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                            Wednesday, May 27, 2020

                            Out of the Crisis #5, ANA Therapeutics: a possible COVID-19 treatment and prophylactic

                            Out of the Crisis #5 is a conversation with three people who pivoted their biotech company to help fight the coronavirus. Akash Bakshi, Nadja Mannowetz, and Andrew Bartynski are the co-founders of University of California, Berkeley-based YourChoice Therapeutics. When they realized the drug they were working with for an entirely different reason had potential to be repurposed as a COVID-19 treatment, they "dropped everything and got to work."

                            YourChoice was studying niclosamide, in spite of its safety and efficacy, for use as a spermicidal contraceptive. They had just filed with the Food and Drug Administration in early March when, in a play for humor during a meeting, someone pondered aloud whether niclosamide might be an effective treatment for COVID-19. That became their new mission.

                            It didn't take much searching to find out that the drug had been tested against SARS-CoV-1 (known to non-scientists as
                            SARS, the 2003 pandemic) and had proved effective against the replication of that virus. The virus that causes COVID-19 is SARS-CoV-2 so the team believed they had not just good reason but a moral obligation to start investigating whether niclosamide would also would also treat and possibly even prevent COVID-19. ANA Therapeutics was founded. It was only a few more weeks before they found data that showed not only that the drug prevents SARS-CoV-2 from replicating, but that From that moment, especially since they were the only biotech company with access to clinical-grade niclomaside, they were determined to get the drug into a phase III trial.

                            Along the way, from investors to suppliers to manufacturers, ANA Therapeutics had the unique experience of being a startup to which "no one said no, and everyone said yes." This has allowed the company to move forward quickly alongside the many other biotech efforts looking for a vaccine. The whole industry, including the FDA, is moving at never-before-seen speeds in order to, as Akash told me, "take multiple shots on goal."

                            You can listen to our conversation on
                            Apple podcasts, Google podcasts, or wherever you like to download.


                             


                            I've also included a full transcript below.


                            Show-related resources

                             

                            Highlights from the show

                            • Akash Bashi on his background. (2:16)
                            • Nadja Mannowetz on her background. (2:38)
                            • Andrew Bartynski on his background (3:12)
                            • Their pre-COVID work: a non-hormonal contraceptive for men and women. (4:13)
                            • The moment they realized their project might have applications for COVID. (6:27)
                            • Their original vision for their company, YourChoice Therapeutics, and using niclosamide for contraception. (8:05)
                            • Discussion about niclosamide and safety. (10:58)
                            • Akash tells the ANA origin story. (13:12)
                            • Andrew on waves of treatment for COVID and the potential and value of repurposing existing drugs. (15:46)
                            • All three on why a startup is doing this work instead of a big company, including issues of speed and decision-making. (17:43)
                            • The moment they decided to pivot and build a new company. (21:16)
                            • Moving drug compounds from Europe to the US after the flight embargo and what the data showed. (22:57)
                            • What happened after the pivot, and getting the drug into the clinic. (25:42)
                            • How the new speed of biotech has changed their experience. (27:50)
                            • The potential of niclosamide for treatment and as a prophylactic for at-risk populations, like those with co-morbidities and front line workers, and later for everyone as we begin to travel and reopen the economy. (29:26)
                            • Discussion of how vaccines and treatments work together to mitigate disease. (35:24)
                            • Andrew on what comes after social distancing. (39:27)
                            • The timing of trials for niclosamide and how soon it could be available. (38:43)
                            • What are the drug trials like? (39:06)
                            • Differences between potential drug treatments that haven't panned out and niclosamide. (40:35)
                            • The importance of well-controlled clinical data in trials before recommending usage. (43:26)
                            • Differences between coronaviruses and other viruses. (44:41)
                            • On how pursuing research into other viruses and pandemics like SARS and MERS could have helped us now. (45:47)
                            • Lessons we can learn from this about what to invest in for next time. (48:19)
                            • On how structural changes focused on short-term thinking, goals and outcomes, along with lack of planning for low-probability events, have affected us. (49:28)
                            • Getting funding for their work wasn't difficult and it came from investors who think long-term. (51:36)
                            • Scientific background on niclosamide, what we know about how it works to stop viral replication. (52:48)
                            • The next necessary wave of research. (54:37) 
                            • What it felt like to pivot away from their vision. (55:19)
                            • Where they found special support and encouragement. (56:29)
                            • Where the company is going from here. (57:00)
                            • Discussion of health care workers as heroes, their risks (57:25)
                            • Akash's aunt's surgery during COVID-19. (59:02)
                            • Advice to companies thinking about pivoting to COVID-19 relief efforts. (1:01:05)
                            • Ways for non-health care professionals to help. (1:02:19)
                            • What they think the new normal looks like, and where we go nect. (1:04:29)


                            Transcript for Out of the Crisis #5, ANA Therapeutics


                            Eric Ries: This is Out of the Crisis. I am Eric Ries. I've always been a believer in science. And I'm incredibly grateful to live in an era where the scientific method is so widely deployed. And yet, we all know that as a society, we still struggle to give the respect and support to the researchers who are laying the foundation of future progress.

                            In Silicon Valley, it's not just the companies that have had to pivot and change direction, so have investors, VCs, the entire ecosystem of the startup community of biotech as an industry, has had to make a very dramatic change to work on pandemic relief, disease prevention, laying the foundation for future prosperity. And although I've only had a bit part in that transformation, it's been really amazing to see it happen and unfold in real time.

                            I sat down to interview three scientists who were working on a drug that has the possibility to get us out of this crisis in months, not years. I first met this company as the crisis was breaking, and was given the opportunity to invest. But their story is so much more interesting to me not just as an investment, but as a lesson for what it's like when the world completely changes your plans and you just have to go with it. It's also a source of inspiration and comfort to me.

                            People are talking about a vaccine that could be ready in 18 months or 24 months, but that feels a long way off. It's really important that we realize that there are therapies like this one that will work. We don't know exactly which one will make it to the clinical trials, we don't know which one will have the greatest effect, we don't know if we'll ever be able to develop one that can be used prophylactically to prevent the disease, but I have a lot of confidence that one of them will. Combined with contact tracing and widespread testing, a therapy like this could allow us to reopen the economy and go back outside. And that will feel pretty amazing.

                            Here is the story of ANA Therapeutics.

