Aptinyx Inc.
Q4 2018 Earnings Call Transcript

Published: 21 Mar 2019

[Operator:]

Good morning and welcome to the Aptinyx Fourth Quarter and Year-End 2018 Financial Results Conference Call. At this time, all participants are on listen-only mode. Following the formal remarks, we will open up the call for your questions. Please be advised, the call is being recorded at the Company's request. At this time, I'd like to turn the call over to Nick Smith, Senior Director of Corporate Development at Aptinyx. Nick, please proceed.

[Nick Smith:]

Thank you, operator. Good morning and welcome to Aptinyx's fourth quarter and year-end 2018 financial and operating results conference call. This morning, we issued a press release with our fourth quarter and full year 2018 financial results along with the business updates and upcoming milestones. The release is available on our website under the Investors and Media section. Today on our call, Norbert Riedel, our President and Chief Executive Officer will review the Company's strategy and recent business and clinical highlights. Then, Ashish Khanna, Chief Financial Officer and Chief Business Officer of the Company will review the financial results. In addition, Andy Kidd, our Chief Operating Officer is with us today for the Q&A portion of the call. Before we begin, I'd like to remind everyone that statements made during this conference call will include forward-looking statements under the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties that can cause actual results to differ materially. Forward-looking statements speak only as of the date they are made, as the underlying facts and circumstances may change, except as required by law, Aptinyx disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. Please see the forward-looking statements disclaimer in earnings release issued this morning and the risk factors in the Company's current and subsequent filings with the SEC. It's now my pleasure to turn the call over Norbert.

[Norbert Riedel:]

