potential of esketamine as a first-line treatment for depression. Dr. Manji discusses the challenges of bringing a novel psychiatric drug to market, including regulatory hurdles and insurance coverage issues. He also explores the broader implications of esketamine's success for mental health treatment, including the fight for parity and the future of psychedelic medicine development. This episode offers invaluable insights for clinicians, researchers, and anyone interested in the future of psychiatry and drug innovation.
[00:00:00] In May 2019, a groundbreaking medication with the first novel mechanism of action in 60 years reshaped our approach to difficult to treat depression. Today on the Psychiatry Tomorrow podcast, we're revisiting this landmark achievement with the pioneer who made it possible. Ketamine, like many chemical molecules, It comes in two versions, an R version and an S version, and the S version is four times more potent at the NMDA receptor, so you can get away with a very small amount of drug that could lend itself to intranasal delivery, and that's when we started to think about delivering it.
Developing it as an FDA includes treatment for treatment with depress. Welcome to the Psychiatry Tomorrow podcast. I'm Dr. Carly McMillan, and in each episode we interview thought leaders in the deep end of Psychiatry's Next Frontier, dive into the latest [00:01:00] research, innovative treatments, technology and policy development, shaping the future of psychiatry.
Join us on this journey to discover what's next in mental healthcare so you can stay ahead of the curve.
I'm Dr. Alison McInnis, VP of Scientific Affairs at AusMind, and I'm thrilled to bring you a conversation that every clinician and neuropsychiatric drug developer needs to hear. We're diving deep into the Spravato story. The journey of esketamine from lab to FDA approval isn't relevant to this drug only.
It's a potential roadmap for how other psychedelics might navigate the complex path to clinical use. For clinicians, it offers insights into a treatment that could change your approach to depression. For drug developers, it's a masterclass in bringing a novel psychiatric medication to market. Our guest today is Dr.
Husseini Manji, the visionary scientist behind esketamine. Dr. Manji offers an insider's perspective on what it takes to bring a truly [00:02:00] novel psychiatric medication to patients. Starting with his groundbreaking research at the NIMH. and taking us through the rigorous FDA approval process at Johnson Johnson.
We'll explore how targeting the NMDA receptor directly led to rapid relief for treatment resistant patients, potentially changing our understanding of depression treatment. We'll delve into the challenges of the approval process. The potential for ascetamine to become a first line treatment. We'll explore how targeting the NMDA receptor directly led to rapid relief for treatment resistant patients, potentially changing our understanding of depression treatment.
We'll delve into the challenges of the approval process. The potential for esketamine to become a first line treatment and the broader implications for mental health innovation. Whether you're on the front lines of patient care or at the forefront of drug development, this episode offers valuable insights into the past, present, and future of psychiatric medicine.
Join us as [00:03:00] we unpack the Spravata story and its lasting impact on the field of psychiatry. Let's dive in.
We've talked to several guests on our podcast about sort of the despair that clinicians were feeling in the early aughts. And, you know, our personal experience and then the findings of STAR D told us that at least a third of patients weren't getting better on the traditional medications. And as you said, a lot of pharmaceutical companies had sort of left the space, very discouraged about figuring out novel approaches.
And then you came along. And so how did you become convinced that, that eschetamine was going to be the next blockbuster where you put your energies? Yeah, I think that's a very good question, and I think, you know, it's illustrative as to how some things can have a big catalytic effect, and I think that's what it means for auto history not to be the case.
So, while I was at the NIH, a lot of my basic science work was looking at something we sometimes call plasticity pathways, and you know, plasticity has many [00:04:00] different view of definitions. One way to think about it is the mechanism by which we increase or reduce the strength of information flow to specific synapses.
And, you know, for example, us having this conversation two years from now, you remember this conversation, you may not remember every single detail. But you remember we discussed, you know, sort of the golden age of neuropsychiatry, excedamine, etc. Because to the best of our knowledge, there are some changes happening in, you know, the strength of synaptic connection at this speed that are making some of this information, you know, more long term storage.
And a lot of basic science work that start to look at their, um, possibility. That's certain with sectors, in particular, the NMDA and AMPOVA sector, their movement into or out of synapses seem to play a major role in regulating certain forms of [00:05:00] synaptic and neuroplasticity, and my group started to wonder whether some of these same molecules could be involved in the pathogenesis of depressive ward by volatile tissues, and potentially with treatment.
