Good afternoon, and welcome to Supernus Pharmaceuticals' conference call to discuss top-line data from the exploratory open- label Phase 2a study of SPN-820 for major depressive disorder. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. Instructions will follow at that time. As a reminder, this conference call is being recorded. I would now like to turn the conference over to Peter Vozzo of ICR Westwicke, investor relations representative for Supernus Pharmaceuticals. You may begin.
Thank you, Latif. Good afternoon, everyone, and thank you for joining us today for Supernus Pharmaceuticals' conference call to discuss top-line data from the exploratory open- label Phase 2a clinical study of SPN-820 in adults with major depressive disorder. Today, after the close of the market, the company issued a press release announcing these results. On the call with me today are Jack Khattar, Supernus' Chief Executive Officer, and Jonathan Rubin, Senior Vice President, Research and Development, and Chief Medical Officer. Today's call is being made available via the investor relations section of the company's website at ir.supernus.com. During the course of this call, management may make certain forward-looking statements regarding future events and the company's future performance. These forward-looking statements reflect Supernus' current perspective on existing trends and information.
Any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, including those noted in the Risk Factors section of the company's latest SEC filings. Actual results may differ materially from those projected in these forward-looking statements. For the benefit of those who may be listening to the replay, this call is being held and recorded on October seventeenth, two thousand and twenty-four. Since then, the company may have made additional announcements related to the topics discussed. Please reference the company's most recent press releases and current filings with the SEC. Supernus declines any obligation to update these forward-looking statements, except as required by applicable securities laws. I will now turn the call over to Jack.
Thank you, Peter. Good afternoon, everyone, and thanks for taking the time to join us on today's call. Starting with the introduction and agenda on slide four, we will go through a brief executive summary and overview of SPN-820. Then we will cover the design and results of the open-label Phase 2a study and open it up for questions with a Q&A session. Moving on to slide five, SPN-820 is a first-in-class oral new chemical entity that we are developing in partnership with Navitor Pharmaceuticals for the treatment of depression. The drug restores mTORC1 synaptic signaling through a unique intracellular mechanism. We completed a Phase 2a exploratory open-label study in adults with major depression, and we also have a Phase 2b placebo-controlled study in treatment-resistant depression that is currently ongoing.
Briefly, the open- label data that we will present in a few minutes point to a product candidate that rapidly reduces depression symptoms within few hours of the first dose. The effect on the depression symptoms is substantial, as measured by two distinct depression scales. Moreover, SPN-820 is showing a substantial reduction of 80% in suicidal ideation. The drug is well-tolerated, with few adverse events and has a low 2.5% discontinuation rate because of AEs. Next, on slide six, and by way of background, you see a brief description of SPN-820. Through its first-in-class intracellular modulation of mTORC1, it has demonstrated in animal models increased levels of the brain-derived neurotrophic factor, also known as BDNF, along with other downstream modulators. It has also shown increased dendritic spines, thereby supporting increased neuroplasticity.
In an early proof of concept, Phase 1b study has shown significant improvement in depressive symptoms four hours after one single dose. With that background, I will now turn the call over to Jonathan to walk you through the phase 2a study.
Thank you, Jack, and good afternoon, everyone. This Phase 2a study had several objectives. First, we wanted to study subjects with major depressive disorder or MDD. In addition, we wanted to assess the rapid onset of improvement in depression symptoms, and we wanted to evaluate the drug when administered once every three days. Finally, we also wanted to assess safety and tolerability. Moving on to Slide 8. To assess these objectives, we had an open-label adjunctive design. This study was an open-label, single-group study of twenty-four hundred milligrams of SPN-820, given as a single dose on days one, four, and seven.
The subjects in the study included adults 18 to 65 years old with MDD, and they must have had a Montgomery-Åsberg Depression Rating Scale, which I will refer to as the MADRS, total score of greater than or equal to 22 at both screening and baseline, as well as the CGI Severity Score of greater than or equal to four, which is moderately ill or worse at screening and baseline. They had to have maintained a stable, approved dose of their antidepressant therapy or ADT for their current major depressive episode for six weeks or more, and then they had to remain on the same dose and the same ADT during the study. 40 subjects were included in the study. Now, on to slide 9, Efficacy Endpoints.