Thank you, Nick, and good morning to everyone. We appreciate you taking the time to join our first earnings call as a publicly traded company. During the call today, I plan to start with a brief background on the Company and our scientific foundation. I will then discuss the recent clinical results across our pipeline program, including results we recently announced from the detailed analysis of data from our study of NYX-2925 in patients with painful diabetic peripheral neuropathy, or DPN. As you know, from our January press release on the top line data, the DPN study did not meet its primary endpoints, which of course was a disappointment. However, as I will discuss, having now completed detailed analysis of the full data set, we are actually very optimistic about the path forward and the prospects for NYX-2925 in chronic pain. Before getting into these detailed results, I would like to remind everyone of our broader mission at Aptinyx. We are focused on discovering and developing novel therapies to address the vast unmet needs in the treatment of disease of the brain and nervous system. Our pipeline comprises clinical stage programs that are advancing rapidly in development. All of our product candidates come from our proprietary platform of novel chemistry, stemming entirely from internal innovation; and accordingly, our compounds are protected by robust IP affording exclusivity for decades to come. And our efforts are driven by a team of exceptional people who are seriously dedicated to advancing the treatment of difficult CNS disorders. Our compounds target a pivotal receptor in the brain, called the NMDA receptor. NMDA receptors have been a target of interest to drug developers for decades. They are vital to normal brain physiology, and abnormal NMDA receptor function underpins numerous CNS disorders, including chronic pain, PTSD, cognitive impairment and many others. But unlike most NMDA receptor targeted drugs discovered and developed to-date, which are mostly pure antagonists or agonists, our compounds are modulators. They regulate and normalize NMDA receptor function. Each of our compounds bind uniquely to the NMDA receptor, resulting in differences in pharmacology and in preclinical animal models of disease. The way our compounds modulate NMDA receptors in the case of biological, ultimately leading to enhanced synaptic plasticity, which is critical for sensory processing and processes associated with attention, learning and memory. The underlying discussion in these processes is a core element across the indications we are targeting. Our novel modulators address this disruption by enhancing NMDA receptor mediated synaptic plasticity. We launched Aptinyx in the middle of 2015 with only a few preclinical stage molecules. Now, just three and a half years later, we have two product candidates in Phase 2 and another on the cusp of initiating Phase 2. These programs are targeting four challenging CNS indications. This is a remarkable level of productivity and I could not be more proud of the efforts of our team to get to this point. 2018 was a year of significant progress for Aptinyx, marked by important clinical study results and of course, the successful closing of our initial public offering back in June. This past year, we also built on our robust IP state with additional patent issued across the pipeline. All of our clinical stage product candidates are now covered by issued composition of matter IP. Now, let's discuss each of our clinical stag programs in some detail. We will start with NYX-2925 in developing as a therapy for chronic pain conditions. Coming into 2018, we had already established in Phase 1 that NYX-2925 had an excellent safety profile, even at very high dose level. But it had a linear and predictable pharmacokinetic profile and it readily crosses the blood-brain barrier and achieves ample concentrations in the central nervous system. In November of 2018, we reported results from two electrophysiology studies in healthy volunteers, which offered the first confirmation in human that NYX-2925 is not only present in the pain but also active and that they engage with NMDA receptors and effect downstream NMDA receptor mediated processes. These NMDA receptor mediated processes are particularly important in chronic, long-term pain. Chronic pain is very different from acute peripherally mediated. Our mechanism is not active in acute peripheral pain. But, as pain [indiscernible] it becomes increasingly centrally manifested and characterized by a burnt central pain perception and pain processing in the brain. We believe this central [ph] pain perception and processing can be addressed through the normalization of NMDA receptor function. We confirmed this effect NYX-2925 on central pain processing last December when we reported positive results from internal analysis of the study in patients with fibromyalgia. In this exploratory study, we are using a series of neuroimaging techniques to evaluate activity and connectivity in brain regions known to be associated with central pain processing. The change in this objective imaging biomarkers is the actual primary endpoint of this study. The interim analysis of these fMRI images in just 11 patients showed that NYX-2925 resulted in statistically significant changes in these biomarkers. Based on the precedent study by the same investigator of patients who responded to Lyrica, a drug approved for fibromyalgia, we know that these changes in the imaging biomarker are consistent with alleviation of pain and other symptoms of fibromyalgia, and we saw just that in our study as well. Alongside the imaging results, we found that these fibromyalgia patients reported improvement in their pain, moves, and cognitive symptoms, as well as the quality of life. In only 11 patients, the improvement in these subjective symptoms about statistical significance and were comparable to the improvement seen in the Lyrica of study. These are very highly compelling results, demonstrating that the activity of NYX-2925 is available to central pain processing. We plan to complete this study and report the full result in the first half of this year. Let’s now discuss the result of our completed study of NYX-2925 in 300 patients with painful DPN. While the study did not meet its primary endpoint, it did answer four critical questions that inform the path forward in chronic pain. First, we asked if NYX-295 is safe in a DPN patient population. And we saw that NYX-2925 had excellent safety and tolerability with no treatment-related serious adverse events, and an overall adverse event profile similar to placebo. Second, we looked across a 20-fold dose range to see if there is a dose level that exhibits greater activity than the others. And we did indeed identify the 50-milligram dose as the most effective and appropriate dose level for future studies, aligned with our projections from our preclinical work. Third, we wanted to know if NYX-2925 shows activity across the multiple endpoints we use to evaluate symptom relief. And we saw that the 50-milligram dose had activity across the various pain endpoints, as well as the endpoints evaluating common comorbidities of chronic pain including sleep, quality of life, and function. Fourth, we wanted to understand if there are characteristics or parameters that inform the likelihood and magnitude of the patients’ response to NYX-2925. As we announced for the first time just last week at the Cowen conference, we have completed detailed analysis of the full data set. It is revealed that patients who have been suffering from DPN and for longer periods of time, experienced a treatment benefit from NYX-2925 that is statistically significant and clinically very meaningful. So, although we didn't see statistically significant separation from placebo, in the primary endpoint in the top-line readout in January, our subsequent analysis of the full data set has answered all of these questions. This analysis gives us strategy on how to best further study NYX-2925 in patients with painful DPN and has informed and derisked that further study. In the top-line readout in January, we reported the following results from the study. Of the three dose levels tested, namely 10, 50 and 200 milligrams daily, the greatest separation from placebo was