50 min read

ANA Therapeutics: Niclosamide
Out of the Crisis Podcast Transcript

Like almost all scientists, biologists and pharmaceutical researchers, Akash, Nadja and Andrew were not planning to work on COVID-19 treatments a few months ago.

They had just taken a big step with the FDA for their contraceptive treatment and were going full steam ahead in drug development. The company they founded, YourChoice Therapeutics, was poised for a big year. Then, the crisis hit. They realized their treatment could have an impact on COVID. The following weeks saw them pivoting their entire operation to try to help.

In this episode we discuss the science behind their treatment, the story of how they pivoted their company and the challenges they are facing.

Show Notes

Panelists

Producer: Ben Ehrlich

Editor: Jacob Tender

Links

The original audio can be found on Breaker, Apple Podcasts or wherever you listen.


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 are 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 at 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, 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

So hi, my name is Akash. My background is in biochemistry and 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 PhD in biology, it was focused on medical microbiology to study Legionella, Marcela, a bacterium that causes typical 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 PhD in chemical engineering. During grad school, I was working on solar cells and kind of fell in love with startups. So once I graduated, I started working on a company in the Bay Area, developing transparent solar cells, that 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, couldn’t get out of my head, and I’ve kind of been working with them ever since. And then when COVID happened, we kind of felt an obligation to see if our technology had any application there and and kind of went with it. Once we saw there was promise.

Eric

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

Akash

So the real truth is that before the crisis started, the three of us were working on developing 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. And at the same time we received an NIH grant to to fund all of the studies that we 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 and three to six months. And then more and more about COVID-19 started hitting the news and and I’ll let Andrew take it from there as to what happened.

Andrew

Yeah, so we were sort of having our weekly meeting on Mondays where we, you know, go through the the task board and think about what to do next. And it was sort of serendipitous where we had this like breath, where we kind of jokingly were like, okay, like, 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 kind of center of mind for the new cycle and everything else.

Eric

Give us the timeline a little bit. When did you start the company and when How long have you been working on it? And then when when was this exactly? If you recall, when you kind of got the grant?

Andrew

Yeah. So that we we got this grant on like March 5, or six. And the, the submission to the FDA was maybe two days before that, like March 3. And so this meeting, I think was happening on maybe the ninth or 10th of March. And so yeah, that was sort of the, you know, everything was, there was a breath of fresh air kind of where we just finished this big push for your choice. And then we sort of jokingly said, like, hey, what if the compound that we’re working with Niclosamide actually also works for COVID? Because sort of a running joke in our group is that like, Niclosamide works for everything. Because if you look in the literature, it’s shown great promise and 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 kind of planted the seed of like, maybe there’s something there.

Akash

And actually, I’d build on that 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 to play. But what was really interesting in the development is that 90 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 two, which is the virus is responsible for genital herpes. So I mean, if you think about a contraceptive that can go about inhibiting STDs or STI is, I mean, you think that that is somewhat of a gold standard, right. And so that was really interesting. And that builds into the point that that engineer making that it seemed that Niclosamide was this just wonder drug and so was there any proof that it worked on Czar’s code?

Eric

So before we get into the science of that, because I want to, 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, so, what was the original vision for the company and then how did you settle on Niclosamide as a as a product to pursue?

Nadja

YourChoice Therapeutics is a spin out of putting out managed cause lab at the University of California Berkeley. And the 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. And 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 achieve 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 immortal, immortal, 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, it’s a drug that has been on the market for five to six decades.

Andrew

Yeah. Niclosamide was originally discovered in the 1950s by Bayer. And since then originally was commercialized in Europe, and then in the US in the 1980s, as a taper medication originally. And so because there’s not really a tapeworm problem in the US, I don’t think it ever really came to prominence here.

Eric

So this is an established drug. with a long history and track record of being safe for use in humans.

Andrew

Right, 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 like 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 and this drug.

Nadja

And these side effects, they are not severe. We are talking about 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

How did you first become aware of Niclosamide?