The primary endpoint at each time point assessed was the change from baseline in the Hamilton Depression Rating Scale-6, or HAM-D6 Total Score. This efficacy measure looks at acute effects of depression sensitive to acute changes. In addition, we looked at a secondary efficacy endpoint, the change from baseline and the MADRS total score. This efficacy assessment has been widely accepted by FDA as a pivotal primary efficacy assessment. Moving on to slide ten. We looked at safety endpoints in this study, and they included adverse events, or AEs, suicidal ideation and behaviors as measured by the Columbia-Suicide Severity Rating Scale, also known as the C-SSRS. We looked at the Clinician-Administered Dissociative States Scale, or CADSS score, which measures dissociation, and we also looked at the Brief Psychiatric Rating Scale, Positive Total Score, or BPRS-Positive, which measures positive symptoms associated with psychosis.
Now, on slide eleven, here's a schematic of the way the study was done. The screening period varied from one to 28 days, and during that time, a HAM-D6 and MADRS was performed. On the first day of the clinic visit for people who were eligible for the study, a pre-dose HAM-D6 and MADRS was performed. SPN-820 was administered in the morning, and then there were serial measurements across the day. The HAM-D6 was assessed at 2 hours, 4 hours, and 8 hours. The MADRS was assessed at 4 hours. I should also mention that the patient maintained their antidepressant both during screening and throughout the study, and SPN-820 was given adjunctively to their antidepressant. On day 2, there was a remote assessment done.
The HAM-D6 was assessed at approximately twenty-four hours after SPN-820 administration, and then on day three, the HAM-D6 was also assessed remotely, approximately forty-eight hours after SPN-820 administration. On day four, the subject came back in for a pre-dose, HAM-D6 and MADRS assessment. This was about seventy-two hours after SPN-820, and then the procedure was done in the clinic, similar to day one, and then the cycle was repeated with a remote assessment on day five and day six, a clinic assessment on day seven, remote assessment on days eight and nine, and then there was a clinic assessment and a study visit. There was no drug administered on that day, as well as a safety follow-up visit that was done on day twelve. Moving on to slide twelve.
There were forty subjects dosed in this study across eight sites, and there were forty. Those forty subjects were part of the full analysis set, which is defined as those who had a efficacy assessment at baseline, as well as a post-dose efficacy assessment of the HAM-D6 . Of those forty subjects, thirty-eight subjects or 95%, completed the study, and two subjects, or 5%, discontinued the study. Of the two who discontinued, one subject, which represents 2.5%, discontinued related to an adverse event of hypertension, which was assessed by the PI as not drug-related. The other subject, or 2.5%, was discontinued for reasons of non-compliance. Moving on to slide 13. The subjects in this study at baseline were roughly forty years old, mostly female, and mostly white. Going to slide 14.
In terms of the baseline characteristics, this was a sick population. If you look at the baseline HAM-D6 total score, the mean HAM-D6 total score was 13.6, and if you look at the bottom, the HAM-D6 score ranges from 0 to 22, and a score of 13-22 is severe. So this is well within the severe range. The MADRS total score at baseline was 33.1, and a score of thirty-three is considered at the high end of moderate and almost bordering that of severe MADRS symptoms. The CGI-S baseline score was 4.6, which is roughly between moderate and marked. Now, on to slide 15. What did we see? We saw a rapid decrease in the HAM-D6 scores.
On the Y-axis, which we see the mean change from baseline in the HAM-D6 total score. Now, for the HAM-D6, a meaningful clinical threshold of change is considered two to three points, as denoted in the gray rectangle. So what did we see here? We saw on the first day, first dose, at the first time point assessed at two hours, there's a change from baseline of 6.1, which is well beyond the meaningful clinical threshold. This change was sustained on days two and three, when the subject was not receiving medication, and as well as on day four at the pre-dose baseline for day four. So we saw an effect for a single dose that lasted as long as 72 hours.