observed in the 50 milligrams dose group. In the total study population, the 50- milligram showed an average deduction in pain at week four that was 0.38 points better than placebo, on a 10-point Numeric Rating Scale of pain. Importantly, we observed that patients who were not taking a concomitant analgesic medication showed a greater separation from placebo on the primary endpoint as well as the key secondary endpoints. In these patients, the separation from placebo and average pain reduction increased quite substantially from points 0.38 points to point 0.58 points, approaching a clinically meaningful difference. Further, we saw that patients not on a concomitant analgesic medication represented about half of the 300 subjects in the total study population. Although initially considered to be very difficult, in all new patients not on conmed turned out to be quite achievable, an important observation as we plan future steps. Another key finding of the study was that the effect 50 milligram dose did not reach a plateau at week four, the final week of treatment. Across multiple endpoints, the effect improved in a linear manner across four weeks. We may therefore see a larger drug effect with a longer treatment duration such as the 12-week [ph] studies, usually required for the patients. Of course, a first in patient study of this size with many endpoints provides the rich dataset beyond the top-line data. As we announced for the first time last week, further analysis of the full data has revealed that after acquisition of DPN diagnosis increase, patients in the study exhibited an increasing effect of NYX-2925 across pain scores and other endpoints. In a subgroup of 127 patients with advanced DPN, that is DPN diagnosis for four or more years, the reduction in pain scores from baseline to week four was 1.93 points in the 50 milligram group. This represented statistically significant improvement of 1.21 points over placebo. These are large effect sizes, [ph] well above the threshold for clinical significance. And just as we saw in the overall study population, these effects of NYX-2925 were even more pronounced in advanced DPN patients who were not taking a concomitant analgesic medication. In these patients, the 50-milligram dose resulted in 1.85-point improvement incremental to placebo. This sub population of advanced DPN patients is very relevant to the mechanism of NYX-2925. As I discussed earlier, that mechanism works essentially to address the increasingly centralized pain that is perceived and processed when these patients experience prolonged chronic pain. So, there is a very strong mechanistic rationale as to why this group of patients would experience greater treatment benefits from NYX-2925. This is a circle of patients that does not usually experience symptom relief in response to treatment. In fact, they are often excluded from studies in painful DPN for this reason. So, to observe this benefit of NYX-2925 in these patients is highly encouraging. And this was not a small subset of just a handful of patients. Nearly half of the patients in this study had a DPN diagnosis of four years or longer, allowing for rigorous analysis and a practical focus for future study. Finally and very importantly, the efficacy of NYX-2925 in these advanced DPN patients was not observed just on one endpoint, these patients showed consistent, robust improvements across the endpoints we measures including worst pain, pain on walking, daily sleep interference and others. We have pressure tested these analyses and conclusions with a number of independent experts and they have now overwhelmingly regarded as sound and compelling. We're looking forward to presenting these findings in greater detail at the American Pain Society Scientific Meeting in Milwaukee in early April. These results provide a strong scientific and clinical foundation for further investigation of NYX-2925 in painful DPN and highlight its differentiated therapeutic potential. Based on the totality of the DPN and fibromyalgia data I have just shared, we are excited about that potential and we plan to initiate clinical studies that are informed by these findings, later this year. Now, let's turn to our NYX-783 program in PTSD. It is estimated that over 8 million people in the United States alone suffer from post-traumatic stress disorder. In the therapies that are available to treat PTSD are marked by inadequate efficacy and significant side effects. We believe that NYX-783 has the potential to address many of the unmet needs in PTSD with a differentiated mechanism. We have seen very compelling results with this compound in preclinical models including models in which NYX-783 demonstrated an acceleration and consolidation of fear extinction. In patients who develop PTSD, the dysfunction is a natural extinction learning process that is associated with traumatic event, and as a result that fear and anxiety response is record periodically or in reaction to subsequent non-traumatic stimuli. By enhancing synaptic plasticity and learning and memory processes, NYX-783 may be able to address this underlying dysfunction in memory and extinction learning that is at the core of PTSD. We announced in February that we initiated our first study of NYX-783 in patients with PTSD. The study will enroll approximately 144 patients who will receive either placebo or 50-milligram of NYX-783 over the course of the eight-week study. The study is a sequential, parallel comparison design to mitigate the highlight of placebo response in these patients. We are evaluating the effects of NYX-783 on PTSD symptoms across multiple endpoints, including the Clinician-Administered PTSD Scale or CAPS, which evaluates various symptom domains and is used both as a diagnostic tool and as a standard endpoint in PTSD study. We anticipate reporting data from this study in the first half of 2020. Moving to now NYX-458, we are nearing the completion of our Phase 1 healthy volunteer study in which we are evaluating the safety, tolerability, pharmacokinetics spend and brain exposure of multiple dose levels. We expect to report data from the study in the first half of this year. We plan to take NYX-458 into our first Phase 2 study later this year to evaluate its safety and efficacy in patients with Parkinson's disease cognitive impairment. While Parkinson's disease is most often characterized by its motor symptoms, there is an increasing recognition of the cognitive impairment that is associated with the loss of dopamine neurons in the disease. Of the 1 million people in the United States suffering from Parkinson's, it is estimated that about half of them suffer from some form of cognitive impairments. Currently, there's only one therapy approved for cognitive impairment in Parkinson's and it offers modest efficacy to these patients. We are very excited about the prospects of NYX-458 based on the compelling results we have seen on cognitive impairment preclinical, including in a highly relevant, very translatable model of Parkinson's disease in non-human primate. In this model, we saw that NYX-458 was able to reverse cognitive deficits that resulted following depletion of dopamine neurons. On some measures, cognitive performance was restored back to healthy baseline levels. These effects were rapid and they improved [ph] for several months. Additionally, we saw that NYX-458 did not have any negative impact on motor symptoms, and it did not interfere with the antiparkinsonian effect of L-DOPA. These findings are highly encouraging to us and other experts in the field, including the CRO we work with on the study, which has used this model for years and has evaluated numerous compounds in it. We are very eager to evaluate NYX-458 patients. And as I mentioned, we plan to initiate that later this year. Looking ahead, in 2019, we will be acutely focused on clinical execution, and our overarching objective is to expand on the clinical and preclinical findings from this past year. We are advancing the clinical development of each of our product candidates across chronic pain, PTSD, and cognitive impairment and expect to have four Phase 2 studies in progress by the end of this year. With that, I will now turn the call over to Ashish to cover our fourth quarter and our full-year financial results.

