Aptinyx Inc.

Good afternoon and welcome to the APTINX fourth quarter and year end 2020 financial results conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open up the call for your questions. Please be advised that the call is being recorded at the company's request. At this time, I would like to turn the call over to Nick Smith, Vice President of Corporate Development and Investor Relations of APTINX. Nick, please proceed.

Good afternoon, everyone, and thank you for joining us on today's call to discuss Aptinix's fourth quarter and year-end 2020 financial and operating results. Our press release describing financial results and business highlights is now available on our website. On today's call, Norbert Riedel, our Chief Executive Officer, will discuss our business and clinical development progress, and Ashish Khanna, our Chief Financial Officer and Chief Business Officer, will review our financial results. Additionally, for the Q&A portion of the call, we're joined by Andy Kidd, our President and Chief Operating Officer, Catherine King, Senior Vice President of Clinical Development, and Harold Merck, Vice President of Medical and Pharmacovigilance. I'd like to remind everyone that statements made during this conference call will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties that can cause actual results to differ materially. Any forward-looking statements are made only as of today, and we disclaim any obligation to update these forward-looking statements. Please see the forward-looking statements disclaimer in our financial results release issued this afternoon and the risk factors in the company's current and subsequent filings with the SEC. It is now my pleasure to turn the call over to Norbert.

Thank you, Nick, and good afternoon, everyone. We appreciate you taking the time to join us on today's call. We are excited to talk with you today, following what was a productive, albeit challenging year for us at Aptinix. Despite the global COVID-19 pandemic, our team remained focused on responsible decision-making and first-rate execution. And as a result, the past year has been marked by several important achievements in advancing our development programs. Among the key highlights of the year was the data from our Phase II exploratory study of NYX783 in post-traumatic stress disorder, which we reported in October. We are truly encouraged by the early results with NYX783, particularly at a time when mental health is at the forefront due to the trauma, isolation, and loss being experienced by so many. Our Phase IIb studies of NYX2925 in chronic pain resumed late last year, and the early metrics of execution and enrollment are looking very positive. Our clinical development efforts with NYX458 in cognitive impairment presented even greater challenges due to the pandemic, given the vulnerability of this patient population. However, we will be recommencing this study in the coming days, and will then again be enrolling patients in each of the Phase II studies that we have suspended last year. We are keenly focused on executing these studies in a safe, durable, and efficient manner to complete them expeditiously, with particular attention to the quality of the data coming out of each study. This execution will lay the foundation for four Phase II study readouts with our novel NMDA receptor modulators beginning in the first half of 2022. All this important work, perseverance, and attention to detail is only possible with a dedicated and resilient team. I am very proud of the team members we have here at Aptonyx, all of whom are very passionate about our mission to improve the lives of patients who are suffering from challenging CNS conditions. We have a strong cash position with over $140 million at the end, which we expect to fund our operations for multiple phase two study readouts and into 2023. Let's discuss each of our development programs, starting with NYX 2925, our clinical stage development candidates under evaluation in two centralized chronic pain conditions. Fibromyalgia and Painful Diabetic Peripheral Neuropathy, or DPN. Following the pause in enrollment in both the Fibromyalgia and DPN studies due to the escalation of the COVID-19 pandemic last March, we reinitiated both of them towards the end of last year. While we have incorporated certain targeted protocol modifications to facilitate durable study execution, and ensure the safety of patient and study personnel against the backdrop of COVID-19, the key elements of the Phase II study design have not changed. In fibromyalgia, we are evaluating the effects of daily dosing of 50 milligrams and 100 milligrams of NYX2925 against placebo in a 12-week study. We expect to enroll approximately 300 patients in this study. In DPN, we are evaluating the effect of 50 milligrams of NYX2925 against placebo, also over a 12-week treatment period. In this study, we expect to enroll approximately 200 patients with advanced DPN. The primary endpoint for both studies is the change from baseline on the average daily pain score as measured by the 0 to 10-point numeric rating scale. So far, we are pleased that enrollment in both studies has been tracking in line with our expectations. Based on this steady execution and enrollment progress, we anticipate reading out data from each of these chronic pain studies in the first half of 2022. Let's move now to NYX783, which is in development for the treatment of post-traumatic stress disorder. In October, we announced positive results from our Phase II exploratory study in patients with PTSD. In this study, NYX783 demonstrated clinically meaningful effects on multiple efficacy endpoints after four weeks of treatment. Importantly, the signals we observed were very consistent with our understanding of the mechanism of NYX783. The study evaluated two doses of NYX7A3 against placebo in 153 patients over four weeks. The effects were measured on the CAHPS5, which is a holistic evaluation of the range of symptoms experienced by people with PTSD. As this was an exploratory study, and the first time NYX783 was evaluated in patients with PTSD, we were focused primarily on evaluating parameters that would inform our design of future well-powered studies, including the safety and tolerability profile and the degree to which NYX783 exhibited efficacy signals across an array of endpoints. We are encouraged by the data we obtained from this study and believe that NY783 has the potential to become a new therapeutic option in an indication that has not had a new target proved in over 20 years. As we look ahead to future clinical development, we will build on the following key observations from this first study. On the CAHPS 5 total score, we saw a clinically meaningful improvement from baseline with the 50 milligram dose. Importantly, looking at responder rates, a significantly greater proportion of patients receiving 50 milligrams achieved a clinically meaningful improvement on the CAHPS 5 total score compared to the placebo group. These observed effects on the CAHPS 5 total score were driven by consistent and robust improvements from baseline across three of its four symptom cluster scores. NYF783 exhibited a very favorable safety profile with no drug-related serious adverse events and an overall adverse event profile that was in line with placebo. We also learned about certain patient characteristics that appears to influence the overall response to NYX783, which we will incorporate into the design of the next study. These promising signals, which we have seen with four weeks of treatment, provide us with confidence to move forward in this indication. We are pleased that these data have been accepted for presentation at the upcoming Society of Biological Psychiatry annual meeting scheduled to take place virtually April 29th through May 1st. In addition, we have been granted a Type C meeting with the FDA on April 29th to discuss the design of the next study and the path to an NDA in PTSD. While the specific study design details have not been finalized, we expect the next study to be a Phase IIb study with a registration-supported design focused on the CAHPS 5 total score, consistent with other pivotal studies in PTSD. We plan to commence this study in the second half of this year, and we will provide more details at the appropriate time. I am pleased with our progress with NYX783, and maybe most importantly, The data from this Phase II study now provide a third clinical validation of the activity of the novel NMDA receptor modulators from our platform. Across two chronic pain studies and this PTSD study, we have seen that compounds from our platform show improvements on validated clinical endpoints, giving us a solid foundation to confirm these signals in larger more conclusive clinical studies. Let's now discuss relevant updates on NYX458, which is in development for the treatment of cognitive impairment. Following the suspension of our Phase IIa study last March, I am pleased to report that we are now just days away from recommending patient screening in this study. We have incorporated several targeted protocol changes designed to simplify study execution and optimize our chances for detecting signals of efficacy, while, of course, ensuring the safety of patients and study personnel. This Phase II study is a randomized, double-blind, placebo-controlled study to evaluate the safety and potential cognitive benefits of NYX458 in approximately 100 patients. Recall, when we initially started this study, we were enrolling patients with mild cognitive impairment in Parkinson's disease. We are now expanding this patient population to also include mild dementia in Parkinson's disease and dementia with Lewy bodies. It is recognized that these diagnoses represent a continuum with the same alpha-synuclein-related pathophysiology which we believe NYX458 is well-suited to address. In particular, alpha-synuclein buildup has been implicated as a causal factor for cognitive impairment. And further, it has been demonstrated that increases in alpha-synuclein levels reside in decreased NMDA receptor expression and activity. We therefore believe the enhancement of NMDA receptor activity with NYX458 has the potential to address this cognitive impairment. The study will involve two treatment arms, daily dosing of either 30 milligrams of NYX458 or placebo, and will evaluate the safety, tolerability, and cognitive effects on patients over a 12-week period. This is our first study of a new mechanism in patients with cognitive impairment, and it is critical for us to explore multiple cognitive endpoints to characterize the activity of NYX458. Accordingly, we will leverage multiple computerized neurocognitive assessments to evaluate the effect across the key cognitive domains impaired in this patient population. Following significant progress over the last few months, we are pleased to be hosting a virtual investigative meeting March 26 and will then begin screening and enrolling patients. We have received good initial feedback from clinical study sites on the changes we are incorporating and anticipate reporting data from this study in the second half of 2022. To summarize, I'm immensely proud of the way our team has navigated the challenges of the past year. The data we read out in 2020, combined with the tremendous work to get our preclinical studies back up and running, have enabled us to advance our development efforts across each of our programs. With that, I will now hand the call over to Ashish to discuss our full year 2020