                            Akash Bakshi:  Hi, my name is Akash. My background is in biochemistry and cell Biology as well as molecular biology. And while I didn't spend a great deal of time in research, I somehow pivoted into IP licensing, which led me to meet Nadja and we founded YourChoice Therapeutics together, and that's what led to the genesis of ANA Therapeutics.

                            Nadja Mannowetz: My name is Nadja. I am the chief scientific officer of ANA Therapeutics. I got a Ph.D in biology, it was focused on medical microbiology to study Legionella pneumophila, a bacterium that causes atypical pneumonia. I then switched into studying sperm cell physiology, which led to the formation of YourChoice Therapeutics with Akash. And from there, we pivoted into ANA Therapeutics.

                            Andrew Bartynski: Hi, I'm Andrew Bartynski. I have a Ph.D in chemical engineering. During grad school, I was working on solar cells and fell in love with startups. So, once I graduated, I started working on a company in the Bay Area developing transparent solar cells, then I found myself moving over into the medical device space for a couple of years. And then, I met Nadja and Akash and heard what they were working on with regards to contraception. I couldn't get it out of my head, and I've been working with them ever since.

                            And then, when COVID happened, we felt an obligation to see if our technology had any application there and went with it once we saw there was promise.

                            Eric Ries: It seems clear to me that the only true long-term way out of this crisis is through science and the development of new treatments and ultimately a vaccine. And so, I'm really honored to have all of you take some time out from doing that work to share the story with our listeners. Tell us about what you were working on before the crisis started.

                            Akash Bakshi: So, the real truth is that before the crisis started, the three of us were working on developing a non-hormonal contraceptive, not only for women, but also for men. And very honestly, we had just submitted with the FDA to ensure that we both agreed on what steps were needed before we could kick off a clinical trial. We were waiting for a response back from the agency. At the same time, we received an NIH grant to fund all of the studies that we thought were required before going into the clinic.

                            And so, here we were starting a company that was just soon to enter into the clinic, maybe in three to six months, and then more and more about COVID-19 started hitting the news. And I'll let Andrew take it from there as to what happened.

                            Andrew Bartyniski: Yeah. So, we were having our weekly meeting on Mondays where we go through the task board and think about what to do next. And it was serendipitous, where we had this breath where we jokingly were like, "Okay, we have nothing to do, right? We just finished one of our major milestones, we just got this grant." And basically, this was when COVID really started becoming center of mind for the new cycle and everything else.

                            Eric Ries: Give us the timeline a little bit. When did you start the company and how long have you been working on it? And then, when was this exactly, if you recall, when you got the grant?

                            Andrew Bartynski: Yeah. So, we got this grant on March 5th or 6th and the submission to the FDA was maybe two days before that, like March 3rd. And so, this meeting, I think, was happening on maybe the 9th or 10th of March. There was a breath of fresh air where we just finished this big push for YourChoice. And then, we jokingly said, "Hey, what if the compound that we're working with, niclosamide, actually also works for COVID?" Because a running joke in our group is that niclosamide works for everything. Because if you look in the literature, it's shown great promise in a number of different indications.

                            And so, when we said that jokingly, Nadja diligently started going through the literature research, and in five minutes pulled up a paper saying, "Well, here's a paper that shows that during the SARS outbreak in 2004, niclosamide was actually a very potent inhibitor of viral replication." And so, that planted the seed of like, "Maybe there's something there."

                            Akash Bakshi: And actually, I'd build on it just a bit because we knew about the antiviral properties of niclosamide even earlier. Well, I think it tells a better story of how we came about niclosamide. Perhaps my story is I wanted to kill off the niclosamide program as a contraceptive as quickly as possible because I, at the time, did not believe that a pharma company would ever be interested in acquiring a company that was doing a 505(b)(2) play.

                            But what was really interesting in the development is that Nadja actually showed how effective niclosamide was as a contraceptive. But the icing on the cake was that there had been publications that showed that niclosamide inhibited HIV replication and HSV-2, which is the virus that's responsible for genital herpes. So, I mean, if you think about a contraceptive that can go about inhibiting STDs or STIs, you'd think that that is somewhat of a gold standard, right? And so, that was really interesting.

                            And that builds into the point that Andrew was making that it seemed that niclosamide was this just wonder drug. So, was there any proof that it worked on SARS-CoV-2?

                            Eric Ries: So, before we get into the science of that, because I want to come back to that point, for a lot of our listeners, they're not familiar with therapeutic startups and this world. So, if you could walk us through the founding of the company, you were talking about the different FDA pathways and what the exits might look like and what you were considering there. So, what was the original vision for the company and then how did you settle on niclosamide as a product to pursue?

                            Nadja Mannowetz: YourChoice Therapeutics is a spinout of a lab at the University of California, Berkeley. The main goal of this company is to develop non-hormonal contraceptives that can be used by women and men. And our core technology focuses on disabling sperm cells from getting close to the egg, and ultimately fertilize an egg.

                            One way you can think about it is, what if you don't allow sperm cells to produce energy? Because that would ultimately mean sperm cells would not go anywhere. And yeah, contraception achieved. Check. Been there done that.

                            There is a class of molecules that have been shown in other experiments with other cell types that once these cells are exposed to those substances, they cannot properly produce energy. And this is also true for sperm cells. So, niclosamide is known to prevent cells from producing enough energy and this is also true for sperm cells. If you disable sperm cells of producing energy, they become immotile, and immotiles themselves will never reach the egg.

                            And yeah, for us, this is really wonderful because niclosamide, it's not a hormone and it also has a long history of safety in humans because it's a drug that has been on the market for five to six decades.

                            Andrew Bartynski: Yeah, niclosamide was originally discovered in the 1950s by Bayer. And since then, originally was commercialized in Europe, and then in the U.S. in the 1980s as a tapeworm medication originally. And so, because there's not really a tapeworm problem in the U.S., I don't think it ever really came to prominence here.

                            Eric Ries: So, this is an established drug with a long history and track record of being safe for use in humans?

                            Andrew Bartynski: Right. Yeah, I think we found a paper from the WHO that was looking at any complication or adverse event reports over the course of 30 years. There were only 70 reported incidents. So, if you take a drug like Tylenol or aspirin, there's probably more side effect reports from that drug than this drug.

                            Nadja Mannowetz: And these side effects, they are not severe. We are talking about abdominal pain, diarrhea, nausea, vomiting. I think, yeah, these aren't pleasant side effects, but they are definitely more acceptable than suicidal thoughts, heart attack, or anything like that.

