NeuroPerspectives Conference. With us today is Dr. Jonathan Javitt, Founder, CEO, and Chief Scientific Officer of NRx Pharmaceuticals. NRx Pharmaceuticals is a company specializing in developing treatments for central nervous system disorders, specifically suicidal, bipolar depression, chronic pain, and PTSD. Their lead program is NRX-101, an oral fixed-dose combination of D-cycloserine and lurasidone. This targets the brain's NMDA receptor, and it's being investigated in a Phase II, Phase III clinical trial for suicidal treatment-resistant bipolar depression. Welcome, Jonathan. Thank you, Vern. How are you? Good, good. I was wondering if you could just give us a little bit of background on NRX-101 and the specific lead indication that it's being investigated for? Well, let me talk a bit about how we got to here, because here has become pretty interesting for us. So, 1987, Dan Javitt, my younger, smarter, better-looking brother, discovered the role of the NMDA receptor in the brain and its effect on schizophrenia, because drugs that completely block the NMDA receptor actually cause psychosis. So, it became a model for experimental psychosis. Fast forward to 2000, Rob Berman at Yale discovers that ketamine, a potent NMDA receptor, is an extraordinarily potent antidepressant. And that's when we realized for the first time that drugs that block NMDA have a potent effect on depression. Now, it really wasn't the first discovery, because back in 1959, a guy named George Crane, treating tuberculosis patients in the Bronx, noticed that a drug called D-cycloserine was an antidepressant. The problem was, in 1959, nobody had ever heard of NMDA, much less understood that D-cycloserine was an NMDA-blocking drug. So, Crane's work was lost. So, the ball really started rolling in 2000 with Robert Berman. And about seven years later, people in Carlos Zarate's lab at NIH showed that not only do these drugs block depression, but they really turn off suicidal ideation. And suicide and depression are not the same thing. They're related, for sure. But suicidal ideation is a different symptom construct than depression. So, by 2007, we knew that NMDA-blocking drugs, especially ketamine, were potent antidepressants. And unlike all of the known antidepressants at the time, unlike all of the SSRIs, instead of increasing the risk of suicide, they actually turn off suicidal ideation. Now, it's taken from 2007, from those initial discoveries until now, for ketamine to become mainstream. You've got the approval of the Johnson & Johnson drugs, Spravato. And now we're going to FDA with 900 patients' worth of data showing that ketamine is not only a potent antidepressant, but turns off suicidal ideation. Now, the problem with ketamine, the good side is it works within hours. The bad side is that if you use too much of it, it's addictive, it's hallucinogenic, and it's neurotoxic. It kills brain cells. And FDA has been saying in public meetings that they're worried about this. So, we see ketamine, which is a drug that we are taking to market, as a drug that will be used for short-term treatment of acute suicidality and severe depression. Meanwhile, the oral drug you talked about, NRX-101, has just shown in a clinical trial that it's as good an antidepressant as a standard-of-care drug. Not a better antidepressant than the standard-of-care drug, but as good as the standard-of-care drug. However, all of the standard-of-care drugs have a suicide warning on the label. All of the standard-of-care drugs increase a side effect called akathisia. Akathisia is this horrible, irresistible need to move. People say they feel like they're jumping out of their skin. One story that has not only been told, but it's been told both in the media and in a courtroom, is about a Chicago attorney named Dolin who came home from the doctor having taken Paxil and couldn't stop tapping his foot under the table. His family kept saying, "Why are you tapping your foot under the table?" He didn't know. He couldn't stop. The next day, he threw himself in front of a train. That's the story of akathisia. And that was the famous lawsuit against Mylan that resulted not only in a large settlement, but resulted in a foundation that has dedicated its life to telling people the story of akathisia and trying to find drugs that stop it. Well, we have the first antidepressant that stops akathisia. In case you were wondering whether I was going to get to the point, I'm now at the point. We've just shown in a well-controlled trial that compared to the standard-of-care drug, compared to lurasidone, with the standard-of-care drug, akathisia increases, and with our drug, it decreases. It's like one line's going up, one line's going down. You don't need statistics to see that those lines are different. Yes, they were certainly impressive. Those were results that were announced. The final results were announced in May. Now, to step back a little bit, just wondering if you could talk about the FDA's thoughts on this space. Then also perhaps describe the case that is special, in my opinion, that involves NRx and alignment with a registrational trial that could get the drug commercially approved and licensed. So, when you say FDA's thoughts, FDA is well aware of the side effects of this class of drug. It's right there on the label. And they have a strong history of approving drugs that match the effectiveness of the standard-of-care, but decrease side effects. So, there's ample regulatory precedent. Now, our plan actually is we think that we have sufficient data to ask for accelerated approval for the narrower market of people who have akathisia on these standard-of-care drugs, because there's about three million people, 10%-15% of whom get akathisia. And it's a lethal side effect. It's a side effect that's known to result in suicide. So, we believe that there's a basis to ask FDA, with the data we have, to treat that narrow group of people while we do a larger-scale