end fourth quarter financially well thank you norbert beginning with the balance sheet we ended the fourth quarter with 141 million dollars in cash and cash equivalents compared to 98.8 million dollars at the end of 2019. to reiterate norbert's earlier remarks we expect our current cash to fund our operations into 2023 and support achieving multiple important clinical milestones With respect to our income statement, our revenues have historically been related to our research collaboration with Allergan, now a subsidiary of AbbVie. The jointly funded activities under this research collaboration came to their contractual conclusion in August of 2020. So as expected, we had zero revenues in the fourth quarter of 2020 as compared to $1 million for the fourth quarter of 2019. Since the research collaboration activities were ongoing up to August 2020, we did have $1.6 million in revenue for the full year 2020 as compared to $3.7 million for the full year 2019. Importantly, we are not reliant on these revenues to fund our operations. The majority of our spend remains heavily concentrated in research and development. R&D expenses totaled $6.8 million and $32.8 million for the fourth quarter and full year 2020, respectively, as compared to $10.6 million and $44.3 million for the same period in 2019. The decrease in RMD expenses in 2020 was primarily the result of the temporary pauses to patient enrollment across three of our four Phase II studies, as well as the conclusion of the Phase II study in PTSD. We expect R&D spend to increase throughout the year with all three studies back up and running. We reported G&A expenses of $4.8 million and $19.5 million for the fourth quarter and full year 2020, respectively, as compared to $4.5 million and $19 million for the same period in 2019. Finally, we reported a net loss of $11.5 million and $50.1 million for the fourth quarter and full year 2020 respectively, as compared to a net loss of $13.8 million and $57.4 million for the same period in 2019. I will now turn the call back over to Norbert.

