A Novel Psychedelic-Based Therapeutic for Postpartum Depression: Phase 2a Results of Inhaled Mebufotenin (GH001)

Welcome, everyone. I'm Sarah Brownd, and thank you for joining us today for this Journal of Clinical Psychiatry webinar. We're excited to welcome our featured speaker today, Dr. Kristina Deligiannidis. An extremely accomplished clinician and researcher, Dr. Deligiannidis serves as Director of Women's Behavioral Health at Zucker Hillside Hospital and is Professor of Psychiatry, Molecular Medicine, and Obstetrics and Gynecology at the Zucker School of Medicine at Hofstra Northwell. We'll get started with a presentation

from Dr. Deligiannidis, and that will be followed by a short Q&A. Uh, you can submit your questions using the Q&A feature at the top of your screen, and a recording of the webinar will be available on YouTube in the next few days. Dr. Deligiannidis, thanks so much for being here, and I'll turn things over to you at this point.

Thank you so much for the opportunity to review, um, our publication in Journal of Clinical Psychiatry. And, uh, today I will give a brief overview of postpartum

depression pharmacotherapeutic development from that lens, and then share data from a single-arm, open-label, Phase 2a clinical trial of GH001 mebufotenin in postpartum depression or PPD. I'll share data on the main antidepressant effects, safety, maternal functioning, and breast milk concentrations of mebufotenin, all of which are clinically important in the patient population I treat, um, women with postpartum depression. And important

considerations also for postpartum women who are lactating. So we will get started. I have the following disclosures relevant to this presentation. I serve as a research consultant for GH Research, the sponsor of this study, and I have additional disclosures as listed here. My research is funded federally by the NIH and by the state in New York by the Office of Mental Health and the Department of Health and other sources that are listed here. So to set the stage

peripartum depression, uh, which is a major depressive episode with onset either in pregnancy or up to four weeks postpartum, as defined by the DSM, or in pregnancy up to a year after delivery, as defined by the American College of Obstetricians and Gynecologists, is one of the most common complications of pregnancy and the postpartum period, affecting up to one in four women. The APA, ACOG, the American Academy of Pediatrics, and the USPSTF, they

all recommend universal depression screening during pregnancy and in the postpartum period. Yet the treatment cascade remains problematic. Um, for a hypothetical cohort of a hundred postpartum women in the US, approximately twenty will have peripartum depression, so either with an onset pregnancy or after delivery. And of those, um, US data suggest that only ten to fifteen will be screened, six to ten

will receive a diagnosis, four to six will initiate treatment, and only two to three will receive adequate treatment in terms of dose and duration. We have decades of data that show the consequences of undertreated or untreated peripartum depression, and those are significant. They include adverse obstetrical, maternal, and infant developmental outcomes. And unfortunately, perinatal mental health disorders more

broadly, but also including major depressive disorder, are the leading cause of pregnancy-related death in the United States and also other countries as well. Critically, maternal morbidity review committees across thirty-six states in a CDC report found that one hundred percent, every one of these deaths from suicide or overdose were deemed preventable. So I want to present to you in our short time together that this is the clinical

reality that motivates me as a physician scientist, my research, and the development of novel rapid-acting treatments for this patient population. So as a background, serotonergic antidepressants, mainly SSRIs and some SNRIs, have been the mainstay of pharmacologic treatment for moderate and severe postpartum depression. I cite a Cochrane meta-analysis of eleven postpartum, uh, randomized controlled trials,

and they showed that, um, there was a possible benefit of SSRIs over placebo. And the response rates that they report by doing that analysis of the studies to date were of approximately fifty-five percent versus forty-three percent for response, and remission rates were about forty-two percent versus twenty-seven percent when measured at five to twelve weeks of follow-up with those SSRIs. And the reason why the authors noted that serotonergic

antidepressants may show benefit is that the pooled risk ratio confidence interval included one. So they couldn't conclude that there was a statistical difference between SSRIs and placebo in response or remission. The reality is that the majority of patients with postpartum depression receive serotonergic antidepressants in the community and we do find that they're helpful for a subset of women. Generally, we find that combining the serotonergic antidepressants with

psychotherapy improves outcomes and really is the first step for mild, uh, postpartum depression and any subsequent severity of postpartum, uh, depression. We initiate, uh, antidepressants typically when the depression becomes more moderate or is severe. From a lactation safety standpoint, most SSRIs and some SNRIs are associated with low passage into the breast milk. And so we have robust data supporting