                            Eric Ries: How did you first become aware of niclosamide?

                            Nadja Mannowetz: That was based on literature research, looking for molecules that disable mitochondria from producing energy. So, you could say mitochondria are the batteries of a cell, so the energy-producing compartments. So, if you Google mitochondria and uncoupling, then you'll find several molecules and niclosamide always shows up.

                            And yeah, I mean, being a scientist, then you'd start asking, "Oh, what is niclosamide? What is compound X?" And if you would just Google niclosamide, you would find endless papers of, it has been shown at least in in-vitro experiments, to have anti-cancer properties, to have antiviral properties. And then, you'd think, "Oh, this is not only an effective compound, this is also a safe compound." And then, you would conclude it's a very, very promising compound.

                            Eric Ries: So, Akash, maybe you can tell us the company-founding story. Because I think when most people imagine a therapeutics company, they have this idea that people work for many years in a lab working on a novel compound, then it has to go through extensive trials for years and decades to be proven that it's safe, but they have an image in their mind of what drug discovery looks like. But this is a little bit of a different story because we're talking about an existing compound with known properties. How did you have the idea to try to build a company around an existing compound but on new application?

                            Akash Bakshi: It's a great question. This really was a team effort because I don't think that we could have done it if all three of us were not entirely on board. There was that day that a huge weight had been lifted off of our shoulder where we had filed with the FDA to try and understand what their thoughts were on the use of niclosamide as a vaginal gel. We received the grant from the NIH, we said, "Okay, well, whatever the studies are that you need to go into the clinic, you just move forward." And then, there was the day that the three of us were just chatting internally about, "Well, does this even work against SARS-CoV-2?"

                            And on that Wednesday, we had to send an investor update to the investors of YourChoice Therapeutics, in which we gave the update that the Pre-IND was submitted to the FDA. We also just got this grant from the NIH. We also are about to order a compound from our supplier so that we have niclosamide to run our clinical trial as a vaginal gel, "By the way, we think that this shows a lot of promise for COVID-19. And we think that we should run a Phase 3 clinical trial on this drug and we just need to order 15 kilograms," and that'll roughly cost about $500,000. "Let us know if you're interested."

                            And later that night, one of the investors of YourChoice Therapeutics responded and said, "We're in." All of a sudden, we were like, "Well, here we go. What do we do next?" And so, we ultimately decided to put all of the COVID work into a separate company. And that's how things started.

                            Andrew Bartynski: Well, I think what was interesting also and another point that Eric was getting at is, traditionally, biotech is preceded by 5 to 10 years of Ph.D work. In this case, it was preceded by five decades of published literature. And so, I think that the type of company that ANA is is very non-traditional.

                            So, if you think about responses to a pandemic from a therapeutic standpoint, there are going to be three waves of treatment, right? There's going to be the immediate first wave of therapies, which are the only thing that's feasible on that timeline is the repurposing of an existing drug. Because in order to do the necessary efficacy and safety testing for a new compound would take way too long for it to be relevant. And so, in order for us to make a difference in the next, I don't know, 12 to 18 months realistically, the most promising way to do that is through a repurposing of an existing drug with a known safety profile and unknown toxicity profile.

                            After that, you'll start to see new chemical entities come on board because then they've had enough time to actually be evaluated for their safety and efficacy. And then about the same time as that, you'll have vaccines come around, because the development timelines there also are non-trivial.

                            And so, our thinking, I think, in making this company was if there is a drug that has a long history of safe use that's been around for a while, that shows any hint of efficacy against SARS-CoV-2, you are obligated to pursue it because you'll be the fastest compound that could actually treat patients. And so, the goal here, which I think we take very seriously, is to try and find something that can contain the spread of this disease as quickly as possible. From a therapeutic standpoint, you have to go for a repurposed drug first.

                            Eric Ries: I think some people listening will be surprised to hear that repurposing an existing drug that that's being done by a startup and not by a big pharmaceutical company. Do you think that everyone who's got a drug, they would be testing every drug possible against COVID given the scale of the pandemic? Why is a startup in charge of this?

                            Andrew Bartynski: Great question. That's a great, great question.

                            Eric Ries: But Andrew, it sounds like maybe you have a better response than I'm thinking of.

                            Andrew Bartynski: Yeah, so my reason why a startup is well-positioned to do a repurposing play whereas a large pharmaceutical company is not, it comes down to the same reasons why startups aren't good at other things, is their speed and decision-making ability. So, small teams with high levels of trust can make great progress very rapidly, whereas in large organizations, it does take a long time to steer the ship in a direction.

                            And so, I think that large pharma companies will certainly be screening all of the molecules that they have on hand, but the decision time for them to choose a lead produce significant quantity to get into the clinic and run the trial may not be as quick. I think Gilead has definitely done a great job with Remdesivir and getting that into the clinic as quickly as possible to be evaluated. But I think that it is difficult for large companies to typically move that fast.

                            Nadja Mannowetz: I am also not sure how interested big, big, big pharma companies are in marketing a drug that is generic already.

                            Akash Bakshi: Yeah. So, I think that there's also a risk associated with, will the drug work or will it not work, if you had to think about repurposing a drug that you already have, which plays some role in your portfolio, which is why I think... I mean, I don't know. Actually, I don't even believe what I'm saying because everyone that is a manufacturer of hydroxychloroquine is increasing manufacturing capacity to see how that might work as a treatment against COVID-19. So, I don't know how much risk plays into it.

                            I don't know if pricing plays a role either in the fact that maybe if a drug is available for 30 cents, is it really of interest to make that available to everyone as a potential treatment for COVID-19? I'm not sure if that's being used as a part of people's calculation. But I do think it is... I would build on Andrew's point where it's hard to make that decision to say this is the drug within our portfolio that we're going to move forward as a COVID-19 treatment because the data that's available about niclosamide is very sparse.

                            It's all published from 50 to 30 years ago, and every paper that has ever come out again about niclosamide references these same papers. And so, it's very circular in the amount of information that's available. And it wasn't until we started doing additional modeling, until we started really interrogating questions that we started realizing that niclosamide is a great drug. But if you are looking to kill off an idea quickly, niclosamide would have been a great molecule to kill just because what's published about bioavailability or solubility is not particularly great.