Thank you, Ashish. As we advance our development candidates across chronic pain, PTSD, and cognitive impairment, we look forward to multiple potentially catalytic milestones beginning in the first half of next year. Turning the page to 2021, we are pleased to be well positioned both financially and across our clinical operations to continue moving our pipeline of novel differentiated NMDA receptor modulators forward. We will be happy to begin taking your questions now.

At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. Again, that is star, then the number one on your telephone keypad. We'll pause for just a moment to compile the Q&A roster. We have our first question coming from the line of Ritu Baral with Cohen. Your line is open.

Good afternoon, guys. Thanks for taking the question. I guess my focus here is on the April 29th FDA meeting for 7-8-3. Norbert, you mentioned that obviously the primary endpoint is TBT, but could you talk about what other questions you'll likely be asking FDA at that meeting? What are the other main topics of discussion around that trial design? I'm thinking secondary endpoints. severity and inclusion criteria of patients or the safety database that you would need before that would contribute, say, to the pivotal data set.

Yeah. So, Ritu, I'll kick it off, and then Andy can maybe chime in here. You, of course, know that we have completed a PTSD study that has already given us relatively good guidance as to the patient population, the heterogeneity of the patient population, It was a signal-finding exploratory study, but it informs the next study, and the key questions, actually the key points, I should say, are really our thinking about the design of that next study and the development path, as I mentioned, towards an NDA. That includes, for example, questions related to duration of therapy or duration of daily treatment, I should say, and questions of that nature that really have to do with The goal of it being a study that can serve in a registration-supported manner, and that's what the discussion with FDA was mainly centered on.

Yeah, I think the only thing I'd add is really, although the output of the discussion will inform the next study, as Norbert alluded to, our key goal in the meeting is to try to have a better understanding of what the requirements are to reach an NDA in PTSD. There isn't a published guidance on that. And so therefore, we wanted to have the discussion at this stage So the next study can be basically as close as possible and serve as registration supportive and lay the foundation for the rest of the development program. We understand everything that's needed. So as you would expect, most of the major study design elements you know, we would need to understand. Some of them are, you know, more open question than others. Some of them are more just looking for kind of a confirmation. But that's really the goal is to set the next study up in the context of what it takes to achieve an MBA.

Got it. And just a quick follow-up on 2925. As your enrollment has been proceeding. Has the geographical distribution of enrollment varied from your initial expectations, just given the COVID shutdowns and reopenings in waves across the world right now?

Great. I'm going to have Kathleen expect a question for you. Kathleen.

Yeah, thanks. Our sites are in the US. And so we're seeing pretty much according to plan enrollment across our US centers. I think we see from time to time an impact of COVID on a center. But in general, with a couple of weeks of quarantine, or perhaps some substitute staff, we're seeing things function pretty well at this time. So we're working according to plan across all of our centers here in the US. Great, thanks for taking the question.

Thank you.

We have our next question coming from the line of Mark Goodman with SBB Real Living. Your line is open.

Thanks for taking my question. So this is really on the line for Mark. Two questions. First, it's regarding the Phase 2A study of NYX458. So given that you're enrolling roughly 100 patients in total, just wondering how many of them will be DLB patients. And if this study works, do you plan to aim for a broad label to treat cognitive impairments across neurodegenerative disorders in future studies? And secondly, can you provide more color on the R&D expenses in 2021 since you have four phase two studies up running by year end that just give us a sense about the cash burns?

Great. Great question. So let's tackle the first one regarding the inclusion of Lewy body disease. As you pointed out, and I can confirm, the goal here is to say because there is a very common underlying pathophysiology which has a key focus on alpha-synuclein and how that impairs NMDA receptor activity and expression, we think it makes sense to expand to basically be more inclusive of patients that have that hallmark of alpha-synuclein abnormalities. And at this point, I think, as you pointed out, we are looking at 100 patients. I think it is not exactly clear for us to answer today how exactly that distribution will actually fall between Parkinson's and Lewy body dementia, but I would assume we would look for relatively even distribution between the two.

Yeah, I think, Sandy, I think according to the numbers of patients that are right there, you know, there will be a good spread, I think, across the three. There are slightly fewer patients in the dementia with Lewy bodies category as compared with the Parkinson's disease population. But I think there's certainly enough in all three groups that we'd expect to get a good spread. And with respect to your question on broad label, I think this is an exploratory study, so it's a little premature to talk about label. But I do think this indicates, as Norbert mentioned in his main remarks, we believe that our mechanism can work across this entire continuum. And we felt that it was the right decision to include all of the potential patients within the sort of Lewy body Parkinson's grouping at this stage.

Let's pause there and see if that answers your question before I ask Ashish to address the R&D budget that you had as a second question.

Okay. So as I mentioned earlier in the call, R&D expenses in the last quarter of 2020 were just shy of $7 million. We would expect that to increase. in the coming year in 2021 as we are recommencing, have recommenced the two pain studies and we'll be recommencing the study in patients with cognitive impairment. We'll see it increase further later this year as we start up and initiate screening and enrollment in a way that we anticipate to do with the next study in PTSD. We don't typically give quarter by quarter guidance. It is lumpy as we'll have these initiations, but surely we'll see an overall cash burn and R&D expenses. In general, the guidance we give remains that our cash burn expectations and our current balance sheet project a cash runway that extends into 2023. Got it.

Thanks. That's very helpful. Thank you.

We have our next question coming from the line of Chris Raymond with Piper Sandler. Your line is open.