this. Those relative infant doses, sort of a metric of the dose, the percentage of the maternal dose that's weight-adjusted for the infant. Those relative infant doses, or RIDs, are well below the accepted ten percent threshold, though there are some outliers. So with the sort of the landscape, you know, that was in place when I started doing this seventeen years ago, there are still important limitations of continuing down this path. Eighty-six

percent of patients report at least one side effect with SSRIs, and over half report bothersome side effects. Perhaps the most concerning from a public health standpoint is that sixty-three to seventy-six percent of women discontinue their SSRI treatment at least once during the year following their PPD diagnosis, with over a quarter, up to thirty-eight point five percent, discontinuing SSRIs within sixty days. So, you know, you imagine the scenario

where we don't catch everybody with screening and when we do catch them, they're not necessarily referred to treatment. When they connect to treatment, they may not get adequate dose or duration of treatment and then the treatments are not fully effective for those who do adhere to them. This really underscores the need for treatments that work faster, are more efficacious, are better tolerated, and require shorter treatment courses. And so that brings us to the development of neuroactive

steroid antidepressants. It's gonna be a little historical. It's not that long of a history, so it won't be that long. So we've had two neuroactive steroid GABA-A receptor positive allosteric modulators that have received FDA approval specifically for postpartum depression. Brexanolone was approved in twenty nineteen and is bioidentical to allopregnanolone, which is made in the brain. It's made in the periphery and the ovaries, the adrenal glands, the placenta, the testes, and was

administered as a sixty-hour IV infusion. In the pivotal trials that we conducted, seventy-two percent of women achieved response and sixty-one percent achieved remission by the end of the infusion. However, brexanolone was withdrawn from the clinical market in early twenty twenty-five due to the logistical challenges of a sixty-hour supervised infusion, but also the FDA approval of zuranolone in twenty twenty-three. So zuranolone, which, uh, you can see on the right side of this slide, is a synthetic

derivative of pregnenolone, and it's administered orally as a fourteen-day treatment course at fifty milligrams nightly. In the Skylark trial, fifty-seven percent of women achieve response and approximately twenty-seven percent achieve remission at day fifteen. So that was measured the morning after their final course because it's a fourteen-day course. Notably, the median time to first HAM-D response was nine days with zuranolone compared to forty-three days with the

placebo group. And both medications, both brexanolone and zuranolone, showed relative infant doses below one percent in the breast milk. So this is comparable or even lower than what we see for published relative infant doses of the, uh, SSRIs, and certainly lower than what we see, um, with some of our SNRIs. So these FDA approvals represent what I think, um, and I've been doing this work for, uh, many years, uh, all of these clinical trials in

conjunction with our federally funded work looking at, um, how neuroactive steroids are involved in the pathophysiology of perinatal depression and through brain imaging work and steroidomics. So I'm a little, uh, impartial, but I think this really is a paradigm shift in our understanding and, uh, in the treatment of peripartum depression. But there remains a clear unmet need for treatments that are more rapid-acting, that have higher remission rates, and that offer shorter treatment

durations. We're just gonna get better. We're gonna keep doing more for the women who need it. So there are a couple of investigational agents that are currently in clinical development for PPD, and I just wanna briefly highlight two before turning to our study with GH001. Um, LPCN 1154a is an oral formulation. It's a neuroactive steroid, and it's designed to achieve bioequivalent blood levels to IV brexanolone with a

forty-eight-hour at-home treatment course. The phase three trial's primary endpoint of change from baseline in the HAM-D, the Hamilton Depression Rating Scale, at hour sixty was not met when including all sites. However, after exclusion of an outlier study site, an outlier in many, um, standpoints, the data showed rapid antidepressant effects with a median time to response of two point six days compared to thirty-four point seven days with placebo, and those effects persisted through day

thirty. We recently presented these data at ASCP this spring. RE104 is a synthetic serotonin 2A receptor agonist, a prodrug which is converted to an active compound that is a structural analog of psilocin, but with a shorter psychoactive experience of approximately two to three hours. This, in the study, was administered as a single subcutaneous dose, and that phase two trial met its primary endpoint of significant change from baseline on the

MADRS at day seven, with approximately seventy percent of participants in remission by day seven, sustained through day twenty-eight. These data were presented in January at ACNP. Now, both agents are non-approved investigational compounds. I put that little bar in the upper right-hand corner as a reminder whenever I'm speaking about investigational compounds. So this brings us to GH001, the subject of today's, um, presentation and the article that was recently published in the Journal of Clinical Psychiatry.

