Mike: Hello everyone. I’m Mike Ward and welcome to Conversations in Healthcare, a video series brought to you by DRG, part of Clarivate. This is an opportunity for us to hear first hand, the challenges and opportunities facing the healthcare industry, and how business leaders are actually managing those particular challenges, particularly when events like the COVID-19 pandemic are unleashed.
In line with this, I’m delighted to be joined by Jonathan Javitt. He’s the Founder, the Chairman, and CEO of NeuroRx, a private biotech company that’s based in Radnor, Pennsylvania. They, at the moment, have a lead program which is currently in phase three trials, and it’s targeting suicidal bipolar depression.
Earlier this year, in response to the COVID-19 pandemic, NeuroRx in collaboration with Relief Therapeutics, started investigating the potential of Aviptadil, to treat patients with COVID-19 related respiratory failure. Jonathan, I hope you and those you care about are keeping well, and thanks so much for joining us.
Jonathan: Well, thank you. It’s really a pleasure to talk to you today.
Mike: Before we look at what your company has actually been doing specifically to combat COVID-19, it would be useful for us to get some background, understanding the core business model of the company.
Jonathan: We’re a small group of scientists who came together, around the realization that the pharmaceutical industry wasn’t doing nearly enough to develop drugs for patients with suicidal depression. Those are the patients nobody wants, patients who are mildly depressed, who are going to be on antidepressant medications for the rest of their lives. Those patients are highly attracted to the pharmaceutical industry, but these people who get acutely depressed, who have a high risk of harming themselves, nobody wants to touch them.
It happens that my younger, smarter, better looking brother, made a series of extraordinary discoveries, around the molecular basis of suicidal depression, suicidal ideation, that have now become mainstream. But when we started the company, they were not at all mainstream. All around the role of the NMDA receptor, in blocking suicidal depression, suicidal ideation, and that’s really why we started the company.
Mike: How did you choose the programs or the approach that you’ve taken, because in fact, it is of some molecules that have already been approved in different indications.
Jonathan: All of this came from Danes Abbott’s discoveries, patented discoveries, around the role of the NMDA receptor in the brain, and the effect of blocking the NMDA receptor, on rapidly reducing suicidal thoughts. It really began from a drug screening perspective, looking for molecules that would block the glycine site on the NMDA receptor, and lo and behold, one of those molecules happened to be an old tuberculosis drug.
Mike: All right.
Jonathan: It had nothing to do with looking at a drug and saying, what other things could we use this drug for? It had to do with looking at a molecular target and saying what things block this target.
Mike: Right. What does that involve? Does that involve then doing a literature search to actually look at other molecules that could interact with that mechanism?
Jonathan: It starts with a literature search, to give you a broad list of candidates. In the case of neuro psychiatry, there’s not really any high throughput screening that’s very effective. Most of the screening work is done literally in mice, because mice exhibit certain behaviors that can very readily be measured. [Text Wrapping Break][Text Wrapping Break]For instance, if you put a mouse in a beaker of water, it’ll start swimming and then it’ll give up. Drugs that have an effect on human depression are well known to increase the amount of time the mouse keeps swimming. It’s called the forced swim test. Sounds like a fairly crude thing. It actually works quite well. The screening that you do for neuropsychiatry drugs tends to be a small animal based screening and not molecular screening, but hopefully that’ll change for the next few years.
Mike: All right. Beyond the screening, what are the other challenges, when you’re taking, say your existing molecules that have been demonstrated to have activity in other indications? What are the other challenges that are associated with then developing that, say for example, for a new indication?
Jonathan: Well, then once you’ve got strong candidates, it’s a matter of dealing with FDA, making sure that you’ve got sufficient safety and toxicity data to satisfy FDA, that this molecule should be allowed into the clinic, convincing investors that the molecule has a decent enough chance of succeeding, to be worth the financial risk.
Mike: Yes. Is it easy to secure intellectual property?
Jonathan: No, it’s quite difficult, but we’re excited that we’ve been awarded composition of matter patent, because we convinced the patent examiner that that’s really was a novel invention.
Mike: Right, right. Okay. Yes, I mean, because obviously, that’s I guess the key issue around a patent. It has to be a novelty. Where are you actually in the development of the NRX 101?
