Aptinyx Inc.

Good afternoon and welcome to the Aptinex Third Quarter 2021 Financial Results Conference Call. At this time, all participants are on listen-only mode. Following the formal remarks, we will open 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 Patrick Flavin, Senior Manager, Corporate Development and Investor Relations at Aptinex. Patrick, please proceed.

Good afternoon, everyone, and thanks for joining us on today's conference call to discuss Apptinex's financial and operating results for the third quarter of 2021. Our press release describing financial results and recent highlights is now available on our website. Today on our call, Norbert Riedel, our chief executive officer, will review recent business updates. Then Andy Kidd, our president and chief operating officer, will review progress across our development programs, followed by Ashish Khanna, our chief financial officer and chief business officer, who will review the financial results. In addition, Katherine King, Senior Vice President of Clinical and CMC Operations, and Harold Merck, Vice President of Clinical and Medical Affairs, are on the line for the Q&A portion of the call. Before we begin, I would like to remind everyone the 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 statement disclaimer in our financial results release issued this afternoon and the risk factors in the company's current and subsequent filings with the SEC. I'm now happy to turn the call over to Norbert to kick things off.

Thank you, Pat, and good afternoon, everyone. We appreciate you taking the time to join us on today's call. Before we begin with updates from our clinical program, I would like to extend a warm welcome to Dr. Gilmore O'Neill, our newest colleague on the Aptinix Board of Directors. Dr. O'Neill has extensive experience in CNS drug development, academic medicine, and as a practicing neurologist. He currently serves as Executive Vice President of R&D and Chief Medical Officer at Sarepta Therapeutics, where he leads the company's research, clinical development, medical affairs, pharmacovigilance, and regulatory affairs functions. He also brings an impressive background in late-stage CNS drug development from his previous 15-year tenure at Biogen, where he held leadership roles across numerous programs in neurology, pain, gene and cell therapy, and rare diseases, including oversight of numerous global marketing approvals. I am confident Gilmore will serve as an invaluable resource in helping to guide our future development and growth plans, and we are thrilled to welcome him aboard. These past several months have been a particularly productive time for Aptinix, and we are looking forward to an active period of execution and multiple data catalysts ahead. Later this year, we plan to initiate our Phase IIb development program of NYX783 in patients with PTSD. We also recently announced that we expect to report results from our Phase IIb study of NYX2925 in painful diabetic peripheral neuropathy in the second quarter of 2022. Meanwhile, Enrollment in our studies of NYX2925 in fibromyalgia and NYX458 in cognitive impairment is progressing well, with readouts anticipated in mid-2022 and the second half of 2022, respectively. With this slate of clinical development programs moving full speed ahead, we are very pleased to have a strong balance sheet bolstered by a gross credit facility with secured during the last quarter, providing access to up to $50 million. Our current capital position is expected to fund phase two data readouts from each of our pipeline programs across 2022 and 2023. Recall that during our last quarterly call, we announced our plans for the shift transition. in which Andy Kidd will become president and CEO, and I will assume the role of executive chairman effective January 1st, 2022. The rollout of that transition has continued to proceed very well, and our team is prepared to hit the ground running in the new year. I will now turn the call over to Andy to dive into more detail about each of our programs beginning with NYX2925 and chronic pain.