So GH001 is a synthetic form of mebufotenin. It's also known as 5-MeO-DMT, and it's formulated for pulmonary inhalation. It's vaporized. It is a non-selective serotonin agonist with high affinity for the 5-HT1A receptor. So different than some of the other psychedelics or the RE104 that was recently tested in PPD. What distinguishes GH001

from other psychedelic-based therapeutics in development is what I think is a remarkably short duration of psychoactive effects. So the median is just eleven minutes. And this has important practical implications for clinical administration, particularly in the patients I've been working with for the past seventeen years in a postpartum depressed patient population where lengthy supervision of potential future psychedelic sessions may represent real barriers to access. Uh, and

I hope to speak about that a little bit later as well. So GH001 has been well-tolerated in early-stage trials and it's shown potential to induce rapid remission of depressive symptoms across three target indications. It's been tested in TRD, which is treatment-resistant depression. I'm gonna only talk about the PPD today, and then it's also been tested in bipolar two disorder with a major depressive episode. The phase two B has been completed for TRD, and the phase two A has been completed

in both PPD, which I'll talk to you about today, and bipolar two depression. So let's discuss the data with GH001. Again, this is a phase 2a single-arm open-label trial in PPD. So this is our trial design. After screening and a pre-dosing day, patients receive GH001 on day one using an individualized dosing regimen or IDR. So I just want to take everyone through that. And so on day one, and I don't know if you can see

my cursor, you might not be able to, but if you can find on the X-axis where we have day one and you see BL for baseline, you see it go up to dose one. And so each participant received the first dose, six milligrams of the GH001. And the administration of a second or potential third dose of GH001 in the IDR was based on the patient's subjectively reported psychoactive effects. That is, if they achieved a peak experience of greater than or

equal to seventy-five on the psychoactive experience scale. And if the dose was well-tolerated as determined by the trial physician. So that if a participant did not achieve a peak experience and the dose received was well-tolerated, then after a one-hour interval, they could receive the next dose, which would be twelve milligrams. Again, if they did not achieve peak experience with that dose, and that dose was well-tolerated, then they would be eligible after a one-hour interval to receive the

final eighteen-milligram dose as part of their individualized dosing regimen. And so we assessed MADRS total score, also PK data and safety assessments at baseline, and then at multiple time points throughout the dosing. Um, I'll introduce you to the Barkin Index of Maternal Functioning or BIMF. That was assessed at baseline and day eight. I'll tell you more about that. It's something we use quite often in perinatal mental health research, especially in depression research.

Importantly, while research staff provided standard education and support should a participant have a challenging experience, there was no psychotherapeutic intervention. There was no psychotherapy, um, that was given either before, during, or after dosing. So these are our eligibility criteria. They included adult females, um, between the ages of eighteen to forty-five with a major depressive episode with peripartum onset diagnosis confirmed by the MINI and following

DSM criteria. Patients had to have given birth within the past twelve months. So the way this works is that the episode onset, we have to as part of the research team determine that the onset was in gestation or within four weeks of delivery. But participants can present to research up to twelve months postpartum. We know that they present late to clinical care and also to research settings and maybe have had a duration of this major depressive episode for many months

before they present for clinical care. Those participants had to have a MADRS score of greater than or equal to twenty-eight, indicating moderate to severe depression. And patients could not be on an antidepressant at the time of the study entry and had to have ceased breastfeeding at screening or agreed to give breast milk to their baby more than twenty-four hours after that last dose. And this is because there really was no breast milk PK data in humans before this study began. And so we

wanted to, uh, it was very important to assess that in a sub-study, and I'll take you through that data as well. So patients were medically stable and very similar to the other PPD trials we have designed in other therapeutics that excluded patients with psychotic disorder, bipolar disorder, or active substance use as well. So our key assessments were the MADRS which, uh, is a clinician-rated scale to address depression severity.

Scores range from zero to sixty, and a higher score indicates more severe depression, with remission defined as a score of less than or equal to ten. Second, we use that Barkin Index of Maternal Functioning, or BIMF. So many acronyms, uh, used commonly in the work I do in perinatal depression research, which is a twenty-item self-report measure specifically designed and validated to assess postpartum functioning, with scores ranging from zero to one twenty.