Thanks. Hey, Norbert, I was kind of intrigued by your prepared comments on 783 and maybe seeing a prospective characteristic of patients that could respond better. and PTSD. I'm assuming maybe this is something I want to save for when the full data is presented at SOBP, but can you give us a little bit more color on what you're talking about there, and is there an opportunity for sort of a prospective identification of those patients?

So, Chris, thanks for the question. I will have to actually... uh have you wait until we have had our presentation and disclosure of that additional information at the uh society of biological psychiatry meeting it is by their criteria and by ours that we would not want to pre-end information that comes to the meeting so maybe we have another discussion after that and follow up with you i got it okay and

Just to highlight what we're talking about, I think it's things that can be implemented at the clinical development stage to have the right population in the clinical trial. I don't think we're talking about anything that would have label implications, would reduce the size of the eligible patient population, or require any kind of prior testing. It's more just ways to refine the clinical development criteria.

Got it. Okay. Okay. And then just maybe a follow up on 458. So just wonder if you could give a little bit more detail. I know you focused on the 30 milligram dose, but in for simplification, but was there something that you saw in the 10 and the 100 that led to this decision? Or is this just, you know, again, just a decision that was made otherwise?

Yeah, great question. So the reason that we actually opted for the one dose is that we have now actually done several clinical studies, as you know, in fibromyalgia, in DPN, in PTSD. And because we do a very, very thorough characterization of the pharmacokinetics and pharmacodynamics of our compounds, both at the preclinical level of behavioral models, as well as in phase one in Healthy Volunteers where we measure CSF levels of compound as a surrogate for brain exposure, and then the actual data from the patient studies, we have a very good understanding, I believe, as to which dose is the dose that should readily pick up the signal. And instead of making this earlier exploratory study, fundamentally a dose-ranging study, which it is not intended to be. It's intended to be a signal-finding study. I think it's just more efficient to actually do it in that sequence. We pick the dose that we predict and I think reliably predict to be efficacious to define the dose, sorry, to define the readouts and make sure the compound is behaving the way we want it to. And then we look for dose ranging in subsequent studies thereafter. I think that is serving us well, and that is the rationale that is actually why we are making the modification in the way I outlined it, to go from what was three active arms, but is now two active arms. It also serves the benefit that typically two-arm studies have a little bit less variability and more, I think, accuracy in the data overall. So it comes with that added benefit, but the fundamental rationale is the way I outlined for you. It's not dose ranging. It's signifying.

Great. Thank you.

Yep.

We have our next question coming from the line of June Wee with Truist Security. Your line is open.

Hi. Thanks for taking our questions and for the update. So it appears that you'll be pursuing CAHPS-5 total score as your endpoint for the upcoming Phase IIb trial. You know, I was under the impression that there was a hope that the potential for a sub-score or a responder analysis where you had a much stronger effect would be sort of in play as well. So is that totally out of the question? Is that something that you will ask the FDA And that's my first question. And the second question is, what about 548 makes it better suited for cognitive impairment due to Parkinson's and Lewy body as opposed to, say, Alzheimer's? Because based on some of the data coming out of your competitors, NMDA seems to have a very strong signal in Alzheimer's, especially in agitation. So I was just curious about their strategy for Parkinson's in the body as an initial indication. Thank you.

Yeah, that's great. Thank you, Jun. So look, on the PTSD study, as we keep pointing out, CAHPS-5 total is comprised of four subscores. And when we reported the data in October, We paid particular attention to the fact that the reactivity and arousal score achieved statistical significance despite the fact that it was a small four-week study only. What is very clear from the study is also that CAHPS-5 total gave us a very clear separation between active and placebo. and trend it exactly where it needs to trend for it to be a very suitable primary endpoint for us. So when I speculated last October when we disclosed the data that it would be nice to have an open-minded conversation about potential alternatives to CAHPS V in the form of either a sub-score or perhaps responder rates, which were fabulous in our study, I did not mean to imply then that we would rely on those alternatives to feel that we were confident in conducting a next study. And so because the guideline today says PTSD studies should use CAHPS V as a total score, and because CAHPS V is comprised of four sub-scores, three of which give us a very clear, strong result in this study, I'm perfectly comfortable using CAHPS V as the primary endpoint. On your second question, why not 458 in Alzheimer's disease That's a straightforward answer. When we basically created Aptinix by selling Norex to Allergan in 2015, we did not retain the rights to Alzheimer's disease as an indication. Alzheimer's disease and Alzheimer's related dementia is not accessible to us. However, all other forms of cognitive impairment and dementia are. And we feel that Parkinson's disease is therefore a very logical result. And, of course, we have the biological link that we pointed out, namely that the particular correlation between alpha-synuclein and NMDA receptor activity is a very appealing mechanism to us because 458 is a very clean, positive allosteric modulator of NMDA receptors with no off-target binding. causing synaptic plasticity and enhancing cognition, learning, and memory in all of our models. And so it just makes perfect sense for us to say that's the target we have chosen.

Got it. One quick follow-up, if I could. Regarding the first question on CAHPS 5, the data presentation at SOVP, is it fair to assume that the new data could be related to how you would enrich for the responders in your upcoming Phase II, correct? Is that something that we can look forward to?