Jonathan: That molecule has breakthrough therapy designation, it’s in phase three clinical trial under a special protocol agreement. We had to pause the clinical trial in March, because the pandemic was so disruptive, that we couldn’t get patients in and out of the clinic in a reliable way.
Mike: Were you fully enrolled on the trial?
Jonathan: Yes.
Mike: What impact does that actually have on the veracity of the trial, the fact that you’ve had to pause it?
Jonathan: It has no impact on the veracity of the trial, but it certainly has an impact on the timeline of the trial.
Mike: Right, right. Do you have any indication when you might be able to?
Jonathan: Every time we think the pandemic is slowing down, it fools us.
Mike: Right. You mentioned the pandemic, can you give us some background of how you came to identify Aviptadil as a potential in the treatment of COVID-19?
Jonathan: Sure. One of our investors approached us right at the beginning of March, and said, we have this molecule that’s been sitting on the shelf for 10 years. One of our scientists thinks that it may have something to do with COVID, would you look at it? We looked at the data, they certainly didn’t have any data on COVID, but what they had was 20-year old data showing that this molecule vasoactive intestinal peptide, and the only difference between Aviptadil and VIP is that, VIP is a natural 28 amino acid peptide, whereas, Aviptadil is a synthetically synthesized manmade version of that same peptide.
Data going back 20 years showing that this peptide had a very profound effect in the treatment of acute respiratory distress syndrome in the ICU. The notion was that, perhaps it might have a similar role in treating COVID-19 patients on ventilators. So we began looking at it. We became convinced that it was really worth a try. We approached FDA and within 48 hours, FDA had given us permission to take this into the clinic and treat patients. Within 10 weeks, we had successfully formulated the drug, proven its stability, proven that it was sterile, proven that it was potent, and treated our first patient 10 weeks after we first approached FDA.
Mike: How does it work?
Jonathan: Well, sometimes the picture is worth a thousand words, and I brought you a picture, because it is a slightly complicated story. It’s really all about the lung. If the SARS COV-2 virus, the virus that causes COVID, didn’t invade the lung, it would be nothing worse than a bag coal, because it doesn’t really cause much in the way of other symptoms in the body, except sometimes a fever. But if it gets down into the little air SACS of the lung, then all of the trouble starts. It’s really only a very specific cell in the lung. This alveolar type two cell, that is susceptible to the COVID infection.
The problem is, that alveolar two cell has a specific receptor on its surface, like a lock fitting a key. The virus sees that receptor, binds to it, and the next thing you know, the virus is inside the cell, making millions of copies of itself, but even worse, it destroys the surfactant fluid that coats the lung, and without that fluid, the lung can’t transmit oxygen. Well, VIP has been shown in hundreds of scientific papers to bind to that same vulnerable cell, to bind to the alveolar two via its own special receptor. Once it gets into the cell, it blocks the replication of the coronavirus. It blocks the formation of inflammatory cytokines. It blocks the cell death that’s caused by the virus. It’s really a guided missile against the damage caused by COVID-19.
Mike: All right. But VIP though, it’s not just related to the lung, is it? I mean, it exists elsewhere in the body.
Jonathan: It does exist all over the body, and it has some interesting roles. It happens to be a vasodilator. It’s been used for erectile dysfunction, which has nothing to do with its binding to the alveolar II cell in the lung. But it turns out that 70% of the VIP in the body is in the lung, and this peptide is what protects the human lung against all sorts of attack. The reason you can inhale smoke when your house is on fire, you inhale a bunch of smoke, you’ve got a serious smoke induced lung injury. The reason you can heal from that injury and not die is because of VIP.
Human beings occasionally inhale stomach contents, because they vomited and aspirated. Stomach acid has a pH of about two. It would wipe out the lung epithelium except for the protective role of VIP. VIP is shown to have a role in protecting the lung against various viruses. In fact, there’s some very intriguing data that came out of Brazil showing that people who survived critical COVID-19 infection have twice the amount of VIP floating around in their blood as people who died. Even though VIP has other roles in the body, it’s really very heavily focused on the lung.
Mike: All right. It’s almost like a potential biomarker for how likely a patient is going to progress, if they end up on ventilation in an ICU.
Jonathan: Yes. You could actually do a serum VIP level on the way in the door and know a lot.