[Ashish Khanna:]

Thank you, Norbert. In this morning's press release we announced the cash, cash equivalents and investments of $150.6 million at December 31, 2018, this compares to $92 million at the end of 2017. This increase was primarily due to gross proceeds of $117.8 million from our initial public offering in June of 2018, partially offset by cash used to fund operations in 2018. As you heard, we are very busy with clinical development across our programs, and we expect that our current cash will be sufficient for our operating and capital expenditure needs into 2021 to deliver readout on all of the clinical studies that Norbert just mentioned. Revenues for the quarter ended December 31, 2018 were $1 million as compared to $1.2 million in the same period in 2017. For the full-year, revenues were $6.6 million as compared to $5 million in the same period in 2017. Our revenues are earned primarily from government grants and from our research collaboration with Allergan. The increase from 2017 to 2018 was primarily driven by Allergan’s exercise of an option to acquire AGN-241751, a novel compound from our discovery platform which triggered Allergan's payment of a $1 million option exercise fee to Aptinyx. We don't rely on these revenues to fund our operations, but they offset some of the costs associated with the early discovery and research work we do on molecules from our chemistry platform. R&D expenses were $10.9 million for the quarter ended December 31, 2018 and $48.8 million for the full-year 2018, representing increases of $4.2 million and $17.2 million, respectively, over those same periods in 2017. The increase in R&D expenses reflects the progress we have made across our pipeline, including the Phase 2 work for NYX-2925 and DPN, fibromyalgia, and in healthy volunteers, as well as the Phase 1 work for both NYX-783 and NYX-458. G&A expenses were $4.8 million and $12.7 million for the fourth quarter and full year 2018, respectively. This compares to $1.7 million and $5.6 million for the same periods in 2017. The increase in G&A expenses was primarily driven by increase in personnel costs, and professional fees to support the needs of a growing organization and compliance with obligations associated with becoming and being publicly traded company. Finally, our net loss was $14.1 million for the quarter ended December 31, 2018, compared to a net loss of $7.2 million for the same period in 2017. For the full-year 2018, the net loss of $53.3 million compared to $32.1 million for the same period in 2017. With that, I will turn the call over to the operator for questions.