Moreover, as one can see across the x-axis over time, the effect was sustained and actually even continued to decrease to the day 10 end of study point at which the change from baseline was minus 9.6. Recall that the baseline HAM-D6 score was over 13, and the change is now 9.6, reducing it to about 4 overall. Now, moving on to slide 16. Similar to the decrease in the HAM-D6 score, we also saw a rapid decrease in the MADRS scores. Here in the y-axis is the change from baseline in the MADRS total score. So on the first day, after the first dose, at the first time point assessed at 4 hours, we saw a change from baseline of minus 16.6, and a meaningful clinical threshold of change on the MADRS is 6 to 7 points.
This is well beyond that threshold. Similar to the HAM-D6, this was sustained out to day four at the pre-dose measurement, and we saw over time a persistent reduction in the MADRS score out to day 10, to a change from baseline of minus 22.9, going from minus 33 to minus 22.9, a substantial change. Going on to slide 17. We're switching over now to safety assessments. Looking at treatment-emergent adverse events, or TEAEs, of the 40 subjects in the study, 25 or 62.5% had a TEAE. Said another way, 15 subjects, or 37.5%, had no TEAEs throughout the study. 23 subjects, or 57.5%, had a related TEAE. There were no subjects who had serious adverse events, and there were no severe TEAEs reported during the study.
One subject had a TEAE leading to withdrawal, or 2.5%. I mentioned that previously. This was someone who had an increase in hypertension. It was assessed as moderate and not related to study drug. Going to slide 18. We see a profile of a drug that's well-tolerated with few adverse events overall. The most common adverse events noted are headache and nausea, each at 20%, somnolence, six subjects, 15%, and dizziness, four subjects or 10%. All of these adverse events were assessed as either mild or moderate, and as I mentioned previously, none of these were severe. In addition to the adverse events noted in the table, there were no changes regarding dissociative events, and no positive symptoms of psychosis were noted during the study. Going to slide 19. Interestingly, we saw a substantial decrease in suicidal ideation.
Suicidal ideation decreased by 80%. At baseline, five out of 40, or 12.5% of the subjects, had suicidal ideation. By day ten, only one out of 38, or 2.6% of subjects, had suicidal ideation. There was no suicidal ideation observed during the study. I'll now turn the call back over to Jack.
Moving on to slide 20, and to summarize, we believe the data show that SPN-820 represents a first-in-class oral antidepressant that has a rapid, as early as two hours, and a substantial clinically meaningful improvement in depressive symptoms as measured by both the HAM-D6 and MADRS scales. The data also show a continued and lasting effect with one single dose for 72 hours and a substantial decrease of 80% in ideation. In addition, SPN-820 is well-tolerated, with a low 2.5% discontinuation rate due to AEs. Finally, on slide 21, just to give you a brief update on the ongoing Phase 2b study, it is a placebo-controlled adjunctive study in adults with treatment-resistant depression. To date, we have randomized approximately 227 patients and are targeting a total of 236 patients.
The primary endpoint in that study is the MADRS total score. We are expecting enrollment to be completed in November of this year, with top-line data in the first half of 2025. With that, I will now turn over the call to the operator for Q&A.
Thank you. At this time, to ask a question, please press star one, one on your telephone. Again, that's star one, one on your telephone to ask a question. To remove yourself from the queue, please press star one, one again. Please stand by while we compile the Q&A roster.... Our first question comes from the line of Andrew Tsai of Jefferies. Please go ahead, Andrew.
Hi, thanks. Good afternoon. Congrats on the data. Thanks for taking my questions. So with this MDD data on hand, how do you feel about the ongoing TRD study results? Would you expect efficacy to look stronger since that study, I believe, is dosed daily, not in a pulsatile manner, and what would that mean for safety as well? And then secondly, this was a 10-day study. It's still fairly short, big picture, so what gives you the confidence we'll continue to see durability over time, in that five-week TRD study and not see tachyphylaxis over time? Thanks.