Mike: Right, right. Okay. The fact that the VIP does have effects elsewhere in the body, does that create any challenge around potential off target reactions?
Jonathan: Yes, it certainly does. If you look on our information on the internet or on our pharmacy manual, intravenously delivered VIP causes diarrhea, so intensive care units that are using this intravenously have to be alert for that. It can cause a drop in blood pressure, and doctors who are treating critically ill patients need to be ready for that. There are various medicines called pressors that raise blood pressure.
VIP, when it’s inhaled is much less likely to have off target effects. There really been, in hundreds of people who have been given an inhaled VIP for various reasons, severe diarrhea doesn’t happen, and drops in blood pressure tend not to happen. It’s a very different drug because when you inhale something like this, it’s really only going to the lung.
Mike: What progress have you made so far, and what are the timelines for future milestones?
Jonathan: Well, as I said, it took us 10 weeks to get from FDA’s permission to treat the first patient, that was May 15th. It’s now September 15th. Our data monitoring committee is about to take a look at the first unblinded data. They may tell us there’s a safety problem. Although, we haven’t seen any sign of one, and they previously told us they didn’t either. Or they may tell us that in fact, they see some signs, encouraging signs, towards efficacy.
Meanwhile, we’ve just taken a look at the first 21 patients in our open label study, patients who are too sick to be in the phase three trial. They were transplant patients. They were patients who had cancer and were on immunosuppressive drugs. They were patients who’ve had recent heart attacks, and we compared them to 30 similar patients, with the same level of acuity in critical COVID-19, and lo and behold, there was a huge difference in survival. 90% of the people who got our drugs survived, only 27% of the control patients survived. We saw large differences in blood oxygen, large differences in chest X rays getting better. Even though you never know whether case control results will translate into randomized control trial results, when you see an effect this large, you can certainly be encouraged.
Mike: What plans do you have if the trials are successful, and demonstrate the results that you’re hoping to see? What’s the plan to get, how are you going to get this into patients?
Jonathan: Well, we’ve established a manufacturing partnership with the largest manufacturer of inhaled sterile products in the United States. We’ve established a distribution partner with the largest distributor of drugs in the United States. Really, as soon as the FDA gives us the green light, we’re able to bring this nationwide.
Mike: All right. You’ve got the manufacturing capacity and the delivery. Will it have a NeuroRx label on it, or are you looking for a partner to get this drug?
Jonathan: Well, we’re always open to partnership, but the reality is large pharmaceutical partners take, really two years to spin up a drug. We have people who need this drug today.
Mike: What about outside the US? Are there plans to–
Jonathan: We’re talking to all sorts of partners, and I’m sure as the data come along, partners will emerge.
Mike: Reflecting on what has actually happened this year, as a CEO, what are you now doing differently, that’s helping you manage both the disruption around the pandemic, but also thinking about actually how the company might look differently going forward?
Jonathan: Well, we’ve all stopped going to the office. I’ve stopped traveling, and it’s amazing how much of my life was consumed with traveling and business dinners, and things that were not actually driving the mission forward. I’m not entirely sure why we will go back to the way we used to do things. That travel budget was probably a very nice executive salary.
Mike: Yes.
Jonathan: I don’t think we could have done things at the pace we’ve done things, if we did them the old fashioned way.
Mike: Well, I mean, you mentioned the fact that, the speed that you’re able to get through with the regulators. Do you think that that is something that going forward will be something that we’ll be able to retain?
Jonathan: I’m not sure that regulators will work in crisis mode once the crisis has passed. I think I’m going to treasure the 2:00 AM emails I’ve gotten from people at FDA, because I don’t think I’m ever going to see that happen again. But we’ve all learned to do things new ways, and I think that that’s going to create a permanent change in the way we think about doing business.
Mike: Jonathan, thanks very much for joining me today. The insights that you’ve been sharing are really important. I think the work you’re doing, I think we’re all pretty excited by the results that you’ve already shared with us, and the potential of those programs. Definitely good luck with that.
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In closing, I’d like to say Jonathan again, for taking the time to join with us today. I also like to thank all our listeners for tuning in. Until next time, stay safe and healthy. I’m Mike Ward, and I’ll see you in the next episode.
