This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk01: Good afternoon and welcome to the NRX Pharmaceuticals full year 2022 results conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Suzanne Mezuri, Stern Investor Relations. Please go ahead.
spk02: Thank you, Danielle. Before we proceed with the call, I would like to remind everyone that certain statements made during this call are forward-looking statements under U.S. federal securities laws. These statements are subject to risk. and uncertainties that could cause actual results to differ materially from historical experience or present expectations. Additional information concerning factors that could cause actual results to differ from statements made on this call is contained in our periodic reports filed with the SEC. The forward-looking statements made during this call speak only as of the date hereof, and the company undertakes no obligation to update or revise the forward-looking statements. Information presented on this call is contained in the press release issued earlier today and in the company's Form 10-K plan to be filed tomorrow, which may be accessed from the Investor Relations section of the NRX Pharmaceuticals website. Joining me on today's call from NRX Pharmaceuticals are Stephen Willard, Chief Executive Officer, and Seth Van Voorhees, Chief Financial Officer and Treasurer of Stephen will provide a summary of the company's progress, Seth will review the company's financial results, and then Stephen will review upcoming milestones before making closing comments. Following their prepared remarks, Stephen and Seth will be joined by Jonathan Javits, the company's chief scientist, and Matthew Duffy, the company's chief business officer, to address your questions. I will now turn the call over to Stephen.
spk06: Thank you, Suzanne. Good afternoon, everyone, and thank you for joining us. We scheduled this conference call to coincide with World Bipolar Day. As you know, bipolar depression is a lethal condition that affects 2% of Americans, nearly 7 million people, and a similar percentage of the world's population. With the commitment of our investors, our team, and our researchers, we aim to literally bring hope to the millions of patients with suicidal bipolar depression and PTSD who have been systematically excluded from the trials of previous antidepressants. Today we will discuss full year 2022 results and provide a business update. As you can see from our filing, 2022 was a pivotal year for NRS. When we filed our 2021 earnings, the COVID pandemic was just winding down and we announced our intention to redirect our energy to NRX's core business, the development of lifesaving drugs for lethal central nervous system conditions with an initial focus on suicidal bipolar depression. As we promised investors a year ago, we have now completed manufacture of NRX 101 and aligned with the FDA on a path to commercial stage product. We've reinstituted our clinical trials for NRX 101 for patients with suicidal treatment-resistant bipolar depression We've continued to align with FDA on a path to approve NRX 101, and this week we announced encouraging findings from the first evaluation of unblinded data by our independent data safety and monitoring board. As you know from the online publications we have posted, this DSMB initiative is being led by a highly experienced executive team together with leading psychiatrists from around the world. Today we are delighted to announce the appointment of two world-class psychiatrists to our advisory board. Professor Andrew Nirenberg, a chaired professor of psychiatry at Harvard Medical School, is the director of the Dotton Family Center for Bipolar Research at the Massachusetts General Hospital and one of the world's most published scientists in the area of psychiatric research, particularly as it relates to bipolar disease. We are honored to have him as principal investigator of our ongoing clinical trials. Professor Marion Legoyer is one of France's leading psychiatrists and an extensively published researcher in the field of neuropsychiatry, particularly as it relates to bipolar disease and autism. In addition to her academic achievements, Professor Legoyer chairs the Fondation Fundamentale and has facilitated an important collaboration with French psychiatry researchers that I will describe in a few moments. Please see their biographies on our website. I'll begin by reviewing our lead development program, NRX-101. NRX-101 is a fixed-dose combination of d-cycloserine, an NMDA receptor modulator, and lorazodone, a standard-of-care medicine for treating bipolar depression. We initially introduced NRX-101 as a drug that showed benefit in conjunction with ketamine in acute care patients, and this week announced encouraging findings from our outpatient trial of NRX-101 versus lorazodone that may offer a path to a far broader indication. NRX-101 aims to target a critical area of unmet need among patients with bipolar depression, PTSD. And as you will see in our filings, possibly chronic