Jonathan, you wanna take this one?
Sure, so we did this study because we wanted to evaluate every three-day dosing in MDD. The 201 Phase 2b placebo-controlled study is evaluating TRD as well as a few MDD subjects, where the drug is administered once a day. We don't know the results from that study, so it's hard to predict, even based on this study, what will happen in that study. As you know, one of the challenges in doing placebo-controlled studies in depression subjects with depression is a high placebo rate, so we'll have to see how we do with that, but certainly, this data shows a substantial decrease in depression symptoms, as well as a rapid reduction in depression symptoms, and the overall safety profile looks good. I don't expect tachyphylaxis.
That is usually modulated through receptor-mediated mechanisms. It is conceivable that this could occur with our MOA. We'll have to see, but we'll evaluate the data and then we'll make an assessment at that point. As far as durability, you're correct, this was a ten-day study. The other study is a five-week study, and we'll have to evaluate the data as well as evaluate open label data once we do an open- label study, open- label extension study to see how long the effect is sustained.
And then thank you. And then last question is, on the cognitive disorder, can you confirm if those rates were mild and moderate in nature, not severe? And can you give us a frame of reference what other drugs show on the rates of cognitive disorder? Thank you.
Yeah, there were no severe events in the study. So I don't recall if they were mild or moderate. I can look that up. Cognitive disorder is something that is associated with depression. And so it's not surprising that we saw this, saw cognitive problems. And we'll have to see in the placebo-controlled study, do we see it equally in drug and placebo, or is there a difference? And if you look at other studies, you're probably gonna see that as well.
Right. Thank you so much.
Thank you. Our next question comes from the line of Stacy Ku of TD Cowen. Please go ahead, Stacy.
Great. Thanks so much for taking our questions, and congratulations on the data. Just first, based on these results, can you talk about your plans for SPN-820 and MDD, specifically, how you anticipate this being used? And then is it possible to disclose any other metrics, maybe the percentage of patients that might have achieved remission by HAM-D6 or the number of patients that achieved 50% reduction of HAM-D6, maybe any of these endpoints from MADRS? That would be really appreciated as we're kinda trying to parse through the data. And then last, some of the clinicians they've expressed concern around chronic mTOR activation. So what kind of long-term safety are you gonna try to collect beyond those five weeks in the TRD study that might be helpful to kind of give clinicians a little bit more comfort around the safety profile?
Thanks so much.
Yeah, thanks, Stacy. I'll take the first portion of the set of questions. As far as our plan, I mean, we're gonna wait to see what happens with the Phase 2b in TRD. I mean, from a long-term perspective, we would love to develop the product for all forms of depression, whether it's treatment resistant, or MDD and perhaps other indications in the future. So that remains to be seen as far as to where we end up and where the data leads us, as far as number of indications and which indication, you know, is ahead of the other one. I'll let Jonathan, you know, address the other pieces of the question as far, you know, remission, responder rate, and so forth. I mean, that is analysis we're still doing at this point.
Clearly, we will issue more data, you know, as the analysis is complete.
Yeah. Thanks, Jack. We're in the process of analyzing remission and responder data, and that will be shown at a future fall conference. But you can kind of get a sense from this just by looking at the MADRS curve over time, and looking at the baseline, the change from baseline over time, at looking at getting a sense of like how many would be 50%. And as I said, people started out on the MADRS at thirty-three, and they dropped to minus twenty-three or about ten or eleven. So you can get a sense, using a remission criteria of less than or equal to ten, our mean wound up at about ten or eleven.
You can see that by day 10, most of the people or a high majority of people got to remission. As for mTORC activation, mTORC is a very complex molecule that has multiple points at which it can be modulated. It's a complex of a variety of different things. You can think of it like a jigsaw puzzle. We have data which actually we previously showed at the R&D Day last year that shows that the mTORC gets activated only to a certain extent. There appears to be saturation with our molecule, so you can't overdrive the mTORC in the same way as... You can think about it as stepping on the brake, and you can only step on the gas, and you can only step on it so much.