[Operator:]

Thank you. [Operator Instructions] Our first question comes from Ritu Baral with Cowen. Your line is open.

[Unidentified Analyst:]

[Audio gap] on for Ritu. Thanks for taking my question. My first question is, what kind of readouts should we expect from the fibromyalgia full detailed analysis? And I have a follow-up.

[Norbert Riedel:]

Yes. So, I mentioned to you that the fibromyalgia study interim analysis was done on 11 patients. The primary endpoint is of course, neuroimaging biomarkers that are associated with pain perception and pain processing. But we also have subjective secondary markets of pain and others. And so, after study delivered its interim results, we learned what we were looking for to inform the next study. We will nevertheless complete the study by the middle of his year roughly, just to have a look at the additional set of patients and to confirm the same data that I just mentioned, namely the primary endpoint as a bioimaging marker and a little bit more information or a larger number of patients regarding the secondary endpoint, which as I mentioned almost achieved statistical significance, but not quite because the number was small. So, we will of course look for further readouts on that as well.

[Unidentified Analyst:]

Got it. And my second question was, do you have any initial drop of the Phase 2 design for 458?

[Norbert Riedel:]

Could you repeat the question, please?

[Unidentified Analyst:]

The Phase 2…

[Norbert Riedel:]

Yes, I think, I understand this. No. So, I mentioned to you that we are still at the tail-end of Phase 1. The Phase 1 study looks very, very good. We are not quite ready yet to disclose the actual protocol. But, as I mentioned, the study starts later this year. And as we initiate it, we will of course share more specifics around the study and the design.

[Operator:]

Our next question comes from Geoffrey Porges with SVB Leerink. Your line is open.

[Gerard Smith:]

Hey, everyone. This is Gerard on for Geoff. Thanks for taking the question. I just wanted to use this opportunity to ask what are your thoughts on the announcement on Allergan that rapastinel had failed its depression study? I mean, does that change your thinking at all about your program or can you highlight some of the differences? Obviously, different indications, depression versus pain. And then, I’d also like to learn a little bit more about your thoughts for the larger Phase 2 study in DPN? I mean, I guess, we can assume it would be a more selective patient population, more severe disease and different requirements for background medication. So, could you give us a little bit more detail on that? Thank you.

[Norbert Riedel:]