                            Eric Ries: So, let's go to the moment when you had the realization... It sounds like this, originally, you floated this COVID treatment almost as a joke. That was a running joke in your team. But you emailed your investors, you got a sense that there was some interest there. What was the moment when you decided to completely pivot into full-time COVID as a product and effectively build a new company, replacing the work that you were doing before?

                            Andrew Bartynski: Yeah, so I think this is a moment where Akash refers to be a little bit as a bulldozer. And so, when I have an idea in my mind that I am pretty convinced about, I'll sometimes just go do things. And so, this is one of those moments where it was, I think it was 10:30 or 11:00 at night, where I just started following up to the investor update that Akash sent, and tried to put a finger on people to say, "This needs to happen." And so, I think that was when the company became nascent. That was what it was first like, "Okay, this could be a thing."

                            And then, I think the second moment where we were like, "Holy crap, maybe we're right," was when we first got in-vitro data back specifically showing that niclosamide is effective at inhibiting SARS-CoV-2 replication at 150 nanomolar concentrations, like 25 times more effective than what's been shown for chloroquine and 70 times more effective than remdesivir. It's like that was the moment where we were like, "Holy crap, we went out on a limb here and it seems as though we might be right."

                            Eric Ries: Where'd you get that data from? And who first brought to your attention?

                            Akash Bakshi: So, the first thing that we did... So, we raised capital. I mean, to be very honest, we set up an entity and then got money in. And the first thing that we did, as I mentioned, is we ordered compound from our supplier who happens to be in Europe. And literally, the day that we placed the order was the day that Donald Trump said that all flights from Europe to the United States would be halted on Friday.

                            Eric Ries: I remember that.

                            Akash Bakshi: And actually, even in that talk that he gave, he even said something about cargo, which scared the hell out of the three of us because here we are and we need to get drug from Europe to the United States, and we've just learned that we have two days to figure out how to ship all of this over. So, that is one major part of our brains of just logistics had never been something that we ever had, as a team, appreciation for until we had to, in a very tight timeframe, move drug from Europe to the United States when fights were being canceled.

                            But the second thing that we did is we sponsored research in the lab of Dr. Pei-Yong Shi and had him specifically look at the ability of niclosamide to inhibit SARS-CoV-2. So, that was the next step.

                            And when that data came back at 150 nanomolar, meaning for a company that was working on non-hormonal contraceptives, this is like hormonal level accuracy or precision that you're able to fight off SARS-CoV-2. That was just like a Oh-my-God moment. I mean, there are other words that we were probably using, but it was just like, "Wow, this is crazy" of how right we were. We knew that niclosamide was going to work, but it was going to work as well was still a surprise.

                            Eric Ries: So, how can it be that... I mean, at this point, chloroquine has become a national word that entered into the public awareness as a potential treatment. You're saying that this treatment could be dramatically more effective. Why doesn't anybody know about it yet?

                            Akash Bakshi: I wonder to what extent supply chain plays a role, because niclosamide is not available for off-label use or in the United States, at least, or in most Western countries, your doctor can't write you a prescription for niclosamide because no one is selling niclosamide in the United States. And so, I wonder to what extent that plays a role.

                            Eric Ries: Let me see if I've got this right. Last year, you thought you were going to be working on a startup related to a non-hormonal contraceptive around niclosamide, a drug that's been studied for decades and is shown to be safe and has this amazing antiviral properties.

                            You're just about to start clinical trials, you've raised money, you've built the company, you've got your NIH grant, and then this crisis hits. You have this idea that maybe the compound could be useful against COVID. You commissioned research that shows that it's a lot more effective even than you thought. And since the drug is already known to be safe, you realize that you're sitting on a potential treatment for the pandemic. What happened next?

                            Akash Bakshi: We turned all of the resources that we had developed over the last year into quickly getting niclosamide into the clinic for COVID-19. So, we were in this unique position where just a few weeks earlier, we had filed with the FDA for niclosamide as a vaginal gel. The same group that had helped us with that filing, we asked to immediately start working on the filing of niclosamide as an antiviral for COVID-19.

                            The supplier who had provided us GMP material drug, we then got to increase the amount of drug that we needed so that we could move that back into the United States so that we could start making pills. The group that was making the gel for us, we then said, "Hey, could you hold off on making the gel? Can you make pills with the drug that we have on-hand?" And what was crazy is no one said no, and everyone said yes.

                            Andrew Bartynski: Yeah, I would say that that has been the most incredible experience throughout all of this, is that in startups, you're used to hearing no nine times and yes once, and here you're truly hearing yes nine times and no once. And that's really cool.

                            Eric Ries: When I was talking to Sam Altman, he said that one of the most amazing things he's seen is that it's almost like the entire biotech industry has turned on a dime, and every single company has gone all-in on COVID response. And as a result, the clock cycle of the whole industry has changed. All of a sudden, things are happening faster than anyone dreamed possible before. It sounds like you're having that experience. You're like living in real time.

                            Akash Bakshi: That's really true. I would say that the response from the FDA is a funny story. We had filed with the FDA for the vaginal gel, March 2nd, and we ended up getting a response back April 6th, which is a very normal time frame by which to get a response. We filed with the FDA on March 23rd for COVID-19 and I think two days after we got the response for the vaginal gel, we heard back from the agency about our achievement for COVID-19. So, even the FDA is thinking at a super fast speed.

                            Eric Ries: When was the last time you heard about an order of magnitude speed up in government responsiveness? That's a really positive story.

                            Akash Bakshi: I mean, these are all things that just help us continue to move faster as we try and get something into the clinic, so that hopefully there is a treatment for individuals who are COVID-19 positive or even a prophylactic treatment for those that are at risk.

                            Eric Ries: Yeah. So, talk a little bit about the potential here, because I understand that you're limited in the claims that you can make so I'm not asking you to predict the future. But let's say, hypothetically, that when you do the trial, this drug is validated to have the effects that you believe against COVID. And imagine that it works the way that you imagine right now. How soon could this be helping treat people and what could the treatment mean for people who are affected?

                            Akash Bakshi: Yeah, it's a tough question to answer and much of it is based on the results. But yeah, just to build on, if the results are outstanding and it's very clear that we're helping people and not having a negative impact, there's no reason why we wouldn't see being able to make this available by the end of the year.

                            Eric Ries: You said it could potentially be used prophylactically. Explain what that means.