As I said in the script, right, in the written remarks, we have not yet nailed down all the details of that study. But of course, whatever we think is biologically relevant and helpful in looking at this patient population, we should be considering to use to further stratify, primarily for the purpose of making sure that the therapy is as targeted as it can be. But clearly without wanting to go down a path where we basically end up in some niche indication, the broader category of PTSD is our target category.

Thank you. We have our next question coming from the line of Gary Nachman with Remo Capital Markets. Your line is open.

Hi, guys. For 2925, you're looking at the same primary for both fibro and DPN, the change in NRF. So how important will the secondary endpoints be to better inform you on efficacy in the different patient populations? What are the key secondary endpoints? Just remind us that. And also remind us why the 100 milligram dose in fibro but not in DPN.

That puts me at five questions that you asked, Gary. I answered them anyway. So, look, I start with the last one. Why are we studying 50 and 100 in fibromyalgia and only 50 in DPN? That has to do with having studied 10, 50, and 200 in our first 300-patient DPN study. And from that study, we concluded that the 50 milligram dose was by far the right dose. And that, again, goes back to having been able to predict that. from our preclinical work and from the phase one data, in which we also did target engagement studies in phase one. So that's the reason why we actually wanted to expand in fibromyalgia, because the fibromyalgia study, they gave us fabulous confirmatory biomarker and patient reported results for NYX2925. By its very nature of being a fMRI study and spectroscopy study, It had to be small. It only was about 23 patients. And so we wanted to make sure that in this next study, we arrange it a bit broader with the 50 and the 100 milligram dose. That will, by the way, also, if necessary, further inform the DPN study. But those are the key reasons why we opted to do a 50 and 101 and 50 only in the other. No, I don't remember what else you asked.

No, it's on the secondary endpoints, given that the primary is the same in both. And I guess, let me just jump in. The bigger question, if ultimately you look at having just a broad chronic pain indication, if, you know, you have these two different studies in different patient populations, just want to get comfortable, how are you going to be able to merge that potentially into a broader chronic pain indication?

Yes, so Andy is going to answer that for you, but just quickly, the primary endpoint, as you just mentioned, is of course daily pain as it is reported by patients. And then the secondary endpoint in particular is fibromyalgia have to do with what is the hallmark of fibromyalgia captured in the fibromyalgia questionnaire in the PROMIS scores, very much aligned with our earlier studies. And I'm glad you asked the question because it gives me the opportunity to reiterate that we don't rely in either the fibromyalgia or the DPN study on just one endpoint giving us a positive result. Every measure we have taken in these patient populations that have to do with the symptomatology and pain issues that patients have, have given us very clear positive results in both of these studies. And of course, that is a really good starting point in these confirmatory studies that are now running. And now I'm going to ask Andy to address the broader question of indication and labels as we move into college days.

Yeah, thanks, Gary. You know, there was a prior guidance that FDA had, draft guidance that FDA had published, and then they withdrew it. And, you know, in that guidance, there was a rubric laid out for how to achieve different label language in chronic pain, you know, in central or peripheral neuropathic pain, musculoskeletal pain, and so on. And there was sort of a formula you could follow for how many studies and how many indications to get what You know, we don't know exactly what the requirements would be right now because we know that one of the purposes of reconsidering the guidance was to try to, we think, make it more straightforward to bring, you know, safe, well-tolerated, non-opiate pain therapies to patients. And so I think that's something we'd be very keen to discuss with the agency at an end-of-phase-2 meeting. Obviously, like you said, we have these two indications, DPN, obviously, neuropathic pain. Fibromyalgia has been classified by FDA not as neuropathic pain, as a different pain condition. And so, you know, and as you know, we're interested in all kinds of other pain conditions, neuropathic pain and musculoskeletal and other. So we'd be very interested to see how that would work. You know, it's interesting. I think DPN probably, you know, Of course, it's part of diabetes, but the DPN condition is more clearly characterized by pain, and so we have other endpoints, as Norbert mentioned, to look at, you know, worst pain and pain on walking as well as the primary endpoint of average daily pain. But fibromyalgia is a broader condition, and I do think that's an interesting question over, you know, how important some of those other endpoints. Norbert mentioned the FIQ, the revised FIQ, FIQR instrument, and some of the promise scales in areas like fatigue and so forth. So we do look at FIBRA a little bit maybe more broadly from the perspective of the secondary endpoints. I'm interested to see how those could be positioned from a regulatory point of view. And then, yeah, watch this space on the broader label. That's something we're very keen to pursue at the end of Phase 2.

Okay, great. And then just one on 783. I know you don't want to preempt the FDA meeting, but do you think that you'll just need one pivotal study, or you would likely need a second pivotal study in any scenario? I just want to see, is it possible that maybe you could have this one next study, and that would be sufficient to file, if you think that's a possibility? Thanks.

You know, Gary, I think that's actually really speculation at this point, right? Because so much of any discussion along those lines will really be guided by the results of a study. And so I think I'm much more comfortable saying, let's do the study, let's see what the results show, and then let's engage with the agency at that time and understand to what extent that is sufficient or insufficient on the path to an NDA. I think it's just too soon at this point.

Okay. But you're not ruling it out. I mean, it is possible. I guess also given that PTSD maybe is more at the forefront, like you said earlier.

I wouldn't rule anything out at this point, but I think it clearly, since we are aiming for a chronic administration here, unlike some other psychiatric conditions that are more episodic, PTSD is pretty much a consistent chronic disorder. You know, and as such, there are likely to be, you know, requirements for numbers of exposures needed for certain durations of time from a safety point of view, you know, to get to an NDA. But, you know, everything's always, it depends on the perspective of, you know, the urgency of the unmet need as well, of course.