Yes. That would be my pleasure, because it has high effect to the another that I shared with you. So, let's start with rapastinel. I think, it's too early to draw conclusions on the study, because I only know about the top-line data and not a deeper analysis. I will however say the following. When we had our rapastinel study at Naurex, in multiple Phase 2, large Phase 2 studies, we showed a very clear difference between placebo and active in the MDD indication that we studied. And so, it would be really helpful to understand where the differences lie in the design of the Phase 3 studies that Allergan conducted. And at this point, I don't have enough information on that. But, of course, in general, as we look at core CNS indications, you know that there are impacts that are pretty strong in some of these studies, in particular as it relates to placebo and to of course know from our DPN study that we control for placebo effects very tightly, I was recommended across the board of these indications, because they're upon to a pretty noticeable placebo effect. So, too little early to say. But, I believe that mechanistically in with the studies we did, rapastinel delivered very strong results when we had it in all our multiple Phase 2 studies. On DPN, next study, so I think we shared with you the very important learnings from this first Phase 2, and it informs a next study in the following way. We will certainly not have patients on concomitant medication because we now know that we can readily recruit those patients. We will have patients with a longer diagnosis of disease. We mentioned a four-year population that is 127 out of 300 patients. So, it's not a small group and it's readily possible to find these patients. We will do a longer study as opposed to 4 weeks. We will actually do a more traditional 12-week study, which is also helpful, because as I mentioned, we have not seen at all that the 50-mg dose plateaued at four weeks, and suggest that if we had done a longer study, we would have seen incremental further benefits of NYX-2925. And then, lastly, so that we actually focus, of course on the 50-mg dose, because it was the most efficacious dose. We addressed our dose range of 10, 50 and 200 before. And as we mentioned on several occasions, the higher dose was not as effective as the 50-mg dose, which is consistent with what we know preclinically and clinically from our compounds, namely that they approach a U-shaped dose response as you increase dose. So, there are no surprises there. And it was really helpful to know that the 50-milligram dose we had targeted to be the best dose indeed turned out to be the best dose. So, those are the parameters for next study.

[Operator:]

Thank you. Our next question comes from Gary Nachman with BMO Capital Markets. Your line is open.

[Gary Nachman:]

Hi. Good morning. On 2925, what additional data do you plan on showing at APS? Any other cuts of the DPN data you plan on looking at? Any other sub groups where you might see better results from what you guys have described thus far? And then, what portion of the DPN market is more advanced that greater than four years, the cutoff that used? I'm curious how you decided on that cutoff? I mean, it sounds a little arbitrary but I'm sure there's something more behind that.

[Norbert Riedel:]

Yes, great. Gary, thanks for the questions, terrific. So, we have more details on the various points that I actually brought up here as it relates to additional data presented at the APS meetings about two weeks from now. And we will also make that yet another opportunity for us to engage with the scientific and medical community there to further expose our data sets. As I mentioned, we have done quite a bit of work with about 12 KOLs to validate the data that I shared with you, and that will continue for at least the scientific meeting up in Milwaukee. I would say, when you do a full analysis like this, you look at all kinds of subgroups and notes, but I think there are some important parameters that let us to homing in on the longer diagnosis of DPN. First of all, it is a very large subgroup in the total population; it's a 127 of 300, so almost half. Second, when you think about it, with our mechanism being centrally active where you have to have a signature in infant, [ph] if you will, in your brain that this chronic pain is basically something that you perceive all the time, that's the most important sort of like profile based on which our mechanism is based and where we are most mechanistically relevant. So, we didn't look for just any kind of signal. We didn't look for some needle in a haystack. We looked for a very science-based -- or basically analysis of parameters that directly basically inform mechanism of action and results. And so, that I think is an important part that I didn't want to lose. And then, lastly, you said it seems a little arbitrary and I'm actually appreciative of you mentioning that. When you look at patients and their diagnosis of DPN, and you look one year out, two years out, three years out, four years out, five years out, you see actually a remarkable linear improvement of treatment benefits as the diagnosis of DPN becomes longer. And so, it's not a cutoff that seems sort of like arbitrary from the point of view of it all looks the same before the four years and then it's sort of like gets better. We just collected the four years plus, because it is the most pronounced effect there and it is a highly relevant and large patient population that I think is a very logical focus to at least include in our next study.

[Gary Nachman:]

Okay. And what portion of the DPN market is greater than four years diagnosed? I'm assuming it's a big chunk since that was a big portion of your study?

[Norbert Riedel:]

Yes. So, I think the study itself guides us to that. I would say, based on what we saw in the study, it’s somewhere between 40% and 50%. It may be more. And so, that’s of course, a very, very large segment in the market. And maybe most importantly, unfortunately those people and that those patients that don't seem to benefit much at all from existing therapies, because they have literally high, high pain scores, and have been at it for a really long time. So, I think it's a highly clinically relevant population of largely treatment resistant patients otherwise.