Thanks, Norbert, and good afternoon, everyone. As Norbert highlighted earlier, we're very pleased with the progress made over the past several months across both of our chronic pain studies. In October, we completed enrollment in our Phase 2b study of NYX2925 in patients with painful BPMs. The pandemic environment has clearly presented challenges across our industry, particularly for clinical research. Nonetheless, our team's superb execution and the engagements of patients and sites over the course of the past year has enabled us to complete enrollment at a steady pace. The most recently enrolled patients must complete the 12-week treatment period, followed by a 30-day safety monitoring period. We're then expecting to report data from this study in the early to mid part of the second quarter of 2022. This phase 2B study is predicated on data from our previous phase 2 study in DPN. In the prior study, NYX2925 showed the most robust effects in patients with more chronic disease, consistent with its centrally acting mechanism. Based on those results, we enrolled patients in the phase 2B study who have been living with painful DPN over a period of four years or longer. We also did not allow patients to take concomitant analgesic medications during the studies. In the prior study, we saw a greater ability to detect efficacy and separation from placebo in patients who were not on background pain medication. The primary endpoint of the study is the change from baseline in the weekly average of patient-reported daily pain, evaluated over a 12-week period using the zero to 10-point numeric rating scale. While this is a Phase II study, this primary endpoint and the study duration are consistent with typical registration studies for neuropathic pain. Therefore, we believe the data from this study should be highly informative for further late-stage development. In addition to the study in painful BPN, we're also conducting a Phase IIb study of NYX2925 in patients with fibromyalgia. This study is evaluating two dose levels of NYX2925 and has a larger enrollment target of approximately 300 patients versus a target of 200 in the DPN study. Enrollment in the fibromyalgia study continues to progress well. We expect it to read out in mid-2022. Let's turn now to NYX458, our product candidate in development for the treatment of cognitive impairment associated with Parkinson's disease and dementia with Lewy bodies. This is a program about which we're incredibly excited. Given the strength of our preclinical data with NYX458, in translatable models of cognitive impairment. Furthermore, we've recently seen an enhanced enthusiasm for development of new therapies for cognitive deficits associated with neurodegenerative disorders. NYX458 is currently under evaluation in a first inpatient exploratory phase two study to assess safety and tolerability and to detect therapeutically relevant activity on cognitive deficits. utilizing specific measures of attention, memory, and executive function. This double-blind study is comparing a 30-milligram dose of NYX458 with placebo in approximately 100 patients with cognitive impairment associated with Parkinson's disease or dementia with Lewy bodies over a 12-week treatment period. Enrollment in this study is progressing steadily, and we continue to anticipate reporting data in the second half of next year. Finally, we'll discuss NYX783, our product candidate in development for the treatment of post-traumatic stress disorder. We will soon be initiating the first of two planned Phase IIb studies of NYX783 in patients with PTSD. This Phase IIb program follows on our previous exploratory Phase II study in which we observed encouraging improvements in PTSD symptoms among patients treated with NYX783. The first Phase 2b study will evaluate once daily dosing of 50 milligrams of NYX783 versus placebo and is expected to initiate by the end of the year. The second study, which will evaluate once daily dosing of 150 milligrams of NYX783 versus placebo, is expected to kick off in the first quarter of 2022. Each study is expected to enroll approximately 300 patients, include a 10-week treatment period, and use the regulatory standard primary endpoint of the CAHPS 5 total score. We believe these Phase IIb studies, if positive, are well positioned for consideration as registration supportive based on discussion we've had with the FDA. Of course, this will ultimately be a matter for the agency to consider and decide on at a later date should the studies prove successful. As you can see, we have a lot of activity underway across all of our programs and disease areas, and we're looking forward to upcoming study initiations and a series of data readouts next year. With that, I will now turn the call over to Ashish to review our third quarter financial results.

Thank you, Andy. As you've heard from both Norbert and Andy, we are pleased with the progress we've made on advancing our pipeline in the third quarter. On the financial front, we made key strategic decisions during the quarter to ensure we are well funded and have financial flexibility through the series of phase two study readouts upcoming. We were pleased to secure a growth capital credit facility from K2 Health Ventures, which provides us with access to up to $50 million in additional capital. The capital we have and plan to draw down under the facility enables us to fund our operations through Phase II data catalysts across all of our clinical development programs and extends our operational runway further in 2023. Let's review our financial results for the third quarter. The majority of our spend was focused on research and development related to our ongoing clinical studies across chronic pain and cognitive impairment. R&D expenses were $16.3 million for the second quarter compared to $6.6 million for the same period in 2020, an increase attributed to a ramp up in clinical development activities across our portfolio. We reported G&A expenses of $4.9 million for the third quarter compared to $5 million for the same period in 2020. Our net loss for the third quarter was $21.2 million compared to a net loss of $11.3 million for the same period in 2020. And finally, we ended the third quarter of 2021 with $125.3 million in cash and cash equivalents compared to $141 million at the end of 2020. As we head into year end, we are both financially and operationally well positioned ahead of the multiple data catalysts we expect in 2022. With that, I'll now turn the call back over to Norbert.