We have our next question coming from the line of Charles Duncan with Cantor Feeds Gerald. Your line is open. Thank you.

Okay, thank you for taking my question, Norbert and team. Lots of great questions asked already. I'll try to pull a few others out. Just quickly on 783, I'm not sure if I caught what the duration of treatment for this next study could be in the end. I know that you haven't yet met with the agency, but can you give us a range on those two considerations in terms of the time Timeline for 783 study?

Yeah, Charles. We're currently considering a range of 8 to 12 weeks right now. And we'll see where that comes at.

And the sample size approximate?

Yeah, I think sample size, to give you rough guidance, I think it will be at least in line with our chronic pain studies. It's not slightly larger. I think we certainly want to make sure that it's well powered.

Charles, are you still there? I think we lost Charles. Charles? Operator, are you still there?

Yes, this one is still open.

Oh, OK. Thank you. Chas, are you done asking? Any other questions for you before we proceed?

Again, if you wanted to ask a question, press star 1 on your telephone. We have our next question coming from the line of Laura Chico with Wedbush Securities. Your line is open.

Hey, thanks, guys, for speaking to me, and I appreciate it. I just have a couple on 783. So obviously, you have the FDA meeting coming up, the SOPD data. I'm wondering if you could just take a step back, perhaps, and just wanted to kind of revisit response rates in the context of perhaps Zoloft and Paxil. I believe both studies saw increased response rates between week 4 and 12, and just trying to understand how that might impact your thinking on the Phase IIb design. Related to that, how are you also thinking about adding in a second dose to that study and kind of how we should be thinking about that there? And then I have one follow-up question for you.

So yeah, Laura, I think definitely it's our assumption that response rate and magnitude of effect will increase over time. Probably not indefinitely, but we definitely think it will increase over time. And so that's part of our thinking. in the answer to the previous question on the eight to 12 week range that we're considering you know and then there's obviously some other factors uh you know to trade off against that in particular with ptsd whereas as you know from the last study and we've we've this has been seen across ptsd studies it's at the higher end of the spectrum for patient discontinuation rates compared to some other indications. And so that's a little bit of something you just have to trade off as you look at even longer durations. So we think that in that eight to 12 week range is probably the sweet spot. And yeah, we'll obviously come to a decision on that. You know, with respect to a second dose, I think that's also something that we're still kind of thinking through. We would be very comfortable, I think, moving ahead with just a 50 milligram dose. And we'll, again, be updating later on as to whether we stick with just a 50 milligram dose or have a second dose as well. I think likely if we did have a second dose, it would be higher than 50 milligrams. But we'll obviously be working through that.

Okay, that's helpful. Thanks, Andy. And then I guess I wanted to circle back on one question more from a strategic perspective. I think Norbert, you mentioned some of the indications related to, I guess some indications may not be accessible in terms of development plans currently. But I was wondering, just fundamentally, would you also consider branching more towards, I guess, neuropsychiatric conditions with 458, kind of beyond the Parkinson's disease cognitive impairment setting, and just how we should be thinking about that more philosophically? Thanks.

Yeah, so great question, Lauren. When we look at our compounds and we do a very extensive profiling of these compounds across numerous behavioral models of disease, we do test them in models of pain, psychiatry, cognition, and that's how we empirically, based on the data we get, assign them to various INDs or into various indications, I should say. So 2925 is by far the best compound in our pain models. 783 in the psychiatric models and 458 in cognition impairment. And so I think along those lines we would expand with those compounds but within those categories of either psychiatry or pain or cognition slash memory and so on. That's more along the lines of how we actually shape indication expansion and choose which compound from a strategic point of view is best suited for which set of indications.

Thanks, guys. I appreciate it.

We have our next question coming from the line of Miles Minter with William Blair. Your line is open.

Hi, guys. Thanks for taking the questions. Just curious on a potential higher dose for 7.83. you're really good at characterizing all those molecules in preclinical models. There's obviously a U-shaped dose response curve here. How high above 50 mgs could you go theoretically and still expect efficacy? And how would you balance bringing that into the trial, I guess, with the risk of increasing placebo expectations from like the bias of just bringing in another active dose into the trial?

uh you know it's hard to answer that because it would require that we extrapolate directly from preclinical to human sort of like conditions i will however say if i take you back the miles to the 2925 study in dpn that we did that we chose a range of 10 to 200 milligrams of daily dosing the 200 milligram dose was efficacious but it began to plateau over a longer period of daily administration, whereas the 50 milligram dose continued to show a very linear improvement from week one to week two to week three to week four. And so I think we can go higher, but it would really be a study that would have to tell us when we would begin to see a plateauing of effect. Let me make this my opportunity to share with you and with him on the phone here that We have this rather unique, I would say, opportunity to push the dose high because of the superb safety and tolerability profile of our compounds, right? We don't have the issue that many other compounds have that basically are limited by a very narrow therapeutic window and index as it relates to where you sort of like to get the best dose before you begin to see safety and tolerability concerns. And so from that point of view, we have in our Phase I studies gone to, like, gram quantities in single administration and not seen any adverse effects. But that's actually, from a point of view of what the relevant therapeutic dose, much, much less important. And so I go back to my earlier comment and say I think we have learned in our preclinical models where the sweet spot is as we go into clinical studies with patients. And that has now actually turned out to be pretty predictable in three cases where we have done it. And so that's probably a better way of looking at it. I can't give you a direct answer because there is no sort of like 100% correlation between preclinical animal models and human patient population.