                            Akash Bakshi: I mean, that's another area that is really of interest to us is, if you use an antiviral, either just after you think that you might have been infected or if you use this just because you're at risk, what we're learning is that low doses of these antivirals can actually play a really important role in preventing a virus from really having its full course.

                            And so, one thing that we think about, given the safety of niclosamide over long periods of time, is that this actually seems like a great drug for individuals who are in the healthcare space, who are likely working with COVID positive patients as a post-exposure prophylactic because they're just at risk of getting COVID-19 from those that are around them, and that we think could help with 13 million healthcare workers in the United States.

                            But then, we also think about the other patients who are maybe over 60 or have other comorbidities like asthma, that are problematic and who can afford to get COVID-19 and that we also see as a potential, just given the safety profile of niclosamide that it could be something that they take to potentially de-risk or prevent them from getting COVID-19 in the first place.

                            Eric Ries: So, you're saying that for nurses like... I mean, certainly our national shame in this country has been the fact that we have frontline health care workers treating COVID-19 patients without protective equipment, who hasn't seen the images and gotten the Facebook messages about nurses desperate to find rain ponchos and God knows what else. It's been awful.

                            So, you're saying that those folks who are at most at risk, this is a drug that they could potentially take on a daily basis just to prevent them from getting the disease or getting the worst symptoms of the disease? What would be the effect if you took it prophylactically and it worked?

                            Andrew Bartynski
                            : Yeah. I mean, I think the best example of this would be something like PrEP for HIV, right? And so, in at risk populations, if they have sufficient antiviral drug concentration in their blood, it's possible to prevent infection from occurring. And so, that would be the goal here. Obviously, you have to run the clinical trial in a well-controlled fashion to prove that's the case.

                            But our hope is that once we're able to prove that this is an effective antiviral in COVID positive patients, the logical next step for us and the real broader societal need will be for prophylaxis for those who are at high risk of exposure or at high risk of significant complications if they do become infected.

                            Akash Bakshi: And I actually think, just building on what you're saying, Andrew, I think that a drug that works prophylactically would play a really important role in opening up the economy again. Because, I think, I wonder to what extent COVID-19 is, like how 9/11 changed travel for everyone for the rest of their lives, I wonder if this just changes how we interact or how we go about the rest of our lives.

                            And so, again, I wonder if travel will be the same. I wonder if how social distancing will play a role for us long-term because it's not as though COVID-19 is going anywhere. And until there's a prophylactic treatment, how do we engage in a way to prevent ourselves from getting COVID-19? Or if you have it, how do you know... Just because of the latent time that it takes to actually show itself, how do you know who's safe? And so, that's why I see this playing an important role.

                            Eric Ries: A lot of people that I've talked to have their hopes pinned on a vaccine. So, even people who are looking at the worst-case scenario, a very common refrain I hear is, "Look, 18 months or 24 months from now, at a worst-case scenario, there will be a vaccine. This problem will go away and things will return to normal." And of course, we all pray that that's true, but I keep having this thought as a lay person in the back of my head, I say, "Well, that sounds good, but if the virus doesn't mutate. Maybe we build the perfect vaccine for this strain, but a new strain emerges, and there's a second peak, God forbid." My understanding was that the second strain in the 1918 pandemic, that was really deadly.

                            And so, even in a world where there might be a vaccine coming, it seems really prudent to me or maybe even essential that we have other forms of attack of treatment, of prevention. So, talk a little bit about the difference between antiviral drugs and vaccines, and whether you see both playing an important role or is it just over different timeframes? How do those two concepts fit together?

                            Andrew Bartynski: Yeah. I think there's actually a great analogy here between antivirals and antibiotics. And yeah, resistance is obviously a concern. And the way that they mitigate that in antibiotics, right, is you have broad spectrum and highly targeted versions of these compounds. And so, I think a similar strategy for antivirals makes a lot of sense, right?

                            If you only have a single attack vector that you're going against a virus for, it's possible that it can mutate around that vector. But if you're taking multiple approaches to either inhibit replication, prevent entry of the virus into cells, or to just target the virus particles themselves, I think that gives you that robustness to evolutionary pressures.

                            Akash Bakshi: And I would say that I think we're all hoping for the vaccine to come out as well, right? I mean, what Andrew is pointing, an antiviral is something that you're also dependent on individuals to be compliant around. So, are you taking your pill every day? Do you take it at the right time so that we can make sure that the PK levels in your bladder sit at the right level? A vaccine is hopefully once, or I mean, some vaccines take three times to administer but at least a vaccine would help a lot in this area.

                            The other thought about that is, do we have... We need multiple shots on goal, so there needs to be a shorter-term response. Because even right now, let's say, without a treatment that was available, are there enough face masks for Americans to use when we go out or if you were to take public transportation? I don't think that that's available right now. And so, again, I think of this as, all of it, a jigsaw puzzle where there's not one answer but there are a lot of pieces that come together to help fight COVID-19.

                            Andrew Bartynski: But I also, I don't want to be just doom and gloom as though there's no hope. Right? As we've seen, social distancing does work, so that's great. That's step one. We have something that works. That's the necessary first step. And then, everything that we do from here on out will be an improvement on what was there previously, right? We know social distancing works. So, when we see flare ups happen again, we can always default back to that state.

                            The question is, what comes next in terms of allowing us to increase social interaction? And the way that we do that is through better basically medical countermeasures, right? So, it's through therapeutics, through vaccines that we're really able to go beyond where we are today and return to some degree of normalcy.

                            But I don't think the focus should be that there's no option now. I think the focus should be, we have something that works now and you can see that already taking effect in places where social distancing has been aggressively implemented.

                            Akash Bakshi: That's right.

                            Andrew Bartynski: The real question here now is to return to normalcy, what's the quickest path and what's the safest path? I think that's what we're trying to focus on.

                            Eric Ries: So, how soon could this happen? How soon do you think you could have some of the trials go well and you could have this drug in the hands, for example, of nurses to use prophylactically?

                            Andrew Bartynski
                            : So, our most aggressive timelines put that somewhere in the six-month timeframe. But again, that's always dependent on the outcome of clinical trials and the supply of drug that we're able to manufacture.

                            Eric Ries: What are the trials like for something like this?