Here, the higher scores indicate better maternal functioning. We also conducted PK assessments of mebufotenin and its metabolites, bufotenin and 5-MIAA, in breast milk using liquid chromatography and tandem mass spec, and we measured safety throughout. So these are the key demographics. Uh, in this proof of concept study, we had ten postpartum women, mainly White and not Hispanic or Latina, enrolled from sites in the UK and the Netherlands, as at the time the IND was not available in the US when this study was actively enrolling.

The mean duration of the current depressive episode was approximately thirty weeks or seven and a half months, and the mean MADRS was thirty-six point seven, so indicating severe depression, but also including women with moderate depression. And the mean BIMF was sixty-eight point eight, which is impaired. So here are our data. Uh, primary results show the significant reduction in MADRS total score from baseline to day eight. There's a rapid decrease in the MADRS scores following administration of GH001, with a mean change from baseline significant at each time point.

That's at two hours, day two, and day eight. All ten patients achieved depression remission at day eight. And this slide, though the lines overlap, I promise there are actually ten colors and shapes and lines and trajectories. Um, it provides a more detailed view of the individualized patient MADRS total scores at each assessment point. They're just really on top of each other, so you really can't discern them very well. But you can see that each colored line represents one patient's

trajectory and that they each showed substantial improvement. Again, they came in around thirty-seven, and they had a mean reduction from baseline of thirty-five point four points on the MADRS at day eight. So in addition to the depressive symptoms we measured, we were very interested in maternal functioning as measured by the BIMF. You know, again, working with this patient population over so many years, the functional impairment is so clear. Not only is the

patient's impairment for taking care of herself and taking care of, um, her activities of daily living, showering, eating, caring for herself. You see the challenges that they're having putting everything they can to taking care of their infant, but really struggling to care for their infant or their other children. And so this slide shows, and it measures those sorts of things. It shows a significant improvement in those BIMF total scores from baseline to day eight. So

we saw an improvement of thirty-four point one points. This is a fifty-six percent improvement in maternal functioning with GH001 administration. And that BIMF, it measures a bunch of domains, so things like self-care and mother-child interactions and psychological well-being and social support adjustment. Um, we saw across the board in six out of the seven domains, we saw this improvement. So suggesting broad benefits as reported by the patient. But you know, benefits, uh,

that are important both for mother and infant well-being. And then a key consideration for any medication used in lactating, uh, women is its presence in breast milk. Um, we know that if there's any ambiguity of the presence in breast milk or the safety in breast milk, that will be a no-go for many women that are lactating and breastfeeding and, um, are seeking, uh, and require antidepressant treatment. So this slide shows the rapid elimination of mebufotenin and its

metabolite 5-MIAA from breast milk. The metabolite bufotenin was below the level of quantification with liquid chromatography tandem mass spec. So this was a sub-study, so it is a small sample. It's four out of the ten, uh, women that were in the study. And in those four, three had received the GH001 at doses of six plus twelve as their IDR, and one participant had the six plus twelve plus eighteen for the sub-study. So as you can see, both mebufotenin and its

metabolite were below the level of quantification by around eight hours post-dose. And that indicates fairly rapid elimination from breast milk. And as I said, something that's so important as we think about novel therapeutics, we wanna minimize infant exposure and facilitate treatment for women choosing to include an antidepressant as part of their postpartum depression care routine. So regarding safety, GH001 was generally well-tolerated. The most common treatment

emergent adverse event was headache, and that was in five out of ten women. All TEAEs were transient and resolved without intervention. And there were no serious AEs or discontinuations due to AEs. No patients withdrew from the trial. All patients were assessed as ready for discharge within the same day. Um, and so really, it was just a matter of kind of getting the assessment done so that they could go home, uh, because the clinical assessment of discharge readiness, it was already cleared for discharge. But we had to get through the other study assessments

before we could, uh, discharge them, but they were ready for discharge. So this really suggests a, um, a safety profile that allows for a brief medical, uh, supervision or intervention. These safety findings again, um, I could just keep thinking about my patient population for postpartum women, just really important for those women. Important for all of our patients but, uh, especially for those caring for infants and who really struggle with having childcare. Many of these women, um, do not have, uh, support at home. And to have something