Yep, fair enough. And then on 458, in the Parkinson's disease population specifically, What's the exclusion criteria for the motor dysfunction in those patients? I'm curious because you're subjecting them to computerized cognitive tasks, and I assume they have to pass and be able to do these tasks based on to be involved in the trial, but just wondering whether you foresee any complications on the motor function side of just patients being able to complete these cognitive tasks that you're trying to assess.

No, absolutely, Miles. We definitely have a series of inclusion-exclusion criteria for these patients on a few different things, but motor symptoms and the overall progression of the broader Parkinson's symptoms is definitely part of the inclusion-exclusion criteria for that exact reason, to make sure that we have patients whose motor symptoms aren't so severe that they, you know, that they must be able to accurately measure cognitive status and cognitive impairment. And there's others as well. And I think maybe this is a good time to also say, as we broaden the diagnostic groups that are allowed to be included within the alpha-synuclein kind of family, we are applying all of the same inclusion-exclusion criteria to all of those patients. So a lot of the potential things that you could be worried about confounding or introducing heterogeneity we had already kind of considered and already decided, you know, what does the patient population we want to look at and be applying those same criteria to all the patients now within that alpha-synuclein continuum of diagnoses.

Okay, so just to clarify, the Montreal cognitive assessment scores required by those patients, it's still greater than 17 points regardless of whether they have payday or Lewy body dementia coming in the trial?

Exactly. That's a really good example. So as we go from MCI to mild dementia, we haven't changed the floor, if you like, the lower bound of the MOCA score range that you have to have. And we believe that that lower bound is still going to pick up quite a few patients that are in that mild dementia and dementia with lytic body grouping, which is, again, is part of our rationale for being very comfortable in broadening it out.

Thanks. Appreciate the clarity.

Thank you, Mike.

We have our next question coming from the line of Ram Selvarajan with HC Weinreich. Your line is open.

Hello, everyone. This is Maz speaking on behalf of RAM. Great questions, great discussion. We also appreciate the detailed press release. Three or four from me, if I may. This question applies to the Phase IIb ongoing in 2925. and 458 as well. Has the recent acceleration in the SARS-CoV-2 vaccination efforts affected the timing of these readouts at all? And, you know, especially in terms of 458 since, you know, particularly given the age group in this trial would have been the first among those to be eligible for vaccination.

I'm going to have Catherine address the question for you, but I think generally speaking we have monitored the environment enough to know that clinical study sites and patients are again safe in conducting these studies, which is of course what we were hoping and waiting for, and that turns out to be confirmed by looking at the enrollment rate that we are getting. I don't think that is fundamentally different for the upcoming 458 study in Parkinson's, but let me have Catherine maybe add additional color to the comments I just made.

Yeah, I think that's right, Norbert, and I think we're on track with enrollment. Perhaps the vaccination acceleration has helped remove an obstacle to enrollment for some patients, but in general, we're progressing very much according to plan.

Perfect. Thanks. And then, you know, we're looking forward to the SOBP meeting 29th of April. Can you give us a flavor of what kind of data analysis will be presenting? Will there be anything new here?

Alex, maybe you would ask that question. It was a little difficult to hear. Did you understand the question, Harald?

Yes, I think I got this. So basically, we did quite an extensive data analysis, really based on the understanding of what the disorder is about. We looked into things which have been described in the literature, predicting the outcome, and we looked into the pattern of our data themselves, and we were definitely prevent things which are plausible. This is not a fishing expedition which we did, but something which is guided by science, by things which have been described in the literature, and which we found in our data set. So there is precedence for what you are describing, and this gives us confidence that with those determinations, we will improve the signal for the upcoming trial. Okay, excellent.

Excellent, thanks. So regarding your recent review in Medicine and Drug Discovery, I'm wondering if you are pocketing any more data in addition to centralized chronic pain, maybe a package of data for a neuropsychiatry PTSD review or a cognitive impairment-focused review?

I apologize. I don't think we could hear your question clearly. The line is not clear that you're speaking on.

Were you asking about other review articles that we might anticipate?

Other review articles in addition to chronic pain, so maybe neuropsychiatry or cognitive impairment.

Yeah, I think absolutely. So we do have some things teed up in terms of additional preclinical data that we can in the queue for publication and the other preclinical work that remains ongoing even in our clinical indication because we always want to understand the mechanism of action better. And I think the paper that we published on review paper kind of pulling a lot of that together in chronic pain was a great opportunity to kind of tie a lot of that published data together in one place. And we certainly would look to do that in the future in other areas. You know, I'm not sure. We don't have anything for that imminently in the works, but I think that as we accumulate data, we'll certainly look to repeat that kind of publication.

You know, I think maybe to add on to that, we keep pointing out that we have the opportunity that what we do in the clinic is based on very extensive preclinical work we conduct. And so in particular, the 2925 paper as a mechanistic paper showing activity in numerous models of chronic pain really was meant to substantiate the enormous amount of work we do before we actually elevate the compounds to become IND-ready and go into human studies. And so we have similarly comprehensive data decks, of course, and preclinical data on 7, 8, 3 in psychiatric models as well as 4, 5, 8. And so as Andy said, I think over time we will actually make that more visible in how we actually put it in the appropriate publication format.