                            Andrew Bartynski: That's a great question. And I think that's been one of the main difficulties that's been exposed in the COVID pandemic. So, the mainstay of evidence-based medicine is the randomized control trial, right? This is where you have your placebo group, you have your drug group, you randomly assign patients to them, you can do a very orderly follow-up where they come in, and you know all of the parameters that you're doing, you know your patients have only done what you've told them to do. And that kind of got thrown out of the window in the beginning of February.

                            And so, doing these trials is actually extremely challenging. And that's because we're in situations where there's no PPE, we're in situations where a variety of different medications are being used at the same time because we're looking for any way to ameliorate the symptoms of patients.

                            And so, what we're trying to do and our goal, is to really run a well-controlled trial, so that you can make scientifically-based conclusions about the efficacy of niclosamide. And so, what's been done so far with some of the other studies that have come out is that they've either been extrapolated from really small sample sizes or they haven't necessarily been very well-controlled, which is understandable because it's a very difficult time to do those studies. But it also becomes difficult to say what's working when you don't have good data.

                            Eric Ries: When I heard that the more recent data about chloroquine has been that some of the early benefits maybe were overstated or maybe were a sample size, wrong extrapolation. So, talk a little bit about why some of the existing potential treatments haven't panned out as well as you hope and how those are different from the compound that you're working on.

                            Akash Bakshi: So, one of the biggest differences between hydroxychloroquine and niclosamide, at least, from where we're standing is, again, safety profile is something that plays a really important role. And often what we're seeing in these hydroxychloroquine studies is a big ratcheting of a typical dose.

                            If, let's say, you're going to India during malaria season, your physician will likely give you one tablet that you take once a week. And that's just been my experience when I went to India with my mom as a kid. But now, what we're doing or what we're seeing individuals do is one pill a day. You ratchet up a drug that has known side effects. But by comparison, niclosamide, just because the IC50, or the concentration that's required to inhibit the virus's growth, is so much lower, you actually see that you don't need to really necessarily change the dosing from what has historically been done.

                            So, that allows us to just think about safety in a different paradigm, or at least hope that the drug continues and remains to be very safe in patients who are COVID-19 positive.

                            Eric Ries: I've heard in the vaccine world that there's some talk about accelerating the trials, accelerating the pace of getting this data by recruiting volunteers given how many people have been involuntarily exposed anyway. Is something like that possible here if there were volunteers who are willing to take the compound and have their data recorded? Is there something like that that could accelerate the timeline?

                            Akash Bakshi: Yeah, I wonder. I mean, I think the first trial that we're trying to run is in COVID-19 positive patients. And so, I think that necessarily those patients who are COVID-19 positive are likely looking for treatment anyways, but absolutely when we move to a prophylactic space, I think the first line of defenders that we would think of are health care workers who are an ICU user regularly engaging with COVID-19 positive patients.

                            Eric Ries: If somebody had been exposed to COVID right now and they were able to get their hands on this drug, would they be able to take it for this purpose?

                            Andrew Bartynski: I would not advocate that until clinical trials have been completed.

                            Akash Bakshi: I fullheartedly agree.

                            Andrew Bartynski: Yeah, I would strongly advise against what we saw happened with chloroquine, where somebody took something that they thought would be helpful and ended up overdosing and passing away. I think that is the worst-case scenario of what happens in medicine, and I think it's exaggerated in the current climate where people are scared.

                            So, again, our emphasis here is on well-controlled clinical data to support widespread use. And until that data is there, I think it's important for everyone to think, "Does this actually work?" And so, I think a lot of the treatments that are out there today, I think people need to think a lot more critically about whether those drugs are working.

                            Akash Bakshi: I figured you would say that, but I want to give you a chance.

                            Andrew Bartynski: I think it's important. That's something that you really have to hammer.

                            Nadja Mannowetz: And to build on what Andrew just said, I think we have to just make sure to understand how COVID-19 patients react to niclosamide.

                            Eric Ries: So, if you're listening to this now, do not start taking off-label drugs without having the appropriate data come in.

                            Andrew Bartynski: Yeah, everybody should refer to their physician, and I hope that their physician refers to their best judgment.

                            Eric Ries: What is it about coronavirus that is different or difficult compared to other viruses that we've battled through history?

                            Andrew Bartynski
                            : Well, they do seem to keep propping up, don't they, right? So first, we had SARS, then we had MERS, and now we have COVID-19. So, I think one thing that's problematic about them is their virulence or their capacity to spread and their mortality. Right? And so, I think that's the thing that makes this different than a standard flu that comes through, I guess.

                            And then, another thing that's been problematic, so they have propped up time and again, but they haven't stuck around long enough for us to be able to complete the development necessary to find a treatment. And so, COVID-19 and SARS-CoV-2 I think is the first coronavirus, to my knowledge, that was persistent enough and virulent enough for us to have the capacity to develop therapeutics or vaccines against.

                            Eric Ries: One of the things that really struck me about the story of COVID-19 is how many times people have referenced things that we learned during SARS or one of the previous epidemics that could have been applied here but it wasn't because we just didn't seem like it was worthwhile. Given the effectiveness of this drug was known against SARS, couldn't these trials have been done? Could we have been better prepared to bring drugs like this to market faster? Couldn't we have a fast trial pathway or infrastructure we could have developed that would make us more able to respond now?

                            Akash Bakshi: I think that's right, had SARS and MERS perhaps been pursued more or had there been more work that went into looking for treatment then, we could really build on that now. But instead we're picking up from where researchers left off in SARS and MERS and are trying to quickly move forward with something that works against COVID-19, and really took out all of the thoughts that they had then.

                            Andrew Bartynski: I think this is endemic in the infectious-disease space where the perceived necessity of a treatment is directly correlated with a number of cases at the moment, which is just like a bad metric, right? The real metric should be funding should go into something or something should be developed until there is a treatment. And then, once there is a treatment, yeah, then maybe you don't need to pay as much attention to it.

                            But I think that, again, this is hindsight being 2020. It's easy for us to say we should have done more at the time. But I think, again, resources are competitive and time is scarce. And so, once people see a disease decrease in its caseload or prominence, it gets relegated.

                            Eric Ries: Such a classic short-term thinking. One of the themes that's come up in a lot of these conversations is that this is not the moment for recriminations and blame, but I do think it's important for us to learn from the mistakes that we made in the past. So, I'm really a believer that we will get through this crisis, that there will be a recovery. It's going to get darker before it gets better, but we'll get to that other side.