pain. Multiple investigators around the world have published encouraging findings on the use of d-cyclosterine in these areas. However, the NRX discovery of the unique synergy between NMDA and 5-HT2A targeted drugs, together with the discovery of the critical dosages at which d-cyclosterine may be effective in these conditions, has resulted in a portfolio of 90 patents around the world 48 of which have now been issued, all related to the treatment of bipolar depression, major depressive disorder, PTSD, and other central nervous system conditions. It is well established that patients with bipolar depression are at far greater risk of self-harm than those with major depressive disorder. Tragically, however, patients with suicidal bipolar depression have been excluded from the clinical trials of known antidepressants. To our knowledge, NRX is the first company to attempt to bring a medicine to people whose only FDA-approved treatment alternative is currently electroshock therapy. D-cyclosterine has been shown to reduce suicidal ideation in our stable V trial and similarly been shown to reduce suicidal ideation by independent investigators in a peer-reviewed study reproduced in our 10-K filing. The tragic reality of bipolar depression is that if you know two people with this condition, the odds are that one will attempt suicide. And if you know five people with this condition, the odds are that one will die from suicide. As the first potential oral NMDA antagonist to target bipolar depression with suicidality, NRX 101's proof-of-concept data from the Phase II stable B trial has shown a highly differentiated therapeutic profile compared to the other commercial therapies and investigative drugs under development. Our Phase II data showed a statistically significant reduction in both depression and suicidality compared to standard therapy in patients with bipolar depression who were acutely suicidal and those who were initially stabilized with ketamine. To our knowledge, no oral drug therapy has ever demonstrated a reduction in in both depression and suicidal tendencies in this patient population. This is a potentially life-saving event because antidepressants carry black box warning labels regarding the potential for increased risk of suicide in vulnerable populations. Based on NRX 101's differentiated therapeutic profile, we believe that we have the potential to address this significant unmet need for patients who are currently underserved by available treatment options. Based on our Phase II results, the FDA granted breakthrough therapy designation and a special protocol agreement for NRX101 in bipolar depression with acute suicidality. The breakthrough therapy designation allows for an expedited rolling submission of a new drug application for investigational drugs that have demonstrated substantial improvement over existing approved therapies. and the special protocol agreement allows for a single registrational trial of NRX101 in this indication after stabilization with ketamine, using a protocol similar to the STABLE-B trial with a patient population of fewer than 100. During 2022, we made substantial progress in advancing our development plans for NRX101 for the treatment of bipolar depression with suicidality, as well as a new area, PTSD. As you recall from our initial public filing, our psychiatry drug development program was halted by the closure of psychiatry study sites during the COVID pandemic. This time last year, we advised investors that we were reinitiating our psychiatry program. Our first order of business was to transfer our manufacturing and analytic technology to the United States, and we were fortunate to secure Alchemy, headquartered in North Carolina, as our lead manufacturing partner. Over a period of six months, we transferred our manufacturing and analytic methods to Alchemy. And by September, manufactured our first phase three and potentially commercial scale batch of NRX101. We submitted our manufacturing and stability data to the FDA in October 2022. And in January 2023, we reached alignment with FDA on our proposed manufacturing plan based on a type C meeting to review our chemistry, manufacturing, and controls. As a result, NRX is now positioned to conduct registrational trials of NRX 101 and able to make NRX 101 available through expanded access and right-to-try programs for patients who have exhausted approved treatment options. We're excited about this milestone in particular as we believe that adopting a commercial-ready manufacturing process at this stage of our development can lead to a more seamless NDA submission, review, and approval process under our breakthrough therapy designation without the need for bridging studies. In January 2023, we initiated a Phase III registrational clinical trial of NRX-101 for the treatment of severe bipolar depression with acute suicidal ideation and behavior and contracted the first study set. The study was designed to show that following stabilization in the acute care setting, treatment with NRX-101 is superior to lorazodone in