trial that replicates the finding that we just saw. I think the question you're asking me is, what do we need to prove to get our drug approved? Yes. The best counsel we've gotten so far says that we need to prove what we've just shown. We've now shown it for the second time. We did a phase II, phase III trial of the Stabil- B, and we showed a decrease in suicidality. The decrease in akathisia was equally large, but because the sample size was smaller, it had a p-value of 0.11 instead of a p-value of 0.05. This time, we hit 0.03. So, if we do a registrational trial of this drug against placebo, we think we're almost certain to win, because this drug has demonstrated its effectiveness several times in several trials. We didn't beat placebo in this trial because there was no placebo. We went up against the standard-of-care drug. We showed that we're as good as the standard-of-care drug on depression and way better, not only on akathisia, but on time to remission from suicidality. No oral antidepressant has ever shown an improved time to remission from suicidality. Now, with the idea that this is likely that more specific patient population, how large a study do you anticipate a registrational trial will need to be? Well, FDA's going to want exposure on somewhere between 300-500 patients in order to approve it. So, yeah, we could get efficacy with a smaller number of patients. But at a certain point, if you're going to say to FDA, "We want to treat 100,000-200,000 people," they have some ability to be lenient on numbers. But if you say, "We want to introduce a drug that could potentially be used by three million people," they're going to say, "Well, we have these ICH guidelines. They're cast in stone. You've got to show us efficacy data on somewhere around 500 people. You've got to show us exposure data on somewhere around 1,500 people." And those are international guidelines. I assume, should you get approval for that narrow patient population, you will likely conduct a study in the larger patient population? Of course. Or do you not need to? Yeah. I mean, if anybody who wants to be able to treat two million people, it's going to have to come in with sufficiently large clinical trials to convince the FDA and the medical community that we know what this drug does, because once you turn a drug like that loose, a lot of people are going to be exposed to the drug. Yes. Now, one interesting facet of this drug's development, NRX-101, is a collaboration with an Asia-Pacific partner called Lotus Pharma. Can you provide us some details on what that relationship is trying to do and what are our expectations as far as the future is concerned? Well, yeah, as you've mentioned, we have this collaboration with a U.S.-focused company, Alvogen, and Lotus. They have the first option to take this drug forward into clinical trials. We're waiting to see whether they exercise that option or not. In advance of having done so, they've invested in the drug and in getting it to the point where it's at. If they do choose to move forward, they'd be an enormously strong partner. When they took a risk on the drug, nobody really knew what it would do. Now we know. We know that we've got the first oral antidepressant that has shown a statistically significant benefit on suicidality when every antidepressant has a suicide warning on the label. We have the first oral antidepressant in history to show a reduction of akathisia, which is the worst side effect of every one of these antidepressants. Now, what are the economics of this collaboration, and how much have they provided as far as funds so far? So, they've put in an initial $5.1 million commitment, which was enormously helpful to us, because quite frankly, at the time we got into this, you haven't seen a lot of people wanting to take risk on this segment of patients with bipolar depression. In fact, there are only a couple of drugs, lurasidone, quetiapine, olanzapine, cariprazine, that are approved for treating bipolar depression. Well, that's a secondary indication for them. They were all initially approved as atypical antipsychotics. So, the pharmaceutical industry has not historically been willing to invest in this space, even though seven million people have this disease. And what's worse is it's a lethal disease. If you know two people with bipolar depression, one of them is going to attempt suicide. If you know five people with bipolar depression, the chances are one of them is going to die from suicide. It's a more lethal disease than breast cancer, than prostate cancer, and nobody's working on it. That's actually how we started working on it. Now, I have to. In the space because it was easy. Now, I have to check my bottle, of course. But what do you anticipate such a therapy would cost once it gets on the market? So, we've done a fair amount of payer research. The payers have said to us, given the risk that these patients are at, the payers have said to us that as long as the price is under $10,000 per patient per year, we're not going to see a lot of formulary restrictions. That's what they've said. Will they actually do that in practice? Who knows? They didn't say it to us. They said it to professional researchers that we hired. They tend to give, as you know, they tend to give pretty pessimistic answers when professional researchers call them and ask them questions. Were we to capture one million of the seven million patients with bipolar depression? Were they to decide that our drug offers benefits over the other drugs on the market? You're potentially talking about a $7 billion drug. Yeah. Are we going to do that? No. Quite frankly, for a company like ours, if we had $100 million in the first year of launch, you and every other analyst on the street would think we were heroes. But the opportunity out there is extraordinary. Yeah, it certainly would. Now, what are the next things we'll hear now that you have final clinical results as far as