                            What are the lessons you want people to learn from what you've seen so far? What are the investments we should be making to make ourselves more able to respond and react, make our society more resilient for next time?

                            Akash Bakshi: At a high level, I would think more investment in the life sciences just more broadly. I mean, I think infectious disease... So, the three of us did not originally intend or did not originally start our first company thinking of infectious disease at all. We just happened to be in a position where we could quickly move and enter into the space and do good.

                            I think infectious disease likely has not been nearly as much funding as it really needs. And I think more funding for the basic sciences or continued working on spaces is obviously important, I think. And we hear about that all the time, where we hear more and more bacteria are becoming antibiotic-resistant and what are we doing to create more drugs for that.

                            Eric Ries: The next time you hear someone saying, "What is basic research for? What is it ever done for us?" maybe they'll remember this moment.

                            Akash Bakshi: Oh, yeah, hopefully.

                            Eric Ries: It's such an easy thing to cut funding for because it has no practical benefit whatsoever, until it becomes a civilization-ending catastrophe. Then you would say, "Why did we fund this research all along?"

                            Andrew Bartynski: Yeah. I mean, I think there are two very structural changes that have happened in maybe the past 50 years in the world. And some of it is just the focus on short-termism. And the windows of thought have seemed to continuously get compressed in time, where we don't really have 5-year plans, 10-year plans, 20-year plans anymore. We're just constantly very focused on of short-term goals and outcomes.

                            And then, coupled with that, there's just the lack of planning for, I guess what are called, low probability events, right? I think this is just like a humanity or a very human problem, where if we see something that has a 1% chance of happening, in our minds, we very easily make that 1 to 0. And we do have to realize that 1% chances and 1% outcomes do happen, and we should prepare for them even if that ends up being something that we don't see the realization of, maybe it's our children that do or something like that. And so, you have to really think about the full spectrum of risks that can occur and not just the ones that we think would occur in the short term.

                            Eric Ries: I hope this is also something people will keep in mind next time they start criticizing tech startups for being useless. Because thank goodness, that you are working on this tiny, little obscure problem in your own little company. It probably didn't seem like it was necessarily the most world-changing thing at the time you were doing it. Certainly, I can imagine the skepticism you must have gotten from other people having done a lot of startups myself. And now, you could be in a position where we're all going to be incredibly grateful that you did it.

                            I would have thought that one of the difficulties in raising money for this pivot, I mean, just to put myself in the seat of an investor would be people saying, "Wait a minute, if a vaccine is coming, isn't the economic opportunity here limited to pursue this drug as a COVID treatment?" So, how did you overcome that kind of business skepticism, if you encountered any, as you were trying to get the startup and the pivot funded?

                            Akash Bakshi: So, I think somewhat luckily, it's not something that we've heard a lot because I think, folks think of it maybe in two ways that, A, if you develop a treatment for COVID, I think that there's definitely financial returns that are possible, if not, reputational gains that will result from doing this work. But the other is, again, thinking about the long term while we're waiting for a vaccine. So, if no other treatment is developed, there is a lot more pain that folks will feel as a result of just the economy not opening up fully. That's another consideration to think about.

                            And then, the last is also the fact that as we think about a treatment, sure, you can go after those that have been infected, but the prophylactic is a bit of a longer play, and one that would span the entire period up until everyone has been vaccinated, which still will be years after the vaccine is ultimately developed and shown to be effective and safe.

                            Eric Ries: Nadja, do want to just give us a science background just about niclosamide and how it works and maybe just a little bit about your research? I just want to make sure that people who are interested in the science behind this have a chance to understand how it works and what we're doing.

                            Nadja Mannowetz: Yeah. So, the mechanism in which niclosamide prevents replication of this virus is still not fully understood. But based on a previous study, we think that it works by the following mechanism. So, think of a cell that is infected with the virus, it then turns on a mechanism that is called autophagy, which means parts of the cell that are infected will be destroyed and recycled in a very orderly manner. So, in that scientific group showed that niclosamide turns on that process of autophagy, meaning the parts of the cell or the cell as a whole that is infected will be destroyed and recycled. Hence, virus replication will be inhibited.

                            As I said, we are not entirely sure if this is also the case for the current virus, but it is a very good starting point to do further research.

                            Eric Ries: What do you think the next wave of fundamental research that's needed here is?

                            Nadja Mannowetz: Yes, so, further research that is needed is to really understand what role niclosamide plays in the whole process. Does it prevent the virus from entering a host cell? Does it prevent the virus from inserting into the host cell's genome? Does it prevent the burst of the cells so that the virus can spread? So, these are all parts that we, as researchers, need to look into.

                            Eric Ries: Akash, maybe you can talk a little bit about what does it feel like to take your whole company and put it on hold to build something new, not really knowing if you'll ever get back to the original vision or plan that you had?

                            Akash Bakshi: I don't think I have yet ever thought that we're never going to return back to the original vision just because I think it's so important. But I will say, it's frightening because you're... I mean, the three of us have all taken a leap of faith in doing something that we think is the right thing to do. But despite being a bit fearful is the fact that I think we've been well-received, and we've received just a lot of encouragement along the way from people who I think are way smarter than us. I mean, when we say that we've not received a lot of nos, it's just because everyone has been so encouraging.

                            Eric Ries: Anyone who you found especially supportive or any stories you can tell us about people that really stepped up to encourage you to take this risk?

                            Akash Bakshi: I would say the YC network has been super helpful, I think our partner, Jared, biopartner, Uri, PB, Sam Altman. I mean, that community is what allowed us to take a breath of fresh air to really consider, to feel more financially stable and fund much of the work that we had to do to get to this point and really allow us to go full steam ahead.

                            Nadja Mannowetz: Yeah.

                            Eric Ries: What are the next steps for the company? Where do you go from here?

                            Akash Bakshi: So, the next step is a clinical trial, and we have some guidance from the FDA as to what they're looking for. And so, it's a matter of raising the capital that's needed so that we can begin enrolling patients and run the trial to see how niclosamide works in COVID positive patients.

                            Eric Ries: Who do you see as the heroes of this crisis?

                            Nadja Mannowetz: Healthcare workers.

                            Akash Bakshi: That's the real truth.

                            Nadja Mannowetz: Yeah.

                            Akash Bakshi: We're just trying to help but they're doing God's work. And it seems so thankless and they're really putting their lives at risk.