Versus if you're missing the brake, so those genetic disorders where there's not a brake, you're missing the brake on mTORC, and you get constitutive overactivity. It's a different case, and it's not the same scenario. They shouldn't be viewed similarly. But in terms of looking at long-term effects, we will have to do an open- label extension study and look for long-term effects in humans, as well as potentially doing carcinogenicity study and looking at that as well. But so far, the safety profile looks fairly good.
Okay, very helpful. Thank you.
Thank you. Our next question comes from the line of David Amsellem of Piper Sandler. Please go ahead, David.
Hey, thanks, and couple from me. Sorry if I missed you addressing this earlier on, but wanted to get your thoughts on what to make of the rate of somnolence and dizziness. I guess the question here is, you know, are there, you know, significant sedating properties here that we need to be mindful of? How do you think about that, both clinically and just even commercially, to the extent it gets that far? That's number one. Number two is, this is a study in MDD. You've got the Phase 2b in treatment-resistant depression. I guess the question here is, as you're thinking broadly about the development program, are you looking at this more as a sort of TRD population with suicidality, or more broadly in MDD?
Help us better understand, you know, at least given what we know now, how you're generally thinking about the various depressive subgroups. Thanks.
Jonathan, do you want to address the somnolence, dizziness, and then I can talk about the development program?
Sure. So there were six subjects, or 15%, had somnolence. All of those cases were mild or moderate. None were severe. No one discontinued it related to somnolence. So our overall impression at this point is that it's really not that significant. Now, the bigger test will be in the larger study, the phase IIb study, which is ongoing looking at the adverse event profile and drug and placebo and seeing is there any difference between drug and placebo and what was the severity and discontinuation. Right now, we're just looking in a blinded fashion and so far what we're seeing is that this drug has a fairly benign safety profile and is very well tolerated.
Regarding the development program, David, as I mentioned earlier, I mean, we really need to see the phase IIb data clearly to make a final assessment as to which way we're gonna go with this drug, MDD or TRD, or which one at first, or maybe together in parallel. Is there any other, you know, important things we have to go after in our program on suicidal ideation or whatever it is? Clearly, I mean, this is the first time we put this drug in humans, you know, at this level with 40 patients. It's really interesting and very exciting and encouraging to see the initial set of data.
Of course, albeit it is an open- label study, but this is a very, very encouraging, at least we believe, very encouraging set of data on both ends, efficacy and safety. So with all that remains to be seen, we're looking at the data, I mean, shortly, as far as the phase IIb, I mean, first half of twenty twenty-five is not too far off, and we'll obviously update everyone as to what specifically the plans will be moving forward. And again, to build on what Jonathan said, I mean, as far as the safety, tolerability, all that, I mean, it's really encouraging to see only discontinuation of 2.5% because of AEs, and the AE is hypertension that was not even deemed to be, you know, related to our drug.
Whether somnolence, dizziness will show up a little bit more in phase 2B or not, obviously remains to be seen.
Okay, thank you.
Thank you. Our next question comes from the line of Annabel Samimy of Stifel. Please go ahead, Annabel.
Hi, thanks for taking my question. Interesting data. I'm curious, the consistency between the HAM-D score and the MADRS score, they were pretty similar. And I guess that's interesting given some of the inconsistencies we saw in phase 1. I'm just wondering, you know, do you have any explanation for that, and does that give you increased comfort for the TRD study that's coming up? And then secondly, if you do continue to explore this in phase 2, the dosing every three days is also pretty interesting. Do you think that you'd be exploring different dosing regimens in phase 2, or different dosage strengths to then this trial, like we already saw? Thanks.
Annabel, I'm sorry. You were a little bit breaking up, but I'll see if we if I can decipher the question a little bit here. If I understood the question, the differences between the HAM-D6 and the MADRS and, and why we used it at different, in different studies or different time points, I'll have Jonathan go through that. And then also the other part of the question, to clarify again, why the different or the the single dose every three days, I guess. I'll ask Jonathan to add some color to that as well.