maintaining improvement in symptoms of depression as measured by the Montgomery-Asperg Depression Rating Scale total score. We met with the U.S. FDA earlier this year to discuss the design of this Phase III trial of NRX-101 and in patients with bipolar depression suffering from acute suicidality, and are following FDA's suggestion to pursue the indication of, quote, treatment of recently suicidal patients with bipolar depression. We conducted our initial stable B trial of NRX101 versus lorazodone in acutely suicidal patients following acute stabilization with ketamine. However, both FDA and prospective commercial partners have suggested broadening the indication to test the use of NRX-101 as a means of maintaining remission for acute suicidality in patients stabilized by a variety of standard inpatient approaches in order that our label, should we prove safety and efficacy, not be dependent on prior use of ketamine. Although NRX is not actively researching the use of ketamine, a potent NMDA antagonist We do recognize its role as a potential agent for stabilizing acutely suicidal patients and recognize FDA's desire for more data on its efficacy. Therefore, we have partnered with the leading psychiatrists in France who conducted what we believe to be the most comprehensive study of ketamine for treatment of acute suicidality among hospitalized patients, particularly patients with bipolar depression. Their study, which is summarized in tomorrow's 10-K filings, demonstrates that patients with bipolar depression had a seven-fold greater response to ketamine in reducing suicidality than did those with major depressive disorder. Our colleagues have provided us with a detailed clinical study report that we have now translated into English and are submitting to the FDA. To our knowledge, this is the first multicenter placebo-controlled trial that shows an enhanced benefit of NMDA-targeted drugs in patients with bipolar depression compared to those with major depressive disorder. We look forward to having Professor Leblayet and her colleagues explain the importance of this study in greater detail and accompany us to the FDA to discuss the findings. In the January 2023 Type B meeting with the FDA's Psychiatry Division to align on the registration strategy for NRX101, FDA suggested a potential expanded indication for NRX101 in addition to reaffirming NRX 101's special protocol agreement, which was originally granted in April 2019. The FDA suggested that NRX's clinical development program be enlarged to allow for the chronic treatment of patients with bipolar depression and intermittent suicidality. This update would broaden the addressable population of the indication, under the SPA or otherwise, to patients with chronic intermittent episodes of bipolar depression and would enable the use of NRX 101 on a long-term basis by a broader segment of the approximately 7 million individuals in the United States with bipolar disorder. Prior to pursuing this extremely broad indication, we have focused our outpatient clinical trial first on those of greatest unmet medical need, specifically those with suicidal treatment-resistant bipolar depression. In other words, we are enrolling patients who are under the care of a physician for bipolar depression and have ongoing depressive symptoms and active thoughts of self-harm despite treatment with available medicine. The object of the double bond study is to demonstrate NRX 101's ability to significantly improve symptoms of depression and suicidality over six weeks when taken twice daily on a home use basis. The population is significantly larger than the severe and bipolar depression population with acute suicidal ideation and behavior seen in the hospital emergency setting and does not require initial stabilization with ketamine or other treatment. This study has the potential to expand the use of our medicine to nearly one million people who currently suffer from severe depression and suicidal ideation despite expert medical care with currently available medicine. These are the patients who are targeted by the recently funded $50 million Patient-Centered Outcomes Research Initiative, which documents the extraordinary unmet medical needs in this area. We announced the initiation of this clinical trial when we met with you a year ago, and this week announced guidance to continue enrolling patients by our independent Data Safety Monitoring Board, what I call a DSMB. who examined unblinded data from the first 50 patients. The DSMB found no futility signal at this stage of the trial. Similarly, no safety signals were identified in association with NRX 101, and the DSMB recommended that the enrollment of the trial continue as planned. According to the study's statistical analysis plan, the failure to identify futility requires that an advantage though not yet a statistically significant advantage, of the investigational drug relative to the comparator treatment must be observed by the DSMB. The DSMB will continue to monitor safety and efficacy in the trial. Based on the DSMB's