Nadja

That was based on literature research, looking for molecules that Disable mitochondria from producing energy. So mitochondria are, 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 that Niclosamide always shows up. And yeah, then I mean being a scientist then use starting all what is Niclosamide? What is compound x? And yeah, 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 anti viral properties and then you This is not only an effective compound, this is also a safe compound. And then you conclude it’s a very, very promising compound.

Eric

Hmm. So Akash, maybe you can tell us the kind of company founding story, because I think when most people imagine a therapeutics company, they have this idea that, you know, people work for many years in a lab working on a novel compound, then it has to go through extensive trials, you know, for years and decades to be proven that it’s safe, but they have a kind of 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. And how did you have the idea to try to build a company around an existing compound, but a new application?

Akash

It’s a great question. And 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, but so that there was that day that Kind of 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 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 in internally about well, does this even work against ours Cove two, and on that Wednesday, we had to send an investor update to to the investors of YourChoice Therapeutics, in which we, we gave the update that look the pre ind was submitted to the FDA. We also have just got this grant from the NIH. We also are about to order compound from our supplier so that we have Niclosamide to run our clinical trial for as the gel. But by the way, we think that this shows a lot of promise for COVID-19. And we think that we should run a phase three 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. And all of a sudden, we were like, Well, here we go, and what do we do next? And so we ultimately decided to put all of the COVID work into a separate company. And, and that’s how that’s how things started.

Andrew

Well, I think I think what was interesting also and another point that Eric was getting at is, traditionally biotech is preceded by five to 10 years of PhD work and in this case it was preceded by five decades of published literature. And so I think that the type of company that ama 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 in 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 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. 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 stars Koch to, you are sort of 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 kind of have to go for repurpose drug first.

Eric

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 to 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 the startup in charge of this?

Andrew

Great question.

Akash

But Andrew sounds like you have a, maybe you have a better response than I’m thinking of.

Andrew

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 are 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 produced significant quantity to get into the clinic and run the trial may not be as quick. I think Gillian has depth They done a great job with rendez severe 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

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

Akash

Yeah. So I think that there’s also a risk associated with will the drug work or will it not work if if you had to think about repurposing and 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 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 that may be, you know, if 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 if that’s being used as part of people’s calculation. But I do think it’s it is I would build on Andrews 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 all the data that’s available about Niclosamide is very sparse. It’s all published from 5050 to 30 years ago, and you have every paper that has ever come out, again, about Niclosamide references, the 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 business is a great drug. But if 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

So let’s go to the moment when you had the realization, you know, it sounds like this, you know, originally you voted this as a covert treatment almost as a joke. It was, you know, just because you That was a running joke in your team, but you emailed your investors, you’ve got a sense that there was some interest there, like, 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

Yeah, so I think this is a moment where Akash refers to be a little bit as a loser. And so when when I have an idea in my mind that I am pretty convinced about all sometimes just Gotta do things. And so this is one of those moments where it was, I think it was like 1030 or 11 o’clock 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 like, this needs to happen. And so I think that was that was when the company sort of became nascent, like that was what 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 code to replication at 150 nano molar concentrations, like 25 times more effective than what’s been shown for Clark when and 70 times more effective than room death severe. And so like that was the moment where we were like, holy crap, we sort of like went out on a limb here, and it seems as though we might be right.

Eric

Where’d you get that data from? who and who first brought to your attention?

Akash

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 all flights from Europe to the United States would be halted on Friday. I remember that. 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 we’re like, here we are. We need to get drug from 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 like one major part of our brains of just logistics had never been something That I have we ever had as a team and 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. Pay on ci, and had him specifically look at the ability of Niclosamide to inhibit SARS code to so that was the that was the next step. And when that data came back at 115 animal meaning for 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. Sorry, go to that was just so like, 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 like we knew that that Niclosamide was going to work but that it was gonna work as well was delicious. Surprise.