Well, so Annabel, I just wanna make sure that I'm getting the question correct. Did you want you were looking at across this study, or you were looking in comparison to the phase 1B study that Navitor had previously conducted?
Right. What I'm curious about is, given the, you saw some pretty good consistency between the two scores in this study, and, you know, that's notable given the inconsistencies seen in phase 1. And given what we've seen in terms of the similarities of the scores, does that give you increased comfort moving into the TRD study and what that might mean for the TRD study?
Okay, got it. Yeah, so we did look at the data in comparison to the phase 1B study conducted by Navitor that's been previously reported. In that study, there was a statistically significant effect on the HAM-D6 that was seen within a few hours, and there was just a mild to moderate effect on the MADRS. And in looking at those two studies, there are several important differences. One, the 1B study had a single-blind placebo lead-in. That design is actually somewhat controversial. There are pros and cons of doing it, but what is known is that when you do that, it reduces both the effect for the placebo arm, as well as the effect in the active arm. In addition, that study was not an adjunctive study.
That study was a monotherapy study, and the demographics of that study were a little bit different than the demographics in the open- label study that I'm reporting today, or that we're reporting. Notably, in the 1B study, it was mostly older males. In this study, we're seeing younger females. The younger females in the baseline age of forty, more representative of what we see in the depression world. In the 1B study, I mean, they just I think there was some selection bias in terms of who they were evaluating at their centers, in coming up with an older population of males. I think predominantly, if you put all those three things together, that's why you are seeing some inconsistencies in the data.
Now, what this means going forward, we'll have to see with the data. I can't make any predictions at this point for the phase 2B. We'll see when we unblind the data and report it publicly. As for dosing every three days, we wanted to get a sense given the 1B finding, where a single dose showed a change in the HAM-D6 in a TRD population in a few hours that was sustained for 72 hours after a single dose. We wanted to see, well, okay, is dosing every three days the way to go with this product? And so we have data now for dosing every three days.
In the 2B study, we'll be dosing every other day, and then once we get the results from the 2B study, we'll compare the two. We'll make a decision if we want to go forward with once a day dosing or every three-day dosing. And as Jack mentioned, we'll make a decision if we want to go forward with treatment-resistant depression or MDD.
Clearly, to add to that, Annabel, I mean, clearly, these studies are exploratory in nature, as we said. We're looking at different aspects of the drug, try to understand it, you know, as much as we can under a wide range of scenarios and possibilities, whether it's dosing, endpoints, and so forth. At the end of the day, of course, MADRS is the key, you know, score that we're looking at as an endpoint in the pivotal, you know, phase three studies that we will go with eventually, typically. We wanted to explore, you know, the drug under different scenarios, different dosing levels, and so forth.
I mean, that's why, clearly you do these kind of studies, so you have a much better understanding of the drug itself before you design, your phase threes, moving forward. So hopefully, that's a little bit helpful to shed a light on.
Thank you.
Thank you. At this time, I'd like to turn the call back over to Jack Khattar for closing remarks. Sir?
In concluding our call this afternoon, I would like to reiterate the exciting and what we believe, the competitive emerging clinical profile of SPN-820. It is an oral, first-in-class new chemical entity with a novel and unique mechanism of action for the treatment of depression. It has the following highly differentiated clinical profile. First, a rapid onset within few hours from one single dose, with meaningful clinical improvement in two distinct depression scales, including MADRS. Second, a continued and sustained improvement after only three doses through day 10, with what looks like to be one of the highest reductions seen in the MADRS scale. Third, substantial 80% reduction in suicidal ideation, and also a well-tolerated, no serious or severe AEs, no dissociative effects or psychosis, and a low 2.5% discontinuation rate due to AEs.
With that, I thank you for joining us this afternoon, and we look forward to updating you further on our next call.
This concludes today's conference call. Thank you for participating. You may now disconnect.