the program and potential registrational trial? Well, the next thing you're going to hear is you're going to hear us filing for approval on ketamine. Okay. Because it needs to be done. But I mean NRX-101. Well, but remember, there's $800 million of nasal ketamine being sold in the United States. So, again, if we sell $100 million of ketamine in 2025, you're going to think we're heroes. And you're not going to complain that we did it with ketamine and not with NRx 101. So, the next thing you're going to hear from us is a new drug approval for ketamine. And people keep saying, "Well, why hasn't the FDA approved ketamine?" Well, the answer is simple. Nobody's applied. And FDA doesn't have a habit of approving drugs in the absence of a New Drug Application. And why has nobody applied? Nobody's applied because in order to apply to get a drug approved, you have to have a drug in your hands. People keep forgetting that. And we've gotten some nasty comments from short sellers on the internet. Why do they keep telling us about manufacturing data? Well, we keep telling people about manufacturing data because in order to file our ketamine NDA, we've got to have 3 manufactured lots, and we've got to have 12 months of stability. Because if we don't have that, the psychiatry division of FDA won't even get to look at our drug because the manufacturing division will refuse it. So, that's what we've been focused on. Lot number 1 made it to 9 months of stability this month. Lots 2 and 3 just made it past the initial quality checks. And not only is it going to be the first new formulation of ketamine since the Korean War, it's going to be the first unpreserved formulation of ketamine. Well, you might say, "Well, why does that matter?" That sounds like kind of inside baseball. Well, take a look at the neurotoxicity data on ketamine. Take a look at the fact that this big bottle of ketamine that everybody's using to treat people is associated with clear evidence of neurotoxicity on repeated dosing. And then take a look at the fact that that label says it contains benzethonium chloride. There's more than ketamine in that bottle. Inside that bottle is a very toxic preservative, benzethonium chloride. Go Google on it. So, our formulation, as far as we know, is going to be the first preservative-free formulation of ketamine, which we think is going to be a lot safer for patients. So, you're going to keep hearing about that, and you're going to see us file a New Drug Application in the fall. Meanwhile, we're going to finish the manufacturing file, the Module 3 for NRX-101, because again, you can't file a new drug application until you've got all the manufacturing data in your hands. More drugs fail in biotech on manufacturing than on efficacy. So, we're going to get that manufacturing file nailed down by September. And then you're going to see us file an application for accelerated approval in that narrow population of patients who have akathisia on existing drugs, who have nowhere else to go short of electroshock therapy. And we hope that given the urgent medical need and the fact that nobody's ever shown an ability to control this lethal side effect, we hope that FDA will give us an interim way to treat this extraordinarily needy group of patients while we do the larger trials aiming at the 7 million person population. I do want to ask you about the whole therapeutics aspect of NRX-100, i.e., ketamine. But also to round out the discussion on NRX-101, I was wondering if you could talk a little bit about Qualified Infectious Disease Product designation for NRX-101, fast track approval, and the opportunity and plans in evaluating NRX-101 and complicated urinary tract infections and other infectious diseases. Thank you for that. People have called us crazy because whoever heard of a psychiatry drug that happens to be a urinary antibiotic. Yeah. But sometimes nature has a sense of humor. And in this case, the D-cycloserine molecule is a small molecule. If you're a brain cell, the D-cycloserine binds to the NMDA receptor in your brain cell, and I've already explained what NMDA inhibition does. If you happen to be a bacteria, instead of looking like glycine, which is what brain cells see D-cycloserine and says, "Oh, that looks like glycine. It's going to bind to my glycine site." It's like a lock and a key. But instead of looking like glycine, D-cycloserine looks like a different amino acid called alanine. And alanine is not all that important to human beings, but it's incredibly important to bacteria because it is essential to the cell wall that prevents bacteria from blowing up from osmotic damage. So, if the bacterium incorporates D-cycloserine instead of alanine in its cell wall, that bacteria explodes from osmotic damage. That means osmotic damage is a fancy word for the cell swells up with water because the cell wall wasn't working properly, and it bursts. So, D-cycloserine is a very interesting antibiotic just in that regard because it works by a completely different mechanism from the penicillins and the cephalosporins and all of the beta-lactam sorts of antibiotics which work inside the cell. This one specifically works by blowing up the cell wall, and therefore it's compatible with all of those antibiotics. But it's also interesting because it's the only antibiotic that is 100% concentrated in the urine. Doesn't have any effect at all on the liver. It goes straight out through the kidneys, straight into the urinary tract. So, you actually get very high levels of this antibiotic in the urinary tract. And you may say, "Well, why do we care about that? There's 1 million antibiotics for urinary tract infections." Well, yeah, there are, but we're losing the fight. So, 15 million people a year get urinary tract infections, and four-fifths of them do very well on conventional drugs. You hear someone say, "Oh, yeah, I got a urinary tract infection. Doctor gave me a prescription. I got Bactrim. I got ampicillin, and