Eric

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

Akash

I wonder to what extent supply chain plays a role. Because Niclosamide is not available for off label use, or your your doctor can’t write you 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

So let me see if I if I’ve got this right. Last year, you thought you were going to be working on startup related to a non hormonal contraceptive around Niclosamide drug that’s been studied for decades and is shown to be safe and has this kind of 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 that you’re sitting on a potential treatment for the pandemic.

Akash

What happened next, 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 Nicholas in mind 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, 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

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 like really cool.

Eric

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. Sounds like you’re having that experience. You’re like living in real time.

Akash

That’s really true. I would say that our the response from the FDA is kind of a funny story that we had filed with the FDA for the vaginal gel, March 2. And we ended up getting a response back April sixth, which is a very normal timeframe by which to get a response. We filed the our we filed with the FDA on March 23. For COVID-19 and I think two days after we got the response for the vaginal gel, we heard back from the agency about Archie men for COVID-19. So even the FDA is well at that superfast speed.

Eric

What was last time you heard about an order of magnitude speed up in government responsiveness? That’s a really positive story.

Akash

I mean, these are all things that just help us continue to move faster as where as 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

So talk a little bit about the potential here because I understand that, you know, 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

Yeah, it’s a it’s a tough question to answer and and much of it is Based on the results, but yeah, just to build on, you know, if everything goes, if the results are outstanding, and it’s very clear that we’re 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

you said it could potentially be used prophylactically. Explain what that means.

Akash

I mean, that’s another area that is really of interest to us is, you know, if you use an antiviral, either, just after you think that you might have have been infected, or if you use this, just, you know, 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 from really having its full course. And so one thing that we think about given the safety of Niclosamide over long over long periods of time is that this actually seems like a great drug for individuals who are, you know, in the healthcare space, who are net are likely working with covered positive patients as a post exposure prophylactic, so because they’re just at risk of getting COVID-19, from those that are around them that we think could help with 30 million healthcare workers in the United States. But then we also think about, you know, 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 in in 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

So you’re saying that, you know, for nurses like what, 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, you know, I mean, who hasn’t seen the images and gotten the Facebook messages about, you know, nurses desperate to find rain ponchos, and God knows what else it’s been. 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, you know, on a daily basis, just to prevent them from getting 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

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. And obviously, you have to run the clinical trial in a well controlled fashion to prove that’s the case. But our hope is that having proven once we’re able to prove that this is an effective anti virus 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 that they do become infected.

Akash

And actually think just building on what you’re saying, Andrew, I think that a, 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 911 changed travel for the, for everyone for the rest of their lives. I wonder if this just changes how we interact, or, 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 treatment prophylactic treatment? How do we engage in a way to prevent ourselves from from getting COVID-19? Or if you have it? How do you know it just because of the Leighton time that it takes to actually show this out? How do you how do you know who’s safe. And so that’s why I see this playing an important role.

Eric

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, and 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. And I but I keep having this thought as a lay person in the back of my head, I say, Well, that sounds good. But if if the virus doesn’t mutate, you know, maybe we build the perfect vaccine for this strain, but a new strain emerges. And there’s a second peak, God forbid, and that’s my understanding is that was 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

Yeah, I think there’s actually a great analogy here between antivirals and antibiotics. And where 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 that robustness to evolutionary pressures.

Akash

And, and I would say that I think we’re all hoping for the vaccine to come out as well. Right? I mean, I mean that the Andrews point, 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 to so that we can make sure that the PK levels in your bladder sit at the right level of vaccine is hopefully once or I mean, sometimes some vaccines take three times to administer but at least the vaccine would would help a lot in this area. And but the other the other thought about that is, you know, do we have we need multiple shots on goal. So there needs to be a shorter term response because even right now, with 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 I think this, again, I think of this as all of it a jigsaw puzzle where there are multiple, there’s not one answer, but there are a lot of pieces that come together to, to help fight COVID-19.