[Gary Nachman:]

Okay. And then, just a couple more on fibromyalgia. Would it make sense to look at patients there also with advanced disease mechanistically, just given what you learned with DPN? And in the PTSD study, you said you’re just using the 50-mg dose. I'm curious, why you didn't want to do more dose finding with that compound? Thanks.

[Norbert Riedel:]

Okay. So, I -- Andy can start with giving you a little bit of a sense of how we are going about it. And then we can come back to the PTSD study.

[Andy Kidd:]

Yes. Gary, Andy Kidd here. So, I think in fibromyalgia, there are some -- clearly some things that we will read through and learn from the DPN study that we apply to fibromyalgia. And then, there are also some important differences. One of the key things in fibromyalgia obviously compared to DPN is that the disease itself, the disease process, is very different. And we know from discussing fibromyalgia with fibromyalgia experts that typically with fibromyalgia, there is a clear state of pain and pain perception right from the beginning when fibromyalgia diagnosed. And we also know that fibromyalgia tends to be diagnosed fairly late, so, after the patient that’s already been experiencing pain for quite a while. So, we will certainly set some kind of a cutoff period that you have to diagnosis this is fibromyalgia for a certain period of time. But, we don't envisage it being anything like greater than or equal to four years. In DPN, as Norbert mentioned, it’s a little different because patients obviously know they have diabetes. The presentation of DPN can be a little more heterogeneous and probably takes a little longer for the central processing abnormalities in chronic pain to become predominant. So, there are different indications in that respect.

[Norbert Riedel:]

Yes. Regarding PTSD, so we are studying one dose 50-manufacturing. And it is based on the fact that we have consistently across our pipeline been able to really accurately translate and extrapolate our preclinical data including pharmacokinetics and brain exposure into human clinical study designs. And so, if I use the example of DPN, and DPN as we discussed issue several times, the 24 dose range, pretty much that 10 may not be enough, 50 should be right dose, and 200 is probably more than needed, and the results actually confirmed that very nicely. So, with that enhanced confidence in making accurate projections from preclinical to clinical and from Phase 1 where we do see it explore [ph] to measure actual brain exposure in human study subjects, we decided that the 50-milligram dose should be dosed that people [ph] are looking for, makes it therefore a study that is relevant but not overly large with respect to the number of patients we want to enroll because it is meant to inform a next study and for this to be primarily a safety and a signal finding study in a PTSD population.

[Operator:]

Thank you. Our next question comes from Charles Duncan with Cantor Fitzgerald. Your line is open.

[Sadia Rahman:]

Hi. This is Sadia Rahman on for Charles. Thanks for taking my questions. Can you discuss the rationale for looking at those sub population in DPN? Is there evidence for further quantification after DPN has been diagnosed or in other pain indications, either looking at brain markers or baseline pain scores or other metrics? And also, is there precedence for looking at such a subset and other clinical trials?

[Norbert Riedel:]