So we did a lot of animal studies, and you know, I think it's, we all recognize that the roving studies are far from perfect, but we tried to make them as sort of grounded to the clinical situation as possible. And we're able to show that, in fact, changes in the NMDA and, or anvirus sectors did seem to play a role, you know, when you, um, perform certain stress experiments, et cetera, and animals develop what we might call a behavioral phenotype, like learning to help with this, you were able to show that changes in these molecules happened, and that led to, you know, the corollary, which is that, could you improve the condition By targeting those receptors, and certainly [00:06:00] in preclinical study, that seemed to be the case.
And so we wanted to ask the question, does it really hold up in humans? And, um, you know, I was at the NIH at the time, and we've been fortunate that, something like two years prior, the Yale group, under, um, John Bushman's leadership, had published a small study, where they identified the ketamine at a low dose, and that the low dose ketamine is an MDA catalyst.
And we're struck to find that some depression patients showed an improvement in their depression and showed improvement relatively rapidly. So we thought, okay, if we're going to use an NMDA antagonist, which is what I wanted to do, why not build upon the ketamine work? Because ketamine, as you probably know, is this very old treatment, and the good news about that, It's that, you know, decades of safety data.
It's even used in, um, children as an anesthetic because it's so safe and we know it protects the blood brain barrier, etc. And at a [00:07:00] very low dose, which is what we wanted to use, it's a selective NMEA antagonist. So we basically designed this study when we wanted to look at treatment resistant depression.
And the definition often is, if you fail two previous antidepressant trials. In the study we did at the NIH, because often what happens at the NIH is, um, doctors send their most refractory patients. So these are patients who on average have failed six different antidepressant trials. Some had failed electroconvulsive therapy, and they've been depressed continuously for three years when they came to the trial.
Um, we brought them to our inpatient unit, had them off all medications. And gave them either intravenous placebo or intravenous low dose ketamine. And we were struck to see that not only was there a remarkable response, but he could start to respond within two hours. And at 24 [00:08:00] hours, 70 percent of these individuals, um, were classified as responders.
And interestingly, even though the drug was done from the system within hours, their depression came back gradually, so they remained well for something like four to five days, and then the depression came back. So we were, you know, very impressed, we're excited about this, and it suggests that if you, you know, go to what we might consider a rights target.
The NMDA receptor, you're bypassing a lot of steps that, for example, with, you know, SSRIs, you're increasing interest in the Arctic serotonin, which has to go through a lot of steps to bring about changes in the NMDA receptor. If you directly target the NMDA receptor, you're bypassing all these steps. So, one, you're having an antidepressant effect, which is rapid, and secondly, it seems to work in people in whom these conventional treatments have failed, because our thinking was that if one [00:09:00] of the steps in a given individual is faulty, if you increase serotonin all you want, it's not going to change an endangered receptor function.
So that was exciting. And then, you know, we hypothesized that by Turning on these plasmin between pathways, the effect might be somewhat durable, even once the drug is gone from the system. So in almost all our treatments, we think you need the receptor to be occupied 24 7. Here it looks like you're hitting the plasticity of the pathway, then the drug is gone.
Because it takes a while for the plasticity changes to unwind, you actually remain well for several days. And so that was, you know, sort of a big finding, um, Tom Insel was the director of the NIH at the time, he referred to it as the biggest breakthrough in psychiatry in about 50 years. Um, a little bit after that, I made the decision to move to the, um, NIH, rather, Felipe and I can go to [00:10:00] J& J.
My initial thinking was this has really shown us information as to what the correct target might be. And let's start to develop a brand new drug which might work on subunits of NMDA receptors or amyloid receptors. And that's indeed something that's going on. And as you probably know, that takes 10 or 15 years.
And once I became there, I started to think about the fact that this really seems to work well, but you need an IV administration, in many places you need an anesthesiologist, and it's not as, you know, accessible. So could one have a different way of developing a practical, convenient treatment that might recapitulate these effects?
And my thinking was that you needed Entry into the brain relatively rapidly, and one way to achieve that was by delivering it intranasally. [00:11:00] Now, you know, I'm sure if you've taken a nasal decongestant, You know that you deliver a very small amount of drug. So, we had to start to figure out that you can't deliver ketamine because you need, you know, a higher amount.
And we were able to show that ketamine, like many chemical molecules, comes in two versions, an R version and an S version. And the S version is four times more potent at the NMDA receptor, so you can get away with a very small amount of drug that could lend itself to intranasal delivery. And that's when we started to think about delivering it, developing it, as an FDA approved treatment for treatment resistant depression.