Andrew

But I also I don’t want to be just doom and gloom as though there’s there’s no hope. Right? Like, as we’ve seen, like social distancing does work. So that’s great. Like, that’s step one. We have something that works. That’s that 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. So 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, you know, better basically medical countermeasures, right? So it’s through therapeutics, through vaccines, that were really able to go beyond where we are today and return to some degree of normalcy. But I think that we don’t need to you No, I think 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. That’s right. The real question here now is to return to normalcy. What’s, what’s the quickest path and what’s the safest path? I think that’s what we’re trying to focus on.

Eric

So how soon could this happen? How soon do you think you could have some of the trials go? Well, you could have this drug in the hands for example of nurses to use prophylactically.

Andrew

So our most aggressive timelines, put that somewhere in the six month timeframe. But again, that’s always double On the outcome of clinical trials and the supply of drug that we’re able to manufacture,

Eric

What are the trials like for something like this?

Andrew

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, I’ve 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 PvP, 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

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 to 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 from the compound that you’re working on.

Akash

So one of the biggest differences between hora Quinn are hydroxychloroquine and Niclosamide, at least from where we’re standing is again, safety profile is something that plays a really important role. And, and often what we’re seeing in these hydroxychloroquine studies is a big ratcheting of the typical dose 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. This has been my experience when my 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 IC 50 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 for What has historically been done? So that allows us to just think about safety in a different paradigm or or at least hope that the drug continues, it remains to be very safe in patients who are COVID-19 positive.

Eric

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 in voluntarily exposed anyway, is something like that possible here? If there were volunteers who were willing to take the compound and have their data recorded? Is there something like that that could accelerate the timeline?

Akash

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

Eric

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

I would not advocate that until clinical trials have been completed. I full heartedly agree. 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 that’s, 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? Yeah. 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.

Eric

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

Andrew

I think it’s important we have to really, you know, that’s something that you really have to hammer.

Nadja

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

Eric

So if you’re listening to this, now do not do not start taking off label drugs without having the ability appropriate data come in.

Andrew

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

Eric

What What is it about Coronavirus? That is different or difficult compared to other viruses that we’ve battled through history.

Andrew

Well, they do seem to keep cropping up, don’t they? Right. So first we had SARS. Then we had murderers and now we have COVID-19. So I think one thing that’s problematic about them is their violence 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 so another thing that’s been problematic, so they have cropped on 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 stars cope two, I think is the first Coronavirus to my knowledge that was persistent enough and viral and enough for us to really need to, or even not even need to just to have the capacity to develop therapeutics or vaccines against.

Eric

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. Hear but it but it wasn’t because we just didn’t seem like it was worthwhile. You know, given that the effectiveness of this drug was known against SARS, couldn’t these trials have been done? Like if we, you know, could we have been better prepared to bring drugs like this to market faster? Couldn’t Couldn’t we have a fast trial pathway? Like I said there infrastructure we could have developed that would make us more able to respond now.

Akash

I think that’s right, had had SARS and MERS perhaps been pursued more 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 and SARS and MERS and are trying to quickly move forward with something that works against COVID-19 and really got all of the thoughts that they had then.

Andrew

There’s I think this is endemic in the infectious disease space where the perceived necessity of a treatment It is directly correlated with the number of cases at the moment, which is just like a bad metric, right? Like the, 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, you know, 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, you know, caseload or prominence, it sort of gets relegated.

Eric

Such a classic short term, short term thinking, you know, one of the themes that’s come up in a lot of these conversations is that, you know, 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 you know, 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 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

At a high level, I would think more investment in the life sciences at broad, 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, where we just happen to be in a position where we could quickly move in and enter into the space and do good. I think infectious disease likely has not gotten 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 More and more bacteria are becoming antibiotic resistant. And what are we doing to create more drugs for that?

Eric

The next time you hear someone saying what do we what is basic research for what is it ever done for us? Maybe they’ll remember this moment.

Akash

Oh, yeah, hopefully.

Eric

You know, 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 say, why did we find this research all along?

