$RLFTF Javitt Transcribed... CEO Roundtable with Dr. Javitt on Sept 10, 2020
by Uncle Gee Gee
I've transcribed the video and found many little nuggets of detail worth reading through.
For your weekend enjoyment...
CEO Roundtable with Dr. Javitt on Sept 10, 2020
15:55 Write - Jonathan, how does a clinical stage small molecule company that’s develop CNS-oriented therapeutics get involved in treating respiratory failure in Covid-19? I just want to understand how that happens.
16:20 Javitt - Well you know it’s like one of those extraordinary accidents, but some people say chance favors the prepared mind. And believe it or not vasoactive intestinal peptide, which is the active ingredient we’re working with, is a neuro endocrine peptide. And we were originally thinking about this in the CNS context. Then one of our investors came along and said well we have this company over in Switzerland that’s been thinking about this from a Covid-19 perspective. And sure enough it turns out that when Professor Sammy Said, who spent his whole life developing this peptide, really understood what it did, even though it was first identified in the intestine, which is why it has this funny name, 70% of the VIP in the body is in the lung, and it seems to have one critical function in the lung, which is to protect the Type II Alveolar Cells. Most people never heard of the Type II Alveolar Cell. In fact when I was in medical school, I don’t even think we knew that there were Type I and Type II cells. But this rare cell (there’s only about 5% of all the cells that line the lung), is the cell that is critical where the flow of oxygen’s coming in to the blood stream. And it makes the surfactant that lines the lung. Without the surfactant, the lung can’t transmit oxygen. And this funny virus, this virus that humanity’s never really encountered before SARS came along, attacks that one cell. It’s almost like hitting a needle in a haystack. And it attacks that one cell because that one cell happens to have ACE II receptors on its surface. So those funny spikes you see on the virus, they bind right to that receptor just like a key fitting a lock and the cell says come on inside, and as soon as the virus is inside the cell, it starts to make millions of copies of itself, it starts to let inflammatory cytokines loose all over the body, it ruptures the cell and it shuts down surfactant production, so all of a sudden, people who don’t even look that sick, have no oxygen in the blood. They can’t walk from their bed to the bathroom without falling down on the floor.
And… what we learned, what we expected is this would be a potent anti-cytokine. We thought we’d do a great job at blocking cytokines, and a great job at increasing surfactant production. And then lo and behold, a group of people we never heard of, at the Oswaldo Cruz Institute in Rio de Janeiro, reached out to us and said, you know that molecule you’re working with… here’s the data that shows that it blocks the replication of the SARS virus in human lung cells. So it was (inaudible 19:13) for us. It was, now we see why we’re seeing extraordinarily rapid recovery in the clinic. When we went into the clinic with this drug, and we literally went from paper files (because nobody has used this drug in humans for 10 years), from paper files to freshly formulated drug, with a fresh FDA certificate of analysis in human beings, in 10 weeks. When we went into the clinic, we expected to see an anti-inflammatory effect. We expected to see some of the same effects that Dr. Said saw in 2005 when he used this drug against Acute Respiratory Distress Syndrome, caused by sepsis, where seven out of eight people walked out of the ICU alive, when you would expect at least five of them to have died. What we didn’t expect to see, was chest x-rays clearing in 3 and 4 days. We didn’t expect to see that some of the early results we reported, where uh, you know out of the first 21 patients we treated outside our clinical trial, they were too sick to get into our clinical trial, 11 of those people have done very well, and 19 out of those 21 people have survived 28 days, which is the cutoff that NIH generally uses, 28-day survival is a critical endpoint. So we’ve been very surprised by the magnitude of response we’ve seen in the open label studies, and now we’re about a month away from the first unblinded look at the Phase III randomized control data. So, you know, we’re wondering, are we seeing the world’s biggest placebo effect, or are we really on to something.
21:15 Write - Rob Write asked a question regarding the company’s core competency and whether there was any internal struggle about pivoting on their strategy.