Thank you very much, Ashish. As we approach the start of the new year, we remain focused on continuing to execute across all of our clinical development programs. With multiple phase two readouts over the next 24 months and anchored by a strong balance sheet, we are well prepared as we approach a potentially transformative period of value creation for patients and shareholders alike. We are happy to take your questions now.

Thank you. If you would like to ask a question, please press star followed by one on your . If for any reason you would like to remove that question, please press star followed by two. Again, to ask a question, press star one. As a reminder, if you are using a speaker phone, please remember to pick up your handset before asking your questions. We will pause here briefly as questions are registered. The first question is from the line of Ritu Baral with Cowan. You may proceed.

Hi, guys. Thanks for taking the question. I wanted to ask about the next readout, that's the 2925 DPN study that's completely enrolled. What is the, what do you think the final, since you have final study conduct, or at least dropouts, what do you think the final powering on the study is, you know, what should we be thinking around the primary endpoint of the numeric rating scale for pain? And I think more importantly, given the changes, patients with longer chronic pain and no comm meds, what should we be anticipating the placebo to be compared to last time? And then I've got a quick follow-up. I promise it'll be quick.

Thanks for the question, Ritu. As you can really imagine, we have discussed this with quite a number of clinical KOLs, and I'm going to have Andy give you our thinking as to what we expect with respect to meaningful difference in treatment group versus placebo group.

Yeah, thanks, Norbert. You know, in terms of the clinically meaningful effect, I think we've all just said that anything above, you know, pain score difference between active and placebo of 0.5 or greater would be clinically meaningful. It's always a little bit hard to create a single cutoff like that. It obviously depends a little bit on safety profile. I think the better tolerated the drug, the lower a difference is clinically meaningful. We think we're powered in the range of what is a clinically meaningful signal. It depends a little bit, of course, on the variance that we see in the study, which we don't yet know. But I think we're quite comfortable with where things have turned out in terms of final enrollment and discontinuation and so on. As for the placebo effect, it's quite hard to tell. I mean, we did quite a few things in the study to try to control the placebo effect, but I guess we won't know if that was successful until we see the data.

Got it. And then there's a range of secondary outcomes listed on clintrials.gov. I think about 12 ranging from patient global impression to police score to use of rescue medication. Is there a hierarchical analysis of the secondaries within the statistical analysis plan? Or can you at least sort of...

uh prospectively direct us to which ones you think are the most clinically important and do you want to take that as well yes certainly um so i think we'll we'll you know we'll discuss um or i guess deferred detailed discussion of the statistical um plans until we until we have data to talk about but i do think um you know the the um obviously other than the primary end point Measures of global impression are certainly interesting. I think some of the other measures of pain, other than just average daily pain, which we're looking at, are interesting as well. This is a study, though, where, as you know, and patients with DPN, pain really defines the condition, and a lot of weight is really on the primary endpoint here.

Got it. Thanks, Andy. Thanks, Norbert.

Yep. Thank you, Rachel.

Thank you, Ms. Farah. The next question is from the line of Charles Duncan with Cantor Fitzgerald. You may proceed.