findings, together with the recent completion of Phase III Anticipated Commercial Stage Manufacture of NRX-101, the company has upgraded the ongoing trials with Phase II B-3 trial whose results may be used in a future registrational filing should the primary endpoint commit. With the guidance to the DSMB at hand, the company has now requested a comprehensive breakthrough therapy planning meeting for NRX 101 as was suggested by FDA in their recent correspondence. Based on the comments and guidance from the FDA in its recent Type B meeting, regarding the registrational acute suicidality trial and a potentially broader indication, as well as the guidance we received from the DSMB regarding our currently enrolling Phase 2B-C, sorry, 2B-C3 clinical study of NRX-101. The company is evaluating changes to its registrational program for NRX-101 and will seek to consolidate the current clinical trial. This broader indication may also offer significant advantages in commercialization. Data is expected by the end of this year. We are evaluating the potential of NRX 101 in post-traumatic stress disorder, or PTSD, another area of high unmet need, which is also associated with suicidality. Approximately 9 million individuals in our country experience PTSD. and one-third have severe PTSD with 10% experiencing suicidality. Between 17 and 22 members of our armed forces of veterans are lost every day to suicide. Depression and PTSD may be driven by pathways that are similar to those that drive depression and other conditions. However, NMDA antagonists are the class, and d-cycloserine in particular may have a more specific effect in the treatment of PTSD. In a preclinical PTSD study described in today's filing, tomorrow's filing, B-cycloserine demonstrated the ability to extinguish recurring images of traumatic events, also known as fear memory, in a validated WKY model of PTSD. This model has similarly been used by others to document a PTSD-specific effect of ketamine, Repeated IV ketamine has also been demonstrated to improve PTSD scores in a randomized controlled trial. Unlike ketamine, however, NRX-101 is not neurotoxic, is not addictive, and has not caused psychedelic side effects in clinical trials. We anticipate that our investigational drug will show antidepressant effects in PTSD compared to placebos. And we hope that it will demonstrate specific effects of fear memory component of PTSD and directly reduce symptoms of PTSD itself. Today, there is no approved medicine for these specific PTSD symptoms. We are on track to initiate a phase two study of NRX 101 and PTSD in the second quarter of 2023. We are incredibly excited about the potential life-saving effects of NRX 101. And in order to continue to support the clinical development of these programs, we announced the close of a $2.9 million registered direct offering to support our pipeline efforts, and more specifically, the initiation of an expanded access protocol and safety database for NRX 101, studying treatment-resistant bipolar depression with risk of self-harm. This database allows us to investigate the expanded indication put forth by the FDA's Psychiatric Division in our Type B meeting for our registrational trials, and we look forward to providing you all with an update of our clinical activity in the months to come. The continued financial support from our existing shareholders based on our existing data and ongoing clinical trials demonstrates their commitment to people living with serious CNS disorders and the potential of NRX-101 to become commercially successful. Finally, we achieved a number of significant corporate milestones in recent months. In February, we received notice of the issuance of a U.S. patent for NRX 101, which covers the use of NRX 101 to treat patients suffering from depression, including bipolar depression or major depression, with or without suicidality. This patent strengthens the company's intellectual property position until at least 2033. We are pleased to announce that Matthew Duffy has joined us as Chief Business Officer of the company. Many of you may know him from his time at leading pharmaceutical and biotechnology companies, including Pfizer and Medimine, and his efforts in investor relations and investment banking. Matt will be responsible for a range of duties, including investor relations. Similarly, Dr. Martin Brescher, a distinguished psychiatrist who has held leadership positions at the FDA, AstraZeneca, Johnson & Johnson, and other leading corporations, and serving as medical director for our clinical trials. These milestones achieved in the years since we reentered psychiatric drug development establish a strong foundation for NRX that enables us to efficiently advance our clinical trials and make a difference in the lives of patients with life-threatening psychiatric diseases. I would like to express my gratitude to the patients, the NRF team, clinical trial investigators, and shareholders for their continued support. With that, I will turn it over to Seth for a review of our financial results. Seth?