21:45 Javitt - I think the thing that is core to our company we’re just not afraid of anything. And we’re especially not afraid to go to FDA and say please help us break the rules. I mean there was 10 weeks from paper files to drug in the clinic in patients. Well that’s never going to happen through traditional GMP manufacturing, through standing up a fill and finish manufacturer. Those people take 6 months just to get their machines tuned up. So we went to FDA and said: You’ve got this list of 50 formulating pharmacies that you say passed your inspection. These 50 tiny little pharmacies that you say are safe, you didn’t shut them down, you actually certified them as formulating pharmacies, how about we make this drug in one of those formulating pharmacies?
We’re literally making this drug by hand in order to be able to get it into a Phase III trial overnight. And FDA was willing to help us break those rules, or at least willing to waive those rules, and recognize that if we’re facing the worst public health crisis in the last 100 years, we’ve got to be willing to do things in new ways, otherwise, we’re just dinosaurs looking at that asteroid coming closer and closer.
23:09 Write - I’m curious Jonathan about the formulating pharmacies idea. That’s kind of uh just an interesting approach, and I imagine your also trying to figure out how to do the scale up as you’re doing it now and it well in advance so things can continue to progress. Can you tell us a little bit about where the idea came about?
23:24 Javitt – Oh we’re hahaha we’re not going to try that one twice. So we’ve actually just signed a contract with one of those fill and finish manufacturers that we’re hoping to announce very shortly, uh and they’re actually the largest manufacturer of sterile inhaled drug in the world. Although our clinical trials with intravenous drug, we’ve already announced the trail that we intend to start quite shortly with an inhaled version of this drug, for people not with critical Covid-19, not the people who were on ventilators that we’re treating right now, but people with earlier stage disease in the hopes of keeping them from going on ventilators.
So we’ve started out the very non-traditional way, and we’re morphing as quickly as we possibly can to sort of rock-solid traditional scalability.
31:10 Write - Rob Write asks the panel about how to remain agile in an environment where FDA is getting political pressure to accelerate development, while also getting pressure from executives to base approvals on science, not political manipulation.
31:43 Javitt - Well I haven’t seen any evidence that FDA is being less stringent with people, they’re certainly not being less stringent with us. What they’re doing is being a lot quicker at being stringent. So, meeting requests that used to take 60 and 90 days, all of a sudden take, 60 and 90 hours to be answered. And when you send them a question, they’re turning around the answer in 48 hours. In 30 years of knowing the FDA, I’ve never seen anything like this. I’ve gotten emails from FDA scientists that they wrote and sent at two in the morning. So, it’s one thing to relax the standards, and it’s another to step up and apply those standards as quickly as you possibly can for the benefit of humanity.
32:42 Write - Rob Write continues the conversation about the FDA working long hard hours, despite typical hiring gaps.
33:23 Javitt - Well part of what’s changed things, and we really have Scott Gottlieb to thank for this, is the 21st Century Cures Act that was passed I guess it’s now, three and a half years ago, and then we have Scott come in as commissioner, being the first commissioner to really implement that act, and congress finally gave the commissioner of the FDA the tools that were needed to attract the best and the brightest, which included some real salaries. All of a sudden, FDA is able to pay salaries that certainly are not at the top of industry scale, they’re not paying anybody millions of dollars, but they’re able to pay somebody enough of a salary to leave a major pharmaceutical company, and take a job as a regulatory scientist to proving drugs, and without that, the agency can’t work.