We have our next question coming from the line of Jessica with JP Morgan. Her line is open. Hey, guys.

Good evening. Thanks for taking my question. Click on following up on the DTN questions. Phase 2 study for 29-25, what do you want to see in that study to feel confident that you'll have a clinically meaningful signal in phase 3? So I guess, what would represent a clinically meaningful separation from the placebo in a phase 3? And how much buffer do you want to have around that in phase 2?

Yeah, thanks, Jeff. It's a good question. I mean, as you recall, this study is essentially a prospective validation of what we found in the prior DPN study. And, you know, I think the clinical meaningfulness is something that has to be kind of calibrated against the safety and tolerability profile. You know, there are drugs out there. If you ask clinicians, typically I think about a 0.5 difference from placebo on the NRF scale sort of gets you in the conversation. But it does depend a little bit on the safety and tolerability profile. Obviously, we feel our safety and tolerability profile is very strong. So I think that's sort of where we would be comfortable with anything in and around that. We obviously saw a difference in the longer disease duration population in DPN. It was much larger than that in the first study. And so I think that's sort of the range that we're looking in. We are, I think, powered to detect down to the lower end of the clinically meaningful range. but hopeful, based on the prior study, that we would be above that.

Great. Thank you.

We have our last question coming from the line of Charles Duncan from Cantor Fitzgerald. Your line is open.

Yeah, thank you for taking our follow-up and apologize to everyone on the call for our IT issues. One quick follow-up on 458 and then a broader question regarding BizDev. On 458 with regard to the conduct of the cognitive impairment study, I guess I'm wondering, you mentioned that this is signal-seeking study. Clearly, perhaps looking at earlier stage patients, are these patients going to be on background DOPA therapy? And if not, is that, call it a confounder in terms of conduct of the study?

Great. Thanks, Todd. Alex, can you take that question, please?

Yes, these are patients who show motor dysfunction, particularly when they have Parkinson's disease dementia. So they're allowed to be on medication, particularly treating those motor dysfunctions, but they have to be on stable medication. We actually broadened a little bit medications, which patients can be on to get into that trial. But I think the importance is that those medications have to be stable. We do not expect to see any major interference. Dopaminergic compounds have an effect on, let's say, motivational aspects, but not necessarily on those cognitive aspects which we are focusing on. So that's definitely something which has a certain level of independence. We don't expect any industry interventions like we've done.

Okay, very good. That's helpful. And then with regard to the concept of NMDA hypofunction imputative mechanism in these, in these indications, I guess I'm wondering, could you see this program being expanded with 458 to, say, other highly prevalent disorders such as cognitive dysfunction associated with schizophrenia? Or could you perhaps more likely see it moving to the orphan space where you see neurodevelopmental disease that involves NMDA hypofunction and cognitive impairment?

I would answer by saying both, Charles. Because as you pointed out, if the underlying dysregulation is a hypofunction of NMDA receptor activity, then I think there would be a scientific rationale to consider indications in both of the categories that you just touched on.

Okay, last question regarding corporate collaboration activity. I guess I'm wondering, as you look across your broadening pipeline, I'm wondering if there is a point at which you might consider corporate collaboration activity for some of the higher, more highly prevalent, you know, call it indications that you're looking at perhaps with 2925. And when do you think it would make sense perhaps post-data in Phase 2, and would it be more XUS type collaboration activity or pan-global?

Yeah, thanks, Charles. This is Ashish. You know, we are well-funded and well-equipped and very much focused and underway in getting the next data in all of our indications, either with studies that are ongoing, soon to be recommencing, or would be initiated later this year. We think those studies across the pipeline offer meaningful input and data that would meaningfully inform and enhance the value of any collaborative discussions. And so we're focused on getting those and have the support of investors on our balance sheet to do that. I think we've talked about in the past that as we think about our pipeline, you know, the area of chronic pain, if we're able to see a replication of the effects that we saw in our first phase two studies, that therapeutic opportunity is very broad. and addresses a number of physician call points that probably is most credibly addressed with a partnership when it comes to commercialization. And so that's something certainly that we'd be interested in exploring at the time when it can be informed by meaningful data and add value to the program. It's a rapid and efficient and responsible advancement. and shareholder value. We think that the next juncture, the next studies offer an opportunity for that, but we're well equipped to take this as far as we need to ensure that we can add that value. Your question about different types of collaborations and structures and scopes of partnership is another good one. There are certain areas where we are not actively advancing our programs. And I think, again, we'd be open to any discussion that can meaningfully enhance the progress we're making toward advancing these programs toward regulatory endpoints. But we're not reliant on those, and we are very much focused on getting the data that are coming next, which we think, again, would meaningfully inform any such discussion.

That's all for Ashish. Norbert, thanks for taking my follow-up.

Thank you, Charles.

There are no further questions at this time. I will now turn the call back over to Norbert for closing remarks.

Thank you, operator. And thank you all for your thoughtful questions and for being on the call. We appreciate your time and your attention. Please stay safe. Be well. Enjoy the rest of your day, the rest of your week, and the upcoming springtime. Talk to you soon. Thank you. Bye-bye.

This concludes today's conference call. You may now disconnect.