spk03: Thank you, Stephen, and good afternoon, everyone. I will now review the highlights of our fiscal year 2022 financial results and our expectations for 2023. For the year ended December 31, 2022, NRX Pharmaceuticals recorded $17.0 million in R&D expenses compared to $20.3 million for the year earlier. The decrease of $3.2 million is related primarily to the decrease of $2.5 million in clinical trial and development expenses related to our discontinued Zysami clinical work. For the year ended December 31st, 2022, we also recorded $27.4 million of general and administrative expenses compared to $74.9 million for the year earlier. The decrease of $47.6 million was primarily related to a decrease of $53.3 million in consulting fees, of which $41 million was related to the fair value of common stock issue. For the 12-month period ended December 31, 2022, our resulting net loss was $39.8 million, which is $53.3 million improved compared to the net loss of $93.1 million for the 12 months ended the prior year. In fiscal year 2023, we expect our annual R&D expenses to decrease further from both fiscal year 2021 and 2022 levels. as we focus solely on the development of NRX 101. Furthermore, we expect our annual G&A costs will decrease in 2023 due to a number of factors, including reduced legal costs related to the relief therapeutic settlement, which has the potential for significant royalty payments to us in the future. Lower insurance costs, especially related to D&O coverage, and as well as other cost initiatives that we have undertaken. Now I'd like to comment on our cash resources. At year end, we had $20.1 million in cash. Our cash resources were enhanced several weeks ago when we entered into a securities purchase agreement with accredited investors who had previously established ownership positions in the company. The transaction involved the sale of approximately 3.9 million shares of the company's common stock combined with five-year warrants in a registered direct offering priced slightly above market at 75 cents per unit for the securities. The investors agreed not to sell these shares of common stock or exercise these warrants for six months following the issuance date. The aggregate proceeds to the company from the offering was approximately 2.9 million. As of the 10-K filing, we evaluated if there is doubt on our ability to fund our operations for the next 12 months. We have the right to make required payments for our current indebtedness in common stock, subject to certain ownership and trading volume limitations. If we are not able to make the required payments for this indebtedness, we will need to raise additional capital to support our currently anticipated operations for the next year, to strengthen our balance sheet as was done with the successful offering done several weeks ago. In addition, we may consider additional cost savings initiatives to further extend our cash resources. With that, I will turn it back to Steve for closing remarks. Steve? Thank you, Seth.
spk06: Over the past year, we have built strong momentum as we advance our NRX 101 program in two indications, while also positioning NRX for future growth with the potential for both a broader bipolar depression population as well as additional indications. Building on that momentum, 2023 promises to be an even more productive year as we continue to execute on multiple regulatory and clinical catalysts. We believe that NRX 101 is a potentially life-saving medicine that could change the treatment paradigm for individuals with bipolar depression who are experiencing suicidality, which is the driving force behind our mission of meeting the needs of underserved patients with serious CNS disorders. We look forward to updating you on our near-term milestones, which are on track for the coming year. Assuming that efficacy endpoints and safety are met in our phase three trial, we plan to initiate the rolling submission of a new drug application by the end of this year with potential for drug approval by the end of 2024. Operator, Danielle, we are ready to take questions from the audience.
spk01: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. We'll pause momentarily to assemble the roster. The first question comes from Jason Colbert of Dawson James. Please go ahead.
spk07: Hi, guys. Thanks. I really appreciate it. Hey, how are you? Thank you for the very comprehensive update. I mean that. It was really, really good. Very detailed. That's what we need. Just want to understand a couple of comments you made. The DSMB lack of utility, which implies... that the active drug is showing efficacy equivalent or even better than comparator, although not yet statistically significant. Can you just talk a little bit about that statement and kind of the math behind it? That would be helpful.
spk06: Sure. Jonathan, do you want to? Sure.