                            Eric Ries: Yeah, it's a profound thing. And I hope one of the things that will come out of this crisis is a renewed appreciation for things that we take for granted, like their incredible endurance and the sacrifices that they make on a daily basis.

                            Akash Bakshi: Without PPE. I mean, sometimes I don't want to throw out the garbage without wearing gloves. And to think that you're really exposing yourself at risk to really just help other people, they're the real heroes.

                            Eric Ries: I saw on social media an image someone had posted of a nurse who had a sign that said, "We're not heroes, we're being martyred and voluntarily against our will," something like that. And I just felt sick.

                            Akash Bakshi: Want me to be very honest? I think I got shivers thinking about it. But just honestly, I have a few cousins who are physicians, and when my aunts and uncles and I, we chat during the social distancing, I'm always asking how are they. I just think these healthcare workers, they're putting themselves at risk, but they also are putting their families at risk and the toll that COVID-19 is having on other patients is truly felt by everyone because I'm sure we all know healthcare workers and we're all worried about how they're feeling.

                            Akash Bakshi
                            : Nadja knows this or Andrew knows this that during the shelter-in-place, my aunt, she had a mastectomy for breast cancer.

                            Eric Ries: Oh, I'm sorry.

                            Akash Bakshi: And the fear then quickly became... I mean, at some point there was the fear of like, "Oh my God, is she going to have her surgery at all?" Then when it was clear that she was going to have the surgery, then the question became like, "Is she going to be at risk of getting COVID-19 for having gone into the hospital?"

                            And so, I just think that though the work that... I mean, the truth is that all the healthcare workers that have been doing all this work, they're putting themselves at risk, but they're doing it at the benefit to allow cancer patients to continue surviving, or allowing folks who might just hit their heads. I mean, I don't think that this is right and I think that it's really stressful that we don't have...

                            This is where I personally feel like there are levels of the things that we need, and PPE is the bare minimum of what we need to begin offering not only healthcare workers, but just the public at large to feel and be safer. And I think it was stressful that the CDC didn't come out with the guidance or the suggestion that we should wear masks in public until just very recently.

                            Eric Ries: Yeah. And there's actually been a private sector group called #Masks4All, we'll put a link in the show description, that has been leading the way on getting the public educated about the need for masks and to make sure we don't use medical masks in public. And that the governor's need to pass executive orders and a whole bunch of stuff that has to happen to help prevent transmission as the economy reopens. And we see this again and again and again in this crisis, private sector leaders, startups, investors, people you'd never imagine stepping up to lead because that's what's needed.

                            If someone is listening to us right now, and they have a startup and they think there's a possibility that they could pivot and go into COVID relief efforts and move away from their original vision or they're feeling some fear about that, some anxiety about that, what advice would you give them?

                            Akash Bakshi: I think you have to do it. Andrew is really good at talking about moral obligation, and I wholeheartedly agree with him. I think of it in a different way. If we had not pivoted, I wonder to what extent... If we were still only working on YourChoice Therapeutics, I think that I would be stressed and feel guilty for not having done something.

                            And the flip side of that is also that as a result of working unimaginable hours that... I joke that if we had not done this, maybe we would have just been relaxing and just watching TV. But this has really given us something to focus our attention and not feel like we're helpless. And it makes us feel like we're playing an important part of the COVID-19 recovery plan.

                            Eric Ries: For people who are not doctors or nurses or healthcare professionals, how can they help?

                            Akash Bakshi: I have an aunt who is not a physician. There are still families in the Bay Area who are unable to have meals because they're unemployed now. And so, my aunt plays a role at the Samaritan House in San Mateo County. And so, I think it's challenging because yeah, she has to social distance. But I think, you don't need to be a medical, you don't need to be a life scientist or a biologist or a tech to help someone because I think this is something that affects everyone in so many different ways.

                            Nadja Mannowetz: Yeah, I also heard about that program, I just forgot the name of it, where you can have a daily phone chat with an elderly person at a... Are these homes called elderly care facilities?

                            First, I thought, "Oh, that sounds interesting," and then I realized, "But I just don't have time."

                            Eric Ries: Yes. So, think of it this way. Well, I'm not using the lab trying to cure this disease, the rest of us can pick up the slack of the thing she doesn't have time to do. We'll look up that program and put a link in the show notes.

                            And listen, this is not a time to feel shy about that. We all have to help in the ways that we can, and I think there's so many important things that need to be done right now. I mean, I was just talking to a group called Frontline Foods, and they have figured out a way for people to donate money so that restaurants that are about to go out of business can provide free meals to frontline health workers. And we're seeing that over and over and over again, people creating these pop-up organizations that can do so much by way of helping. So, not everyone can be in the lab building the cure, but all of us have a part to play.

                            Akash Bakshi: That's right.

                            Nadja Mannowetz
                            : Mm-hmm (affirmative).

                            Eric Ries
                            : So, do it for Nadja. That's all I'm saying. What do you think will be the long-term impact of the crisis? What does the new normal look like?

                            Nadja Mannowetz: So, if I just share how I personally try to answer this, I actually don't know how it's going to feel to take public transportation at some point again, to be around other people. It is, I think, I don't know. When do you start trusting the world again? For me, I personally don't have an answer to that.

                            Akash Bakshi: I can build on that. And I'd say like, when is it safe to go to a bar or a social gathering again, right? Maybe a bar is a horrible example. But I just think when will it be normal again to just meet up with friends in a social setting, at a restaurant or at a place where you're closely packed in with other people? I think that's interesting. Maybe that's coming from the fact that I'm single in COVID-19, I just wonder what that's going to be like. But the other part of me is I love Indian classical music, and I think when am I going to go to a concert where you're sitting so close to the next person and not feel that I need to social distance?

                            Eric Ries: Where do you think we go from here? How do we get out of the crisis?

                            Akash Bakshi: I mean, the number one is that we need PPE. I also think the next step is a safe and effective treatment. Yeah, I think that's the only way. And then, the prophylactic as well. But how all of those things will come in and who will ultimately have the product that works, I think only time will tell.

                            Eric Ries: This has been Out of the Crisis. I'm Eric Ries. Out of the Crisis is produced by Ben Ehrlich and edited by Jacob Tender, music composed and performed by Cody Martin, hosting by Breaker. For more information on COVID-19 and ways you can help, visit helpwithcovid.com. If you're working on a project related to the pandemic, please reach out to me on Twitter, I'm @ericries. Let's solve this together.

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