Yes. Hi. Good afternoon, Norbert, Andy, and team. Thanks for taking our question. I also had a question about 2925 and then wanted to ask you about 458 quickly. Regarding the painful diabetic neuropathy study that is fully enrolled, I guess I'm wondering if you could remind us about the no concomitant pain medications and was there a weaning period? And I guess I'm wondering how you established that they stayed off drugs And then secondarily, is there an open label extension component to that study? And if so, are there any enrollees in that? And then I had a question about the safety database that you could imagine would be required going forward in that indication.

All right, Charles. Those were actually three questions, but let's take them in the order in which you asked. And I think I'm going to have Andy and Harald tackle this. Maybe Andy can kick it off and do it step by step.

Yeah, sounds good. So I can, I'll hit a couple of points. You know, I think in terms of the no-con meds, yeah, it depends which con med, of course, you're talking about as to whether or not it was possible to actually wash off that medication as part of the screening period of this study. So some uh you know drugs that are more difficult to uh discontinue uh it was not considered as part of the protocol you know a patient could work with their physician separately to come off that drug if they wanted to and then after that once they understood that was required to screen for the study they could come and screen for the study within the screening period there were some of the short-term medications that patients washed off uh over a period of up to four weeks so that was sort of how that was was handled um And then I think in terms of open label extension, there will not be an open label extension period for these studies, but we would certainly in future phase three studies would expect to have an open label extension. And I think in terms of safety database, right now we have not met with FDA to discuss the requirements for an NDA. There is a prior guidance on chronic pain that we are using as a guide, but we will not have a definitive sense of the requirements until we have an end of phase two meeting with FDA after data. Harold, do you want to cover kind of any more details on the washout period and then how we made sure that patients weren't going back on that other medication?

Yeah, I mean, at the end of the day, we, of course, are monitoring any concomitant medication during the trial. And if for some medical reason a patient needs to get any kind of medication, that's, of course, something which would be a protocol deviation, but it would be, from a medical perspective, acceptable. We just want to make sure that patients are at the same starting point at the beginning of the trial, so not medications are washed out, I think it's important to keep in mind in that regard that only those patients should be considered for the trial versus doesn't interfere with their general well-being, of course.

Does this answer your question? Yes. No, very, very helpful. Appreciate the color. Just hopping over to 458, if I could ask a question about the cognitive impairment in PD and DLB. Are you collecting any biomarker data, including biomarker data, which is not like something you get from blood or whatever, but so, for example, quantitative EEG or any measures of brain activity in that study?

So, actually, we are not looking at the physiological markers, but the number of blood biomarkers. So, if So there are certain things, for example, inflammation plays a role in these disorders. I look into those parameters, which may be relevant. So we have, let's say, some type of a biomarker program in place. But, of course, we are somewhat limited. I would think that the primary outcome variable, so the computerized cognitive test, should be regarded more as biomarkers as well. They are, of course, kind of an experimental approach to what people do with their cognitive function. What we are trying to do as a second step is to see which of those computerized cognitive tests do correlate with clinical parameters, which then helps us to move forward into phase 2B.

And then a follow-up to that, in that patient sample, are you enrolling patients that you would consider to be relatively advanced in their Parkinson's disease progression and therefore possibly going to experience hallucinations or anything else beyond cognitive impairment? Thank you. I'll hop back in the queue.

yeah so um yeah yeah yeah so um we uh basically disallow patients we are not allowing people who are treated with neuroleptics um with a very small exception where we have a neuroleptic for sleep induction but not for the treatment of psychosis so patients have to be on a level that they didn't have and are not expected to experience any hallucinations, which of course can happen, particularly in patients with Lewy body dementia. Regarding the severity of Parkinson's disease from a motor perspective, of course, we have to make sure that subjects are all tested during their own period, which can of course also interfere with cognitive testing. And there is a range, if you want, of subjects we allow. And one of the criteria, which is really the investigator has to make this assessment, is how much do the motor dysfunctions interfere with the participation in the clinical trial, which basically means how much are these people, these patients, capable of doing the computerized cognitive testing, which needs, of course, some type of a motor control. So that's a cutoff, which is based on the assessment of the investigator.