spk08: Jason, as you know, it's critical that we keep the blinding for the trial in place. The protocol for the trial and the statistical analysis plan are up on clinicaltrials.gov. And all we've been authorized to say by the DSMB is that no futility signal was identified. And our lead methodologist, Dr. Lavin, said that we could offer the additional comment that in this trial, the way this is set up, for that conclusion to be reached, a numerical superiority, though not a statistically significant superiority, would have to be identified. There are some trial designs where as long as you're not worse than the placebo, you're still not futile. we put in place a stricter futility rule than that. But that's really all we're at liberty to say.
spk07: Right. But actually, that's very critical, that last sentence when you talked about it, because that's what I was familiar with. That in most clinical trials are designed that if you're equivalent to the comparator or non-inferior to the comparator, that's how they're mostly designed. And what I didn't understand until this moment was that if your trial design is a little bit different, and in fact you're not futile because of the powering, and I'm assuming because of the powering differences and the assumptions around the effect between active and comparator, that in fact if no futility is shown, it suggests that there is a superiority because otherwise, because the numbers are stacked against you because of the tough trial design. Is that kind of layman's interpretation about rights?
spk08: Well, I don't think I want to wax overly optimistic. I think we're delighted that we didn't hit a futility signal given that we had a fairly strict rule in place. I don't think it would be necessarily fair for us to talk about most trial designs, but we did get permission from our methodologists.
spk07: Let me ask the second half of the question. Sure, I understand. I don't want to beat up this point because you're limited by what you can say. But I was also very interested from a clinical perspective when you talked about potential modifications of the Phase III trial and the combinations of of the two trials together. Can you talk a little bit about what that might mean? And particularly, I was, yeah, particularly the timeline.
spk08: Let's talk about how we got to where we are. Thank you. When this began, it began because people were using ketamine to treat, you know, acutely depressed patients. And everybody saw that ketamine wears off after a couple days to a week. And a lot of people thought that repeat use of ketamine wasn't a great idea. So people suggested perhaps we develop NRX-101 as a maintenance therapy to prolong the effect of ketamine. And that's what we did in the stable B study. We got results that were quite encouraging. As you know, lorazodone was originally approved on a 3.9 point difference between lorazodone placebo, and yet we beat lorazodone, a known good drug, by 7.7 points. Pretty impressive effect. Remember, Ovelity just got approved on a 4 point difference between and placebo, and we didn't go against placebo because it wouldn't be appropriate to do that in suicidal patients. We went against the best available standard of care drug. So that's how we got into this, and that's why we got the breakthrough therapy designation. Along the way, we said, well, what if NRX-101 is actually good enough to be a benefit to patients without prior use of ketamine. And we asked that question just as we were getting back into psychiatry a year ago, where we had just enough of our old phase II material to do a smallish study like this. We said, let's test NRX-101 against lorazodone without prior ketamine and see if there's a signal, see if it's not futile. And that's where we are at this point. And, you know, based on having reached that point and based on having now the availability of newly manufactured, you know, phase three and potentially commercial scale drugs, we're enlarging this to a registration study because we now believe that there's a real potential for this, you know, home use oral pill, actually capsule, to be effective in its own right, not just as a drug to take after ketamine.
spk07: So that's how we got to where we are. Makes perfect sense. And the last question, and you just kind of touched on it also, was breakthrough designation. Is that something that you feel you've been encouraged to go after? Yes.
spk08: Well, we've been awarded breakthrough therapy designation for the original indication of NRX-101 to use after ketamine. And that gives us the ability, the important part of breakthrough therapy designation is it gives you a dedicated resource at FDA a program manager who is committed, if at all possible, to helping the drug get through the approval process. So we have that in place now. And the other key benefit of breakthrough therapy designation is it gives you the right to submit your new drug approval application on a rolling basis. So we've said by the end of the year, we're going to start submitting, we're going to submit the manufacturing data, the preclinical data, so that the whole file is reviewed by the time we finally have the efficacy data to submit. So those benefits of breaker therapy designation are already in place. I imagine that we may have a conversation with FDA when more data are available. about specifically extending the breakthrough designation to this use of NRX 101, but I'm not sure that that would really change our path to approval in any meaningful way.