that, uh, is rapid and, um, that they can return to the home quickly is an important consideration. So just in conclusion, our open-label Phase 2a trial in a preliminary way shows that this GH001 administered as an IDR is associated with rapid antidepressant effects in women with PPD. All patients achieve remission by day eight, with significant self-reported improvements in, uh, maternal functioning across, you know, many of those domains we talked about. Importantly for breastfeeding mothers, mebufotenin and its

metabolite were rapidly cleared from the breast milk. It was generally well-tolerated. And, you know, these findings, it's a proof of concept study, right? They suggest that GH001 may represent a promising treatment option for PPD, addressing both symptom reduction and functional improvement while minimizing medication exposure. There are limitations, right? It's a very small sample size. It's ten individuals. There's a short follow-up period of one week. There's no control arm. There's no blinding. And so, you know, we need

randomized controlled trials, um, with a comparison. We need it to determine true treatment effects and true safety profile. So although they're preliminary, I just want to end that, um, they represent exactly the direction of the field that needs to move toward treatments that work within hours or days rather than weeks, uh, that allow women to return to their families the same day and prioritize not just symptom reduction, but for women to engage fully, uh, in their life. So with that I'll thank you for your attention. And I just want to go

over and check the Q&A to see what we have here from our audience. So let me see if I can do this more. So yeah. So there's a question here. "Are any of these novel therapeutics being considered in perimenopause since we have significant drop in hormones and many times that period can present similarly to someone's postpartum experience?" Yes. I think we're leading the field, uh, leading the charge in postpartum in these, uh, neurosteroid-modulated, uh, depressive

episodes. But yes, there's significant interest in, um, developing some of these therapeutics. I think the neurosteroids will be first to go. Uh, but I hope that the perimenopausal, uh, depressive disorders are also going to be key areas of focus in the future for these therapeutics as we think about, uh, unique periods across, uh, the female reproductive cycle, where, uh, women are at heightened, uh, risk for developing major depressive episodes,

likely due to a neurosteroid-based mechanism. And that may differ across, uh, the peripartum period or the perimenopause, but thus there might be, uh, a stronger biological or biotype that we can target with some of these interventions. And then we might have time for one more question. So how do we see, um, GH001 fitting into the evolving treatment landscape for PPD alongside zuranolone and some of the other options that may be available and how to

counsel? So this is a question I think we're all thinking about, and it's really exciting to be even in a position to discuss a treatment landscape for PPD rather than simply defaulting to SSRIs and hope for the best, right? You know, when I started doing this seventeen or so years ago, that's all we had were the SSRIs. And then, you know, within a couple of years, I was already starting to do some of the neurosteroid, um, interventional work. But to be here now, we've moved to a future where treatment selection for

PPD is gonna be informed by illness severity, patient preference, breastfeeding status, practical considerations around treatment, duration, setting. And our federally funded work is moving to treatment predictors, right? We need to, uh, to move this into a personalized depression treatment algorithm space. Right now, zuranolone is the only FDA-approved option for PPD, and that is a great option. It offers a fourteen-day at-home treatment course.

For many women with moderate to severe depression it can be the first-line rapid-acting option. LPCN 1154a, if it moves forward, again, talking about investigational, uh, agents right now, could offer an even shorter forty-eight-hour oral course with a brexanolone-equivalent pharmacology. For the psychedelics, at least right now, we've got GH001 and RE104, and that's a completely different therapeutic class, right? So these are serotonergic psychedelic-based compounds. These could offer a

one-day or single-dose treatment paradigm, um, with rapid remission. And so, you know, for today, what I can do today is discuss our FDA-approved options. So we have zuranolone, and we have the SSRIs that are FDA-approved for MDD, and we have a rich evidence base for psychotherapy. So it's really talking about the expected time to response, side effect profiles, you know, risk benefits of each of those, plus or minus breastfeeding considerations, treatment durations.

And for those interested in participating in our clinical trials, talking about, um, those options as well. But we're building a toolkit and not a single solution. So we wanna match these treatments to individuals' needs and preferences, to each woman and her family. So that's what gets me really jazzed and excited about the work we're doing in this space. And, um, I think those are all I have in the chat, uh, or in the Q&A. So yeah. So thank you so much for

attending today. And Sarah and others, I don't know if we have any other closing remarks?

Thank you so much for sharing your time and expertise with us today. I know this has been really valuable for our audience. And, uh, thank you to everyone that joined us. We'll post a link to the recording on our YouTube channel, and we look forward to seeing you at future events. Have a good rest of your day.

Take care, everyone.