Perfect. That's one of the reasons I asked. Thanks for taking the questions.

Thank you, Charles.

Thank you, Mr. Duncan. The next question is from the line of June Lee with Truist. You may proceed.

Hi, thanks for taking our questions. You know, just based on the prior questions, it sounds like patients in Phase 2B for DPN study needed to be actively washed out of concomitant payments as opposed to, you know, just enrolling patients who are just not on payments like they were in Phase 2A postdoc analysis. Because our understanding is that in Phase 2A DPN study, in the postdoc analysis that you did, we're in the group of patients who just weren't on concomitant payments. So by washing them out of the pain meds that they were on in Phase 2B, that they were needed to be on pain meds, what kind of bias did that create in the post-op analysis? And I have a follow-up.

Andy, I think you can start that. But just to be clear, it is not, June, it's not as if we were only allowing patients who wash off a concomitant pain medication. We have those that are not to begin with on a concomitant medication as well as those that wash off. So just as a clarification, so I don't leave you with a wrong impression on the study design.

Yeah, Norbert, exactly. I was going to make that point. The question from Charles covered if and when a patient washes off medication, not that that was the only way to get into the study. I think quite a large number of patients in the study will not have been on one of those concomitant analgesics to start with. And actually, as a reminder, in the last study there were patients washing off drugs to get into the study. You were only allowed to be on one other analgesic. So actually, the group of patients that in the last study that were not taking a concomitant medication did include quite a few patients that washed off a pain medication of some kind. I think we may have made the point in the past that a lot of them were not taking something like gabapentin, vergabalin, biloxetine. but there were other drugs that you had to wash off, and actually there were still a number that were taking one of those drugs and washed off. So I think it's likely to be a fairly similar population to what we saw in the last study. Okay.

Okay. I expect clarification. And one more thing I wanted to understand better is in one of your data slides for DPN, you have a slide with a chart with those on concomitant meds, and a separate chart with those with advanced DPN, I believe, for four more years. But do you have a chart or data where the patients are both not on concomitant meds and with advanced DPN? What does that look like? I'm just curious if they have greater than two-point improvement in NRS or something like that.

So we do have this data, We can look up the actual numbers, but those that had a longer duration of disease, four years and longer, and were not on a concomitant medication had the strongest benefit and treatment effect when you compared active against placebo.

That makes a lot of sense, but I'm just curious if that data has ever been presented.

We are looking it up as we speak, so if we can't find it right away, we get back to you.

So, June, I want to make sure, this is Ashish, I want to make sure I'm understanding the question correctly. You're looking for the effects in the last study in DPN among patients who were not on concomitant analgesic medications and with advanced DPN, greater than or equal to four years. Those data, I believe, are on our website in our public presentations, and they're sort of... presented alongside the 127 patients out of 300 who had four years or greater advanced DPN. There's a subset of those who were not on that.

Oh, so the 127 patients are not on concomitant men.

No, no, no. Sorry. Let me clarify. 127 patients were only those who had greater than or equal to four years of DPN. A subset of those patients were presented alongside. It's about half of those patients. 64 of those patients were also not on concomitant analgesic medications. And as you noted, we saw very profound reductions in pain over just four weeks, in excess of two points on the NRS scale, and very significantly separating from placebo, albeit with a subpopulation and lower ends.

Got it. Thank you so much, and looking forward to the data mid to early next second quarter of 22. Thank you. Thank you.

Thank you, Mr. Lee. The next question is from the line of Mark Goodman with SCB. You may proceed.

Hi, thanks. This is Madhu on the line for Mark. I just have a couple of questions on 783 and the PTSD studies. I think you mentioned in a prior call that you would be able to talk a little bit more about your strategies in terms of managing placebo rates closer to initiation. I was wondering if you could give us any additional color there. And then secondly, given this may be one of the two registrational studies, what sort of efficacy should we be thinking about and kind of like the bar there? Thanks.