36:57 Javitt - If you’ve got a, just a couple minutes, I’d love to go back to something Brian said earlier, when he said, you know, we’re focusing on the patients with most severe disease. And it’s certainly true that that’s where we started, uh because those are the patients who are dying by the hundreds and thousands, but, there really is a platform play that I think needs to be thought about by more people than just us. The whole story of this virus is its ability to enter very specific cells in the (upper thellia???). It only enters those weird cells that have ACE II surface receptors, and that’s mostly a couple of cells in the nasal zone, because that’s where the virus seems to get going, and then it goes down to the lung and it enters these Alveolar Type II Cells. And if you can stop that process, then the SARS Cov 2 virus is either asymptomatic or nothing more than a mild cold. And people are talking about, grand platforms and systemic approaches and all of that, but in fact, this virus is doing us so much harm, because its figured out how to hit a needle in a haystack, and the more we can focus on that needle, the more we can focus on how does the virus gets into that cell and how do we stop it in that cell. It may be that we never have a vaccine. I hope we do, but so far, as long as I’ve lived, we’ve never had a vaccine that’s able to stop an RNA virus. And yet similarly with pneumonia, we invented penicillin in the 1920’s, and it was 65 or 70 years before we had a vaccine against Pneumococcus, but we did a great job of keeping people from dying of pneumonia over those 70 years, just because we were able to interdict the process. So I truly hope we wind up with vaccines. I truly hope we wind up with sort of mobile immunologic approaches to this virus, but in fact there’s some very focused things we could be doing that we’re not doing to deal with this particular family of viruses and their determination to eradicate the human race.
50:16 Write - Rob Write asks for final parting thoughts.
50:20 Javitt - I think the most important thing is not to be afraid to break the rules. Yet the pharmaceutical industry is very tradition-bound. People know they’re supposed to do things a certain way, and that’s good, because by and large its kept the American pharmaceutical industry from having some of the crises that other pharmaceutical industries around the world haven’t had, but this is a time where we have to break the rules. I once watched a major pharmaceutical company lose $2 billion of revenue that their shareholders would have enjoyed having, because the person, and it was only one person, responsible for making clinical trial supplies, couldn’t figure out how to make clinical trials supplies for an existing drug, about a 15 year old drug, within 24 months in order to satisfy the FDA’s request for a pediatric trial that would have given them a 6 month patent extension, because you know, making boxes of clinical trial supplies for 150 people was just too much work. If we don’t break the rules, and if we don’t break the rules consciously every day, we’re going to lose many more people to this pandemic than we need to.
by Uncle Gee Gee
I've transcribed the video and found many little nuggets of detail worth reading through.
For your weekend enjoyment...
CEO Roundtable with Dr. Javitt on Sept 10, 2020
15:55 Write - Jonathan, how does a clinical stage small molecule company that’s develop CNS-oriented therapeutics get involved in treating respiratory failure in Covid-19? I just want to understand how that happens.
16:20 Javitt - Well you know it’s like one of those extraordinary accidents, but some people say chance favors the prepared mind. And believe it or not vasoactive intestinal peptide, which is the active ingredient we’re working with, is a neuro endocrine peptide. And we were originally thinking about this in the CNS context. Then one of our investors came along and said well we have this company over in Switzerland that’s been thinking about this from a Covid-19 perspective. And sure enough it turns out that when Professor Sammy Said, who spent his whole life developing this peptide, really understood what it did, even though it was first identified in the intestine, which is why it has this funny name, 70% of the VIP in the body is in the lung, and it seems to have one critical function in the lung, which is to protect the Type II Alveolar Cells. Most people never heard of the Type II Alveolar Cell. In fact when I was in medical school, I don’t even think we knew that there were Type I and Type II cells. But this rare cell (there’s only about 5% of all the cells that line the lung), is the cell that is critical where the flow of oxygen’s coming in to the blood stream. And it makes the surfactant that lines the lung. Without the surfactant, the lung can’t transmit oxygen. And this funny virus, this virus that humanity’s never really encountered before SARS came along, attacks that one cell. It’s almost like hitting a needle in a haystack. And it attacks that one cell because that one cell happens to have ACE II receptors on its surface. So those funny spikes you see on the virus, they bind right to that receptor just like a key fitting a lock and the cell says come on inside, and as soon as the virus is inside the cell, it starts to make millions of copies of itself, it starts to let inflammatory cytokines loose all over the body, it ruptures the cell and it shuts down surfactant production, so all of a sudden, people who don’t even look that sick, have no oxygen in the blood. They can’t walk from their bed to the bathroom without falling down on the floor.