spk07: Perfect. Thank you. And that answer actually answers some of my timeline questions. So really the only critical hurdle for you is going to be, if I'm right, is just patient enrollment and then data analysis once you've completed treating the last patient, right?
spk08: Patient enrollment, data analysis, and we announced after the type B meeting with FDA that they want to see a safety database of 1,500 patients. Now, if you look at recent approvals, approvals actually happened at a smaller safety database than that, but 1,500 is the E1 database. treaty target. The United States and other countries all sort of agreed on the safety database size for drugs to treat non-lethal conditions. This, of course, is a lethal condition. And you've seen us talk about how we're going to start building that safety database not only through our clinical trials, which take a while to enroll and are expensive to enroll, but but also through an expanded access program that would allow doctors who have patients with bipolar depression and have exhausted approved medications for the treatment of bipolar depression to gain access to NRX 101. And there's, you know, a fair amount of precedent for the use of such expanded access programs in this way. So to the extent that people imagine the safety database will be horribly, horribly expensive, recognize that when we did expanded access in COVID, it was on the order of $3,000, $4,000 a patient as opposed to the kind of costs one would associate with a formal randomized control trial. Now, we don't know what expanded access is going to cost us in NRX 101 yet. We don't know whether we're going to be able to gain reimbursement for expanded access, which, you know, if you look in the FDA guidance, can be applied for. But we do see it as an efficient way to get to the NDA while at the same time continuing our clinical trials for safety and efficacy full speed ahead. Thank you, Jim.
spk07: Thank you.
spk01: The next question comes from Bernardino from HC Wainwright. Please go ahead.
spk04: Hi, everyone. Congratulations on the progress, and thanks for taking my question. Hey, Jonathan, Steve, and Seth. What is important for me to perhaps ask about is with the current trial being upgraded to a phase 2B3 study that may be used for registrational filing, with the nuances of this patient population and how they're treated, are there any specific changes that are going to occur or need to occur such that it has been upgraded to a registration study, or is it just merely an upgrade because that's something that you've asked for and you've already fulfilled the requirement?
spk08: Well, one of the things we did is posted the protocol on clinicaltrials.gov, and that's an important thing to do because when and we certainly hope the trial will show efficacy, the reviewers for the scientific journals want to see that we were transparent upfront about what are our endpoints, how are we measuring them, so that to the extent that there are changes along the way, you know, those are known in a transparent manner. The main difference for us between simply phase two and phase 2B3, is, as I said to Jason, when we started this, all we had in our warehouse was Phase II investigational medicine that was made five years ago in China during our partnership with Wuxi Aptec. And that's not investigational product that can be used for registrational purposes. Registration study means that you're doing your clinical trial with medicine that is essentially identical to the medicine that you intend to put on the shelf of the pharmacy. So we're now at that point where we did the hard work to do the tech transfer, to bring the analytic methods over from China to North Carolina and validate those methods. We've upgraded our control of impurities from a phase 2 level to a phase 3 level. So now that we actually have medicine that we believe is substantially identical to the medicine that we would hope to put on a pharmacy shelf in a couple of years, we're able to make this a phase 2B3 registrational trial. So that's not really a protocol change per se. And I think often investors don't realize how these days in biotech, failures in manufacturing and CMC are possibly more likely to bring down a promising drug than failures in an efficacy trial. And that's why we're so fortunate to have Dr. Panaguchi who is one of the world's more experienced drug manufacturing experts, is our chief technology officer.
spk04: Okay. And that's certainly important because conceivably, if it's a study that's very successful, you could also, and I say conceivably, use that phase three material for commercial supply I guess what I was specifically getting at is, is there going to be any change to perhaps the screening of patients such that it fine-tunes those that would enter a phase three level type of a study that is registrational?