So, let's take it in several pieces. With respect to evidence, it is clear and there is lots of work that supports that when you endure chronic pain, you do actually have a heightened, I call it, sensitivity in certain brain regions, well-defined brain regions, as it relates to the perception of that pain and also the processing of that pain. And so, when you look at our mechanism being an NMDA receptor mediated and plasticity triggered, it is really much the approach we're taking of saying as that pain becomes a more centrally manifested chronic pain perception, that's when we can actually provide the most benefit with the mechanism of action, like our NMDA receptor modulator itself. I think, that's really very important component of why this is so relevant. It has also been shown from what I understand that these, call it, at normal brain perception and processing markers that we see are not limited to fibromyalgia, they cut across other chronic pain states. And a perfect example I can give you as I probably best able to relate to is phantom limb pain. So, when you have an amputated limb or when you have an osteoarthritis knee or hip that was replaced, it is quite often the case that patients nevertheless continue to sense pain in that limb that is no longer there are or pain in the joint that has been replaced because over time that chronic pain state manifests itself centrally and that is exactly the mechanism we are pursuing. And so, to answer the last part of your question of other studies that they [ph] done it. I think I mentioned in my script that they actually have primarily tried to exclude those longer, much longer duration patients, because it was considered to be very difficult, if not impossible, to actually provide them with a therapeutic benefit. And so, for us to be most efficacious there is not only very important from a perspective of the patients and the therapeutic opportunity, but also it's really aligned nicely with the mechanism of action that our compounds have. Because they cannot alleviate peripheral pain, they are not analgesics for acute pain. They are molecules that modulate NMDA receptor mediated plasticity, which requires a central manifestation of pain like we have seen in the fibromyalgia patients.

[Operator:]

Our next question comes from Jessica Fye with J.P. Morgan. Your line is open.

[Jessica Fye:]

Hey there. Good morning. Thanks for taking my questions. I just wanted to follow-up on the 2925 data. When we think about the 50-mg dose in patients who had DPN less than four years, did you see any benefit over placebo in those patients?

[Norbert Riedel:]

Yes. Thank you, Jess. I’m glad you followed up. I mentioned a moment ago when Gary asked the question that it wasn't an arbitrary cutoff that went from sort of like we don't see anything to wow, look at what we see. When you plot our data, the efficacy of our data across patients diagnosed with DPN less than a year, one year, two years, three years, four years, five years, you see a really remarkable linear progression of improvement in pain in the 50-mg dose. And so, this is a continuum of efficacy in a continuum or spectrum of increasing duration of patients with the disease. And so, that's the key message that we will also show next week at the APS meeting and discuss. And so, I want to make sure that our audience is not confused by this particular point I make. We are focusing in on patients with DPN that have had a diagnosis of DPN for a long enough time for us to be confident that they are particularly well-suited for this mechanism of action, but it is a continued spectrum as time on diagnosis actually increases.

[Jessica Fye:]

Okay. I guess, when we think about that group that was -- had more chronic pain greater than four years, it seems like the benefit in that population, much of it was driven by a lower placebo response there. Curious if you would want to see a really drug-driven effect to feel more confident that this is mechanistic and not a chance finding? I know that the drug effect increased somewhat as well. But, it seems to be kind of a combination of factors there.

[Andy Kidd:]

Yes. Jess, it’s Andy. It's definitely a combination. So, I think we certainly think it's important to note that the drug effect was also larger and much larger in that group of patients than in the total population. You're right. There was some reduction in placebo effect. That's not unexpected. As Norbert mentioned, these patients are often regarded as more refractory to treatment of any times. There is published data and it's also I think in line with a lot of our scientific advisors input and expectations that typically see a less of a placebo effect and less of a drug effect in patients with more longstanding disease. And so, when we see this pattern of somewhat reduced placebo effect and a larger drug effect, that is what is very striking to us and very encouraging.

[Operator:]

Thank you. I’m showing no further questions at this time. I'd like to turn the call back over Norbert for any closing comments.

[Norbert Riedel:]

Thank you, operator. And thank you, everyone for your questions and for taking the time to join us this morning. We are tremendously proud of the progress our team has made over the past year. And we believe the key findings from our recent clinical studies inform and derisk the further clinical development of our product candidates. We look forward to our upcoming readouts in 2019, including the completion of our exploratory study of NYX-2925 in fibromyalgia, the presentation of the detailed results of our Phase 2 DPN study in about two weeks at APS, and the readout of our Phase 1 study of NYX-458. We remain committed to first class execution across our robust pipeline and to providing the best possible treatment options for patients suffering from diseases of the brain and nervous system. We look forward to update you further throughout 2019. And for now, thank you again for participating. Have a good day and a very good upcoming weekend. Thank you.

[Operator:]

Thank you for joining us today. You may now disconnect.