I'm better today." That's true for 12 million of the 15 million people who get urinary tract infections. And maybe I'm oversimplifying. They may need a third or a fourth generation drug, but they'll do pretty well. Then you've got three million people a year who get something called complicated UTI, resistant organisms. And that's a terrible disease. Yeah. Because you wind up in the hospital on IV antibiotics, or you wind up on one or two really potent oral antibiotics. One of the things those antibiotics do is they cause a side effect of wiping out the normal bacteria in your intestine called the bacteria flora. That's just a fancy word for the normal bacteria that live in your intestine every day. When you're wiping out the bacteria flora, you get a horrible secondary infection called C. difficile. People call it C. diff. Yeah. Sure, we know that a healthy gut microbiome is certainly important for a lot of metabolic functions. Now, what is the next thing we want to hear as far as? Well, a healthy microbiome is important for metabolic functions. But if you get C. diff, you're going to be in the hospital with the worst diarrhea you ever imagined for 2 to 3 weeks. And if you're over the age of 65, you're going to have a 10% chance of dying of C. diff. So, yeah, you start out with a urinary tract infection, and you wind up dead. So, you asked about QIDP. QIDP, Qualified Infectious Disease Product, is a special program that Congress set up with FDA where if you can come in the door with a drug that is shown to kill the bacteria on the congressional list, and we've shown our ability to kill three of them, then you automatically get fast track. You automatically get priority review. And the FDA is open arms for your drug. Okay, terrific. So, moving on, we're running short on time. And so, therefore, just wondering if you could describe a little bit about your plans with HOPE Therapeutics and IV ketamine? So, HOPE Therapeutics is really set up to help get IV ketamine to the world. And we haven't announced the exact funding mechanism, but we've said that we're going to be directly involved in delivering care. And we've said to our shareholders that we expect to be a cash flow positive company in 2025. And that's a function not only of the possibility that ketamine may get approved, but a function of the fact that on the ketamine side, we're going to be in the delivery business. We have active conversations with people who are capable of delivering sufficient capital to roll up $50 million or $100 million of ketamine clinics into an organization that stands for something, into an organization that has a common purpose, that has a common brand, and has a common way of helping patients with suicidal depression. Because today, assuming you don't just go off and try to do something horrible to yourself, your best option is to go to the hospital emergency room. All of a sudden, you're under a 72-hour hold, and there's a security guard standing outside your door, and there's a good chance they're going to try to put you into an inpatient facility. We intend to build a network of care that will really be the first opportunity for people with suicidal depression to get compassionate, effective, and lifesaving care. We're not saying that nobody's doing that right now. People certainly are. Some of them have already expressed interest in being part of our first wave of acquisitions. But what we are saying is that there's not a nationwide model for doing this. There's not a branded organization that people trust the way people who need dialysis trust DaVita. The way people who need a hamburger trust McDonald’s. We intend to build that network of trust. Okay. So, in closing here, so as people may know, HOPE is planned to be spun out as a separate company by NRx to current shareholders and your shareholders. You've already seen prospective anchor investors for the new investment. And it is the plan that once, well, in advance of FDA approval, HOPE is going to actively create the sales force and be positioning itself to supply ketamine under a 503(b) pharmacy licensure, which should be a lower hurdle than regular. Well, quite frankly, that doesn't require FDA approval. Right. Ketamine is already an approved drug. Yeah. It's on drug shortage. So, what you've heard us say is that we're already able to supply ketamine in partnership with a 503(b) pharmacy who happens to be the same manufacturer that's manufacturing the drug we're taking to FDA. So, HOPE doesn't depend on an FDA approval for becoming a cash flow generating company. HOPE simply depends on good clinical execution. Now, if NRx is also able to get FDA approval on ketamine, then you're talking about a very different and very advantageous margin on that product because that helps with insurance reimbursement. So. You did say the word NRX-100. Yeah. When we talk about ketamine right now. We're running out of time, though. So, in closing, though, when do we anticipate HOPE being spun out? The audit on HOPE just got finished, and that was really the rate limiting step. You should expect to see more on the HOPE spin-out within really by the end of the month. Okay. Okay. I think that's all the time we have left. I just want to thank Dr. Jonathan Javitt for helping us to learn more about NRx Pharmaceuticals. Hopefully, you have learned a lot about the other companies we have at the fifth annual H.C. Wainwright NeuroPerspectives Conference. Jonathan, I want to thank you for providing us important insights. Looks like there's a lot of value drivers in the company still totally underappreciated and with the potential to be a cash flow positive company in 2025 from just one of its programs alone. I think this is a great opportunity and time for investment in NRx Pharmaceuticals. I want to thank you and our investors for attending this conference. Well, Vern, thank you and H.C. Wainwright for believing in us. We do. Looking forward to more news.