spk08: Well, one of the things that we're intensely focused on is ensuring that that the psychometric ratings achieved in this study are as accurate as possible. There's been a lot of talk in this psychiatry space about study sites that yield surprising results and getting on top of study sites. And one of the things we've done that we think is a little different from what some have done is we've built a team of expert psychometric raters within the company who are evaluating in real time the ratings that are being achieved at the study site. So they get an audio recording of each rating session as it happens, and we're constantly looking at concordance between people who are being rated by the site rater on the Madras score, on the CGI suicidality scale, and those same sessions being evaluated by our in-house master raters, and we've set up an adjudication system so that if there's more than three points of disagreement, that rating session immediately goes out to an independent adjudicator. If you look on clinicaltrials.gov, we've published some of our information about how we do that. And I think in the coming months, we're going to hope to get a scientific publication out that will give the investment community some sense of how we approach this whole process of trying to keep a clinical trial under control where you don't win or lose based on a blood test. or examining a piece of tissue. You win or lose based on what's inherently a subjective process where an expert psychologist is asking structured questions and assigning a score. And keeping the drift between study sites down as low as possible is the difference between having a very high standard deviation and a great deal of difficulty in proving statistical significance versus having a tighter standard deviation and an easier ability to prove statistical significance. So, you know, that's where we're focusing every day as we try to do our job to bring this medicine to market.
spk04: Perfect. That's helpful information. And Because of the placebo effect, as you know, and the problems with that in these kind of studies, that's why I asked the question. Because, you know, unfortunately, sometimes it's impossible to know if somebody's suicidal unless they actually attempt, you know, suicide. But in the screening process, you can fine-tune the, like you said, the psychometrics as well as possible and, you know, increase the chances for success. I appreciate you providing that additional information and wish you the best of luck for the study. Thanks for taking my question. And you just said something very important.
spk08: You know, and it's one of the early things that FDA guided us on when we first met with them. You know, it's pretty well known that suicidality comes and goes. And it may not be something that patients talk about as readily as symptoms of depression. So the guidance we got from FDA early on, because our original thought was that our primary indication would be the suicidality score, the guidance we got from FDA was to make the primary endpoint for our studies the Madras Depression Scale. And the exact words we got were, look, if you... if you're able to prove that you improve depression in this population of patients who have suicidality, who've been excluded from previous trials, where there's no antidepressant that's indicated for use, no oral antidepressant, because there's been some encouraging data with Johnson & Johnson's esketamine product, but there's no oral antidepressant that's indicated for use in these patients with suicidality, that's great. That's enough to win. And, you know, if at the same time we're able to show that the secondary endpoint of improvement on the CGI suicidality scale is also significantly better than the comparator drug, well, you know, that's even better. But that's why our primary endpoint is the mattress depression scale.
spk04: Thank you, I appreciate that. And I am very hopeful for you and the patients out there. Thanks again for taking my question. Thank you, Bernard.
spk01: As a reminder, if you have a question, please press star one. The next question comes from Ed Wu of Essendian Capital. Please go ahead.
spk05: Congratulations on the progress and also on the DSMB readout. Do we anticipate any more readouts or any interim data for either one of your studies this year?
spk08: We do expect that the DSMB is going to look at the data again at some point. I would guess before the end of Q3, but they haven't told us exactly yet. when that readout is going to be. But they're going to be monitoring the study in an ongoing way to the extent that if safety signals emerge, they might look sooner. But they're working with us very closely because this is a population of patients who are actively at risk of self-harm, which is why they've been excluded from trials of ordinary antidepressants.
spk05: Great. Well, thanks for answering my questions, and I wish you guys good luck. Thank you. Thank you.
spk01: This concludes our question and answer session. I would like to turn the conference back over to Suzanne Messery for closing remarks.
spk02: Thank you, Danielle, and thank you, everyone, for participating. That is all the time we have for questions. Thank you again. This concludes the NRX Pharmaceuticals Full Year 2022 Results Conference Call.
spk01: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
Disclaimer