Supernus Pharmaceuticals, Inc. (SUPN) Earnings Call Transcript & Summary

Good afternoon, and welcome to Supernus Pharmaceuticals conference call to discuss top line data from the exploratory open-label Phase IIa study of SPN-820 for major depressive disorder. [Operator Instructions] 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 IIa 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 17, 2024. Since then, the company may have made additional announcements related to the topics discussed. We have referenced 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 4. 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 IIa study and open it up for questions with a Q&A session. Moving on to Slide 5. 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 IIa exploratory open-label study in adults with major depression, and we also have a Phase IIb 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 a few hours of the first dose. The effect on the depression symptoms is substantial as measured by 2 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 it has a low 2.5% discontinuation rate because of AEs. Next, on Slide 6. 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. And an early proof of concept, Phase Ib study, has shown significant improvement in depressive symptoms 4 hours after 1 single dose. With that background, I will now turn the call over to Jonathan to walk you through the Phase IIa study.

Thank you, Jack, and good afternoon, everyone. This Phase IIa 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 3 days. And 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 2,400 milligrams of SPN-820, given as a single dose on days 1, 4 and 7. 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 4, which is moderately ill or worse at screening and baseline. They had to maintain a stable approved dose of their antidepressant therapy, or ADT, for their current major depressive episode for 6 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 timepoint 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 in the MADRS total score. This efficacy assessment has been widely accepted by FDA as a pivotal primary efficacy assessment. Moving on to Slide 10. 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 CSSRS. We looked at the Clinician Administered Dissociative State Scale, or CADSS score, which measures dissociation. And we also looked at the Brief Psychiatric Rating Scale Positive Total Score, or BPRS+, which measures positive symptoms associated with psychosis. Now on Slide 11, here's a schematic of the way the study was done. The screening period varies from 1 to 28 days. And during that time, a HAM-D6 and MADRS was performed. On the first day of the clinic visits for people who are eligible for this 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 given at -- was assessed at 2 hours, 4 hours and 8 hours. The MADRS was assessed at 4 hours. And 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 24 hours after SPN-820 administration. And then on day 3, the HAM-D6 was also assessed remotely, approximately 48 hours after SPN-820 administration. On day 4, the subject came back in for a pre-dose HAM-D6 and MADRS assessment. This was about 72 hours after SPN-820. And then the procedure was done in the clinic, similar to day 1. And then the cycle was repeated with a remote assessment on day 5 and day 6, a clinic assessment on day 7, remote assessment on days 8 and 9, and then there is a clinic assessment and a study visit. There was no drug administered on that day as well as the safety follow-up visit that was done on day 12. Moving on to Slide 12. There were 40 subjects dosed in this study across 8 sites. And there were -- those 40 subjects were parted a full analysis set, which is defined as those who had an efficacy assessment at baseline as well as the post-dose efficacy assessment of the HAM-D6. Of those 40 subjects, 38 subjects or 95% completed the study and 2 subjects or 5% discontinued the study. Of the 2 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 noncompliance. Moving on to Slide 13. The subjects in this study at baseline were roughly 40 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 to 22 is severe. So this is well within the severe range. The MADRS total score at baseline was 33.1. And a score of 33 is considered at the high end of moderate and almost bordering that of a severe MADRS symptoms. The CGI severity baseline score was 4.6, which is roughly between moderate and marked. Now 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 2 to 3 points as denoted in the gray rectangle. So what did we see here? We saw on the first day, first dose at the first timepoint assessed at 2 hours, there's a change from baseline of 6.1, which is well beyond the meaningful clinical threshold. This change was sustained on days 2 and 3 when the subject was not receiving medication, as well as on day 4 at the pre-dose baseline for day 4. 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 continue 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 timepoint 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 4 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, 6 subjects, 15%; and dizziness, 4 subjects at 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 base lines, 5 out of 40 or 12.5% of the subjects had suicidal ideation. By day 10 only 1 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 2 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 1 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 IIb 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.

[Operator Instructions] Our first question comes from the line of Andrew Tsai of Jefferies.

Congrats on the data. 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 that means 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 5-week TRD study and not see tachyphylaxis over time?

Jonathan, do you want to take this one?

Sure. So we did this study because we wanted to evaluate every 3-day dosing in MDD. The 201 Phase IIb placebo-controlled study is evaluating TRD as well as a few MDD subjects where a 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 will have to see. But we'll evaluate the data and then we'll make an assessment at that point. And as far as durability, you're correct, this was a 10-day study. The other study is a 5-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 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?

Yes. 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. We 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 going to see that as well.

Our next question comes from the line of Stacy Ku of TD Cowen.

Great. Congratulations on the data. Just first, based on these results, can you talk about your plans for SPN-820 and MDD, specifically? How do 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 reached -- achieved 50% reduction of HAM-D6? Maybe any of these endpoints for MADRS, that would be really appreciated as we're kind of trying to parse through the data. And then last, some of the clinicians, they've expressed concern around chronic mTORC activation. So what kind of long-term safety are you going to try to collect beyond those 5 weeks in the TRD study. That might be helpful to kind of give clinicians a little bit more comfort around the safety profile.

Yes. Thanks, Stacy. I'll take the first portion of the set of questions. As far as our plan, I mean, we're going to wait to see what happens with the Phase IIb and 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 leaves us as far as number of indications and which indication is ahead of the other one. I'll let Jonathan address the other pieces of the question. As for remission and the responder rate and so forth, I mean, that is analysis we're still doing at this point. Clearly, we will issue more the data as the analysis is complete.

Yes. 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, looking at getting in a sense of like how many would be 50%. And as I said, people started out on the MADRS as 33, and they dropped to minus 23 or about 10 or 11. So you can get a sense using a remission criteria of less than or equal to 10, our mean wound up at about 10 or 11. So 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, a variety of different things. You can think of it like a jigsaw puzzle. And 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. You can think about it as stepping on the brake, and you can only step on the brake -- a step on the gas, you can only step on it so much. Versus if you're missing the brake, so the genetic disorders, where there's not a brake, you're missing the brake on mTORC and you get constituent 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.