Andrew

I mean, I think there are two kind of like very structural changes that have happened in maybe the past 50 years in the world. And some of it is just the focus on like, short termism. And the the windows of thought have seemed to continuously get compressed in time, where like, we don’t really have five year plans, 10 year plans 20 year plans anymore. We’re just constantly very focused on on sort of short term goals and outcomes. And then coupled with that, there is just the lack of Planning for, I guess what are called like low probability events, right? Where we just, I think this is just like a humanity or a human, very human problem, where if we see something that has like a 1% chance of happening in our minds, we very easily make that one to zero. And we do have to realize that that one 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 the realization of, maybe it’s our children that do or something like that, right. 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 in the short term.

Eric

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 were working on this tiny little obscure problem in your own little company, and you know, not probably didn’t seem like it was necessarily the most world changing thing at the time you were doing it or 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 kind of limited to pursue this drug as a covert 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

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, you know, a if if you develop a treatment for COVID, I think that there, there’s definitely financial returns that are possible, if not, reputational gains that that will result from 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 are those that have been infected, but the prophylactic is a bit of a longer play, and one that would span the entire period up and until everyone has been vaccinated, which still will be years after the vaccine is ultimately developed and shown to be effective and safe.

Eric

Now, did you do you want to just give us a kind of a science background just about Niclosamide and how it works and maybe just a little bit about your research. I want to make sure that people who are interested in the science behind this have a chance to, to understand understand how it works and what we’re doing.

Nadja

Yeah. So the mechanism by which Niclosamide prevents replication of this virus is still not fully understood. But based on a previous study, we think that it works by by the following mechanism. So, think of a cell that is infected with the virus, it then turns on a mechanism that is called a toughie G, which means parts of the cell that are infected will be destroyed and recycled in a very orderly manner. So in that, that scientific group showed that Niclosamide turns on that process of a tapa G, 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

What do you think the next wave of fundamental research that’s needed? Here it is.

Nadja

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 it To the host cells genome, does it prevent the 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

Because maybe you can talk a little bit about like what it felt like, like, 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

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 in doing something that we 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, and we’ve received. Yeah, just a lot of encouragement along the way from people who I think are way smarter than us. Yeah, I mean, I think that’s what when we say that we’ve not received a lot of noes. It’s just because everyone has been so encouraging.

Eric

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

I would say the YC network has been super helpful. Right? I think our partner Jared, the bio partner ri Pb Sam Altman, I mean that that community is what a loud us to take a breath of fresh air to really consider to feel more financially stable as we 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.

Eric

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

Akash

The next step is a clinical trial. And we have some guidance from the 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 then run the trial to see how Niclosamide works in COVID. Positive patient.

Eric

Who do you see as the heroes of this crisis?

Nadja

Health care workers.

Akash

That’s the real truth. Yeah. Who we’re just trying to help, but they’re doing God’s work. Yeah. And it seems so thankless and they’re really putting their lives at risk.

Eric

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

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

Eric

I saw on social media and image somebody 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, I just felt sick.

Nadja

Yeah.

Akash

Want me to be very honest, I think I got shivers thinking about it. But just honestly, I have a number of few cousins who are physicians. And I think when my aunts and uncles and I, we chat during the social distancing, I’m always asking, you know, how are they I think, I just think these health care workers, they’re putting themselves at risk there. 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 health care workers, and we’re all worried about how they’re feeling. And like not he knows this, or Andrew knows this that, you know, during the shelter in place my aunt had to have, she had a mastectomy for breast cancer. 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 the 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 like, I just think that though the work that I mean, and the truth is that all of the health care 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 continue surviving or or allowing folks who may might just hit their heads. I mean, like, I don’t think that this is right. And I think that it’s, 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 PPP is the is the bare minimum of what what we need to begin offering not only healthcare workers but just the public at large to feel and and be safer. And I think it was stressful that the CDC didn’t come out with the guidance of of, or the suggestion that we should wear masks in public until just very recently.

Eric

Yeah, and it’s actually been private sector group called masks for all. We’ll put a link in the show description that has been leading the