Oh, wonderful. Enjoying the Psychiatry Tomorrow podcast and hungry for even more insights into the future of mental health care? Then you won't want to miss out on the Psychiatry Tomorrow newsletter from AusMind. Join [00:12:00] hundreds of forward thinking psychiatrists and mental health professionals staying ahead of the curve with the latest research, technology, and practice strategies delivered straight to your inbox.
It's free, it's easy, and it's the best way to keep your finger on the pulse of mental health care. Just head to ausmind. org slash tomorrow and we'll see you inside. So essentially we have this treatment that works so rapidly and we're bypassing, we're getting to kind of like the end of the final common pathway or closer to it.
So we're missing all these steps that cause sexual side effects and weight gain and all these other, um, uh, problems and, and really getting to the heart of the matter. Um, and that brings me to sort of an interesting, you know, a subject, which is that, um, esketamine was developed as an adjunct. Um, but really if we're, if we're going to a place, you know, where ultimately, um, every person needs to go through this, this pathway in order to actually get undepressed, then, um, can you give this without an adjunct of antidepressant?[00:13:00]
Yeah, the answer is a great question because it's very timely. So initially when I approached the FDA, I had suggested that we might develop it as a monotherapy. You know, this development doesn't stand alone because it seemed to be so good. The FDA, and I think it was a fair comment on their part, indicated that a lot of patients with treatment resistant depression are probably going to be on medications anyway, even if the medications aren't working really well.
Um, their clinicians may not want to take them off the medication and as you know sometimes you know taking people off SSRIs has a withdrawal syndrome so you have to do it very slowly. So they said look why don't you start by adding it to their sort of, uh, an existing SSRI and we indicated that okay we'll do that but we also want to look at monotherapy.
So the initial, um, development program was in treatment resistant depression added to a [00:14:00] conventional antidepressant. We actually continue to do work as monotherapy, and just some weeks ago, um, The submission was filed with the FDA for spiva as monotherapy as well, because it's worked extremely well in monotherapy as well.
And so the hope will be it'll also get approved for monotherapy. Um, I think one of the things you, you mentioned about you sort of, um, the rigor is needed in the industry, so I think one of the, I'd also like to point out, because this were so nory, right, no one had ever developed a rapid acting antidepressant.
An intranasal drug, a medication who you're going to be administering initially once every few days and then once every few weeks, because unheard of in psychiatry, almost everything was new. So we had to work very closely with the regulators, SDA, CHNP, EMA, and others to really figure out how do we want to do it.
The other thing I mentioned in terms [00:15:00] of the rigor, you know, sometimes people almost have this notion that, well, it had to be monographed. He just took it off the shelf, you know, um, gave it to people. Actually, we did about 26 studies overall for the filing packet, because we wanted to look at everything, you know, things you might not even think about, you know, what angle should the person be sitting at when they administer it?
Does it matter if the patient is nasal decongested? What do you want to hear a show about, you know, sort of how long, if you have dissociative syndrome, they last, et cetera, et cetera, et cetera. And then one of the things that, you know, because this was so unusual, the FDA also asked us and we agree is that most of the time for depression studies, you get the approval after you've demonstrated, you know, short term acute effects, and then you do relapse prevention study.
Here, they asked us because it was going to be quite unusual where we were going to be You know, potentially treating people once every three weeks, once every [00:16:00] four weeks. Why don't you do the relapse prevention studies at the same time, so if you will, and then um, present those as part of the package to us.
And that's what we did. So we had, you know, this is the first drug in neuroscience ever to be given, um, breakthrough designation by the FDA. And so we were able to work closely with the FDA, get them our ideas, get their feedback, you know, go back and forth. The paradigm we landed on, as I said, you know, first we had to show that Esketamine worked.
It worked. It worked. Because only ketamine has been demonstrated. Then we had to develop a very specific intranasal formulation and dosage. And because there's some concerns about the abuse liability, we actually developed a very specific, um, disposable intranasal device, so that no one can sort of collect the device and then remove, you know, any residual ketamine from it.
Then we designed a paradigm where the SBA was basically, for [00:17:00] the first four weeks, you'll get the treatment twice a week. Then once you've been, you know, um, you're in a response or remission, then it'll get made much less frequent, depending on what you need, once every two weeks, once every three weeks.