And… what we learned, what we expected is this would be a potent anti-cytokine. We thought we’d do a great job at blocking cytokines, and a great job at increasing surfactant production. And then lo and behold, a group of people we never heard of, at the Oswaldo Cruz Institute in Rio de Janeiro, reached out to us and said, you know that molecule you’re working with… here’s the data that shows that it blocks the replication of the SARS virus in human lung cells. So it was (inaudible 19:13) for us. It was, now we see why we’re seeing extraordinarily rapid recovery in the clinic. When we went into the clinic with this drug, and we literally went from paper files (because nobody has used this drug in humans for 10 years), from paper files to freshly formulated drug, with a fresh FDA certificate of analysis in human beings, in 10 weeks. When we went into the clinic, we expected to see an anti-inflammatory effect. We expected to see some of the same effects that Dr. Said saw in 2005 when he used this drug against Acute Respiratory Distress Syndrome, caused by sepsis, where seven out of eight people walked out of the ICU alive, when you would expect at least five of them to have died. What we didn’t expect to see, was chest x-rays clearing in 3 and 4 days. We didn’t expect to see that some of the early results we reported, where uh, you know out of the first 21 patients we treated outside our clinical trial, they were too sick to get into our clinical trial, 11 of those people have done very well, and 19 out of those 21 people have survived 28 days, which is the cutoff that NIH generally uses, 28-day survival is a critical endpoint. So we’ve been very surprised by the magnitude of response we’ve seen in the open label studies, and now we’re about a month away from the first unblinded look at the Phase III randomized control data. So, you know, we’re wondering, are we seeing the world’s biggest placebo effect, or are we really on to something.
21:15 Write - Rob Write asked a question regarding the company’s core competency and whether there was any internal struggle about pivoting on their strategy.
21:45 Javitt - I think the thing that is core to our company we’re just not afraid of anything. And we’re especially not afraid to go to FDA and say please help us break the rules. I mean there was 10 weeks from paper files to drug in the clinic in patients. Well that’s never going to happen through traditional GMP manufacturing, through standing up a fill and finish manufacturer. Those people take 6 months just to get their machines tuned up. So we went to FDA and said: You’ve got this list of 50 formulating pharmacies that you say passed your inspection. These 50 tiny little pharmacies that you say are safe, you didn’t shut them down, you actually certified them as formulating pharmacies, how about we make this drug in one of those formulating pharmacies?
We’re literally making this drug by hand in order to be able to get it into a Phase III trial overnight. And FDA was willing to help us break those rules, or at least willing to waive those rules, and recognize that if we’re facing the worst public health crisis in the last 100 years, we’ve got to be willing to do things in new ways, otherwise, we’re just dinosaurs looking at that asteroid coming closer and closer.
23:09 Write - I’m curious Jonathan about the formulating pharmacies idea. That’s kind of uh just an interesting approach, and I imagine your also trying to figure out how to do the scale up as you’re doing it now and it well in advance so things can continue to progress. Can you tell us a little bit about where the idea came about?
23:24 Javitt – Oh we’re hahaha we’re not going to try that one twice. So we’ve actually just signed a contract with one of those fill and finish manufacturers that we’re hoping to announce very shortly, uh and they’re actually the largest manufacturer of sterile inhaled drug in the world. Although our clinical trials with intravenous drug, we’ve already announced the trail that we intend to start quite shortly with an inhaled version of this drug, for people not with critical Covid-19, not the people who were on ventilators that we’re treating right now, but people with earlier stage disease in the hopes of keeping them from going on ventilators.
So we’ve started out the very non-traditional way, and we’re morphing as quickly as we possibly can to sort of rock-solid traditional scalability.
31:10 Write - Rob Write asks the panel about how to remain agile in an environment where FDA is getting political pressure to accelerate development, while also getting pressure from executives to base approvals on science, not political manipulation.