All right. Terrific. Thank you. Again, I think we can have you, Andy, kick it off, and then maybe Harald can supplement or complement accordingly. Thank you.

Yeah, sounds good. I'll take the second part first. I think we've said in the past and continue to believe that, especially for a drug with good tolerability, a separation from placebo in the mid-single digits of, say, three to five, low to mid-single digits, is probably sufficient as long as it's statistically significant. You know, we've also talked about, you know, the change from baseline and the responder rate being factors that clinicians really, I think, are more focused on. With respect to placebo response mitigation, we can go into a little more detail on that, I think, when we actually initiate the studies, but there's a few points we can reiterate today, I think. One is, obviously, the study design allows for a one-to-one randomization ratio between active and placebo. We've also, I think, taken some consideration and other study design variables to try to make sure that they're on the side of, you know, minimizing or mitigating placebo effect as we've looked at screening criteria, as we've looked at duration of the study and things like that. I think a key part of the placebo mitigation will also include training, both for subjects, sites, and also for raters. And we can go into a little more detail on what that involves, I think, as we disclose the full study design and some more of the details over the next few months.

Great. Thank you.

Yeah. Yeah, maybe just to add to that, we actually took an early visit out, the more visit and interaction in high-risk patients, the higher is the placebo response rate. Also, we reduced the number or the exposure to the PTSD questionnaire. There's a self-rating scale and there's a investigator-rated scale. In the previous trial, we did both. In this trial, we just focused on the investigator one, which really has the exposure, and I think that should have a huge effect on the placebo response as well.

Thank you. Thank you, Mr. Goodman. The next question is from the line of Myles Minter with William Blair. You may proceed.

Hey, thanks for taking the questions. Just on 2925 to start off with. On the evidence for a potential deepening of response with 12 weeks of therapy in the Phase 2B trial, do you have any other evidence outside of the prior four-week data that we're seeing that doesn't seem to plateau? It still looks like it's on the... efficacy-enhancing trajectory and also the six-week data that I think was the best out of the preliminary fibromyalgia data. I'm just trying to understand with 12 weeks of therapy how much additional efficacy we can sort of expect.

Yes, so I think you already mentioned some of our previous observations, Miles, and thanks for the question, by the way. In the earlier study, we did see like we typically do see a pretty rapid onset of activity or efficacy. And in the 50 milligram dose that we selected to be the dose of the current phase 2b study, we saw a very linear decline from week one to week two to week three to week four with a very clear indication that we would likely see additional improvement thereafter. While typically in studies like this, when you look, placebo begins to plateau. So both of those should contribute to even better and stronger separation than what we already saw. And Ashish mentioned a moment ago that the result we had in particular in advanced DPN and the absence of concomitant pain medication was a very, very dramatic reduction of two points in the concomitant 10-point rating scale. So I think that is a context that we find to be very encouraging and supportive of the current study. The fibromyalgia study that you mentioned, likewise, had a rapid onset. While we did not see it in the lower dose, it was quite readily observed in the 200 milligram dose, which was given about two weeks, actually two weeks after the lower dose, And so the same applies here. And in that study, as we pointed out, it was not just average daily pain. It was worse daily pain. It was a questionnaire. It was performance fatigue scale. All of those very strongly correlated with the 200 milligram dose being very efficacious, which we like to actually point out because we are not relying on a single endpoint. We look at multiple patient-reported outcomes, or in this study, in addition to that biomarker results, that all actually clearly move in the right direction to support that this mechanism seems to be pretty hard and solid in how it changes the brain physiology.

Okay, and then just a clarification question on enrollment number in the Phase 2b. I think it's 229 participants listed on clinicaltrials.gov. If you can't tell me the number you ended up with, can you tell me whether it's over or under?

If we can't tell you the number, we can't be told you the number we ended up with. That's 229.