And in fact, data was presented at the last ACMP meeting in December, where long term data showed that these individuals were kept in response or remission for about four and a half years, which is as long as they would study with administration once every three or four weeks. I know I'm talking a lot, but I'll just make a couple more things related to, you know, the unusualness of this, um, development program is that because, you know, it's a controlled substance, we work closely with the FDA, and in fact, we suggested REMS, which, um, you know, you probably know and for your audience, It's a risk evaluation and mitigation program that basically, um, the FDA often asks, you know, why don't you collect [00:18:00] this information so we can see if there are any safety concerns, if you need to monitor for anything, etc.
And so we developed this program with the FDA saying, okay, this is the way we're going to do it. Um, we also wanted to facilitate access for patients. And so we worked with the DEA, um, obviously, as you know, a drug enforcement agency to get their permission for specialty pharmacies to deliver the asketamine, um, spray with this device to practitioners who might not have co located pharmacies, because if it had to be only at places with co located pharmacies, you know, that are largely the university or specialized hospital settings, et cetera, And so we work very closely to do all these things.
And I think as you know, um, it was approved some years ago. It's now approved in 80 countries. has helped a lot of people. We then did a second, um, indication, which was basically when we were treating people, [00:19:00] we noticed that suicidal ideation went down rapidly. And again, this is probably something, you know, but most file, the branded aggressors exclude suicidal patients because they want to suicide during the trial.
We insisted that we wanted to treat suicidal patients. And obviously implemented a lot of measures to make sure that they were, you know, in a safe environment, et cetera. And then we're able to show that patients that are immune to suicide, we had a marked response rapidly. So that was very gratifying as well.
Because as you know, suicide has turned out to be a major public health concern. Fantastic. I wanted to, one more question in this line, and then I want to switch gears slightly. Um, So this, if we're giving it the, one of the most proximal parts of the antidepressant response pathway, uh, why couldn't this be first line?
Yeah, I, I think it may well be, and I think sometimes people start, you know, at, at a slightly [00:20:00] further line, and then move backwards. So, you know, I, I think it's a, you know, it's the first, observation that many people do respond to SSRIs, etc. Now I happen to think that even for my loved one, why would I want them to go through six weeks and then find out it doesn't work and switch, etc.
If you could have a treatment that, you know, so in our studies, you know, 70 percent of the treatment resistant depressed people Shoulder response and usually within 24 hours. So it clearly works much better and much faster. So I think there's a possibility that it could become first line. You know, and I think, you know, the recent submission for Spravaco as monotherapy could be a way to then even consider it as first line.
Now, beyond the science and the regulation is the question of payers, and I think that's a separate question. So one of the things is when you're trying to develop a [00:21:00] new statement, um, about 90 percent of things fail and often it costs in a hundreds of millions, even for the things that work. And so the companies have to try and recoup their investment.
Um, you know, otherwise, why would they, you know, spend hundreds of millions and have 90 percent of things fail? And unless they can get, you know, what is sometimes considered a reasonable price. And I have to say, in psychiatry, most of our medications are very low priced compared to oncology and immunology.
And you know, we really need to fight for what we might call parity for mental health. Um, you need to get that because that's one of the things that sometimes insurance companies and payers. Also, we sort of prevent you from prescribing a novel medication as a first line, because they know that, you know, because tricyclic antidepressants and SSRIs have been around for 30 to 60 years, they're all generic and they cost pennies.
[00:22:00] So often these insurance companies will want someone to try the medication that costs pennies before they go to a medication that costs dollars. Now, I don't think it's the same, you know, that happens in oncology or immunology, and collectively we need to try and make sure people understand that our patients are suffering These are the chronic diseases of the young, when you're continuously depressed for a long time.
It affects your occupational function, your scholastic functioning, relationships break up, people die from suicide, people have much worse physical health. You shouldn't be asking people to go on what might be an ineffective treatment or two for weeks and weeks before going on to a more effective treatment, which might cost a little bit more to begin with.
But if you're reducing hospitalization, et cetera, it's actually going to be cost saving. So that's a sort of a long ish answer to your question. Some of it is sort of science and regulation, and I think that is moving in the right [00:23:00] direction. The other part of it also involves the ecosystem, which hasn't regarded mental illnesses as seriously as physical illnesses.
And so they've had, you know, sort of a double standard in terms of reimbursement. Wonderful. Thank you. That's it for today's episode of the Psychiatry Tomorrow podcast. We hope you found our discussion informative and inspiring. If you enjoyed the show, why not share it with one mental health clinician in your network?
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