31:43 Javitt - Well I haven’t seen any evidence that FDA is being less stringent with people, they’re certainly not being less stringent with us. What they’re doing is being a lot quicker at being stringent. So, meeting requests that used to take 60 and 90 days, all of a sudden take, 60 and 90 hours to be answered. And when you send them a question, they’re turning around the answer in 48 hours. In 30 years of knowing the FDA, I’ve never seen anything like this. I’ve gotten emails from FDA scientists that they wrote and sent at two in the morning. So, it’s one thing to relax the standards, and it’s another to step up and apply those standards as quickly as you possibly can for the benefit of humanity.
32:42 Write - Rob Write continues the conversation about the FDA working long hard hours, despite typical hiring gaps.
33:23 Javitt - Well part of what’s changed things, and we really have Scott Gottlieb to thank for this, is the 21st Century Cures Act that was passed I guess it’s now, three and a half years ago, and then we have Scott come in as commissioner, being the first commissioner to really implement that act, and congress finally gave the commissioner of the FDA the tools that were needed to attract the best and the brightest, which included some real salaries. All of a sudden, FDA is able to pay salaries that certainly are not at the top of industry scale, they’re not paying anybody millions of dollars, but they’re able to pay somebody enough of a salary to leave a major pharmaceutical company, and take a job as a regulatory scientist to proving drugs, and without that, the agency can’t work.
36:57 Javitt - If you’ve got a, just a couple minutes, I’d love to go back to something Brian said earlier, when he said, you know, we’re focusing on the patients with most severe disease. And it’s certainly true that that’s where we started, uh because those are the patients who are dying by the hundreds and thousands, but, there really is a platform play that I think needs to be thought about by more people than just us. The whole story of this virus is its ability to enter very specific cells in the (upper thellia???). It only enters those weird cells that have ACE II surface receptors, and that’s mostly a couple of cells in the nasal zone, because that’s where the virus seems to get going, and then it goes down to the lung and it enters these Alveolar Type II Cells. And if you can stop that process, then the SARS Cov 2 virus is either asymptomatic or nothing more than a mild cold. And people are talking about, grand platforms and systemic approaches and all of that, but in fact, this virus is doing us so much harm, because its figured out how to hit a needle in a haystack, and the more we can focus on that needle, the more we can focus on how does the virus gets into that cell and how do we stop it in that cell. It may be that we never have a vaccine. I hope we do, but so far, as long as I’ve lived, we’ve never had a vaccine that’s able to stop an RNA virus. And yet similarly with pneumonia, we invented penicillin in the 1920’s, and it was 65 or 70 years before we had a vaccine against Pneumococcus, but we did a great job of keeping people from dying of pneumonia over those 70 years, just because we were able to interdict the process. So I truly hope we wind up with vaccines. I truly hope we wind up with sort of mobile immunologic approaches to this virus, but in fact there’s some very focused things we could be doing that we’re not doing to deal with this particular family of viruses and their determination to eradicate the human race.
50:16 Write - Rob Write asks for final parting thoughts.
50:20 Javitt - I think the most important thing is not to be afraid to break the rules. Yet the pharmaceutical industry is very tradition-bound. People know they’re supposed to do things a certain way, and that’s good, because by and large its kept the American pharmaceutical industry from having some of the crises that other pharmaceutical industries around the world haven’t had, but this is a time where we have to break the rules. I once watched a major pharmaceutical company lose $2 billion of revenue that their shareholders would have enjoyed having, because the person, and it was only one person, responsible for making clinical trial supplies, couldn’t figure out how to make clinical trials supplies for an existing drug, about a 15 year old drug, within 24 months in order to satisfy the FDA’s request for a pediatric trial that would have given them a 6 month patent extension, because you know, making boxes of clinical trial supplies for 150 people was just too much work. If we don’t break the rules, and if we don’t break the rules consciously every day, we’re going to lose many more people to this pandemic than we need to.
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