All right. Sorry, in line. Okay. The final one for me is on 458, the preclinical work that you've done. I think I've seen data on non-human primates with MPTP injections that don't cause motor dysfunction. Just wondering, have you done that work in alpha-somycline transgenic mice? Because obviously patients don't inject themselves with MPTP apart from a few, which is how we found out MPTP actually is a model. But just wondering whether you've done any additional preclinical work there in alternative models.

Yeah, I might have considered actually the alpha-synuclein mouse model, looked at it, I think, quite carefully after we'd already done the non-human primate MPTP work. And I think there isn't really a well-characterized – or we weren't comfortable there was really a well-characterized cognitive deficit in that model that it would be meaningful to kind of show that we addressed. So we haven't looked at that. I think we were not uncomfortable with the fact that the MPTP model does not display severe motor deficits. A lot of work went into the development of that model to try to replicate the cognitive effects that are seen in Parkinson's disease. And part of the protocol of administering MPTP chronically over a long period of time seems to create that deficit. And it just doesn't create as severe a motor deficit at the same time. So it was a model, actually, we were very comfortable with and thought was translatable and the best model to look at.

Okay. Thanks, guys. Any questions?

Thank you, Mr. Minter. The next question is from the line of Gary Nachman with BMO Capital Markets. You may proceed.

Hi, thanks for taking our questions. This is Evan Fawaz going in for Gary Macklin. The first question is regarding 783 for PTSD. What are some theoretical safety concerns having a higher 150 milligram dose? And can you remind us if there were any previous tox studies done and what was the highest dose evaluated there?

Yeah, sure. You know what, let me kick this off. Of course, we know from our preclinical models, of which we employ quite a number, that the dose of 50 that we already tested and the dose of 150 are efficacious and safe, which is important to mention. We also have our phase one data, which is single and multiple ascending dose data, which go much beyond the 150 milligram dose. So in our case, we are really fortunate to have consistently seen a very, very favorable safety and tolerability profile, while other compounds in development might be dose-limited because of safety or tolerability concerns. That is not the case in our studies with these compounds. And so based on the preclinical work we have done and the Phase I work, we feel that the 150 milligram dose is another dose that is worth testing because it should give us a better understanding of additional efficacy without at all entering the space of being concerned about safety or tolerability.

Got it. And then one more follow-up from me. For the 458 cognitive impairment and 2925 fibromyalgia studies, how has enrollment been tracking for those studies given the increase in hospitalizations due to the Delta variant? And how many patients have been enrolled so far in those studies?

All right. Great question. I'm going to have Kathleen answer that for you.

Yeah, we're tracking well in both the 458 study in cognitive impairment and 2925 in fibromyalgia. And things are looking to be on track for our data readouts mid and then second half of next year. We certainly have been watching carefully the impact of COVID across the trials, but we continue to stay on track.

Great, thanks.

Thank you, Mr. Nachman. The next question is from the line of Chris Raymond with Piper Sandler. You may proceed.

Good evening, guys. This is Nicole Gabreski on for Chris. Thanks for taking the question. I guess just around fibromyalgia, I know this is nitpicking a bit, but it looks like timing for the Phase 2b data update has just been modified from first half 22 to now mid 22. I guess, can you just provide any clarity around this change in language? I know the primary completion date on ClinTrials has been June 2022, and it doesn't necessarily sound like you guys had any enrollment issues. So I'm just wondering maybe if you could be thinking about potentially releasing results around a medical conference. So just any clarity around that would be great.

Okay, thank you for the question. Let me make one comment, Miles, just to correct myself. I did not formally mention in my script the 229 for the patient number in the DPN study, but it's on the government website, of course, and that's why I said we told you the number. I meant it more in the sense of the number is publicly available, okay, just for correction. On the question of enrollment, 458 and subamerica are enrolling as plans. We are really pleased with that, just like we were for the DPN study. And as we have done for the DPN study, we will provide better guidance or maybe more definitive guidance as we complete enrollment. But at this point, we think that the fibromyalgia study is likely going to read out in the first half. At the end of the second quarter, it could spill over a little bit. We will see. complete enrollment. And for the 458 study in Parkinson's and Lewy body dementia, that is still on track, of course, as we mentioned, for second half of 2022, supported by the enrollment numbers we have. And so no reason to actually change those timelines that we communicated before.

Okay. That's very helpful. And then maybe just a quick second question on 783. Just around managing enrollment between study one and two, I know that the study starts are staggered, but I guess, is there any concern that enrollment in study one could take longer than expected if, you know, patients or docs are kind of holding out to enroll patients at the higher 150 milligram dose for study two? I guess, have you heard any kind of feedback on that?

Kathleen can give you the answer to that.

Yeah, our strategy there is to actually put the different studies at different investigator sites. So depending on where the patient geographically lands or where they're comfortable going to the clinic, they will not have the option of both studies. They'll be enrolled in the study that that clinic is running. We think that that reduces bias and also gives us a representative sample across both studies. which is important as we advance that development program.

Okay. That's very helpful. Thank you.

Thank you, Mr. Raymond. The next question is from the line of Ram Selvaraju with HC Wainwright. You may proceed.

Hi. This is Ram. Thanks for the update. All of your programs are progressing very well, cohesively. terms of initiations, enrollments, and readouts, just to shift gears, are you able to share any impactful progress in your discovery pipeline? Any new receptor systems, biology, target indications that you're excited about and that you wish to reveal?

That's a great question, and I think it gets too little attention typically when we report So maybe just as a reminder to our audience here, we have been synthesizing these positive allosteric modulators for quite some time. We have designed and synthesized and profiled more than 1,200 of them. And of course, out of that pool, we advanced those that are currently in the clinic. We have a number of compounds ready to be further advanced into IND at the right time. And that gives us a really rich portfolio of compounds to choose from as we advance the programs further. That's the latest on the preclinical part. And, of course, as we discussed before, part of what we investigate with our compounds is where on the receptor do they bind. They bind to a novel binding domain. Within that domain, the sites differ from one compound to the next, but it's a new previously not described domain where the compounds bind. We can characterize that pharmacologically. We can also characterize it quite nicely with our molecular biology tools where single point mutation in that binding domain or binding site can completely abolish the effect of the compound. And so we have quite an extensive library of preclinical data that support the pharmacology and receptor engagement of the compounds. And perhaps there is an opportunity for us to present that a little more broadly at some point, because I do believe it does make us the leader in this space of positive allosteric modulators acting on the NMDA receptor.

All right. Fantastic. Thank you, Norbert.

Yep. You're welcome.

Thank you, Mr. Selvaraju. The next question is a follow-up question from the line of Myles Minter with William Blair. You may proceed.

My question is actually to Ashish. You've got a debt facility in place and also an active ATM. Are we expecting that you're just going to draw down both of those continuously? Are you going to wait for a data readout and sort of how do you think about utilizing both of those facilities moving forward to fund the pipeline? Thanks.

Yeah, thanks for the question, Myles. I think that we've always been attentive to the balance sheet and will, of course, continue to be, but we're pleased to be in a position with a strong balance sheet that funds multiple phase two data readouts actually across each and every clinical program in our pipeline in fibromyalgia, in DPN, in PTSD, and in cognitive impairment. That gives us really nice flexibility both with regard to cash and the access to capital both ahead of the data but also through the data. I don't think we're in any rush or need to think about incremental financing. We'll appropriately think about balance sheet enhancement at the appropriate time, but especially in support of the next steps in development. But we're in a good position right now.

Okay, cool. Thanks.

Thank you, Mr. Minter. I am showing no further questions at this time. I would like to turn the call back over to Norbert for any closing comments.

Thank you, operator, and thank you all for your questions. We appreciate your time and your attention. Please be well and enjoy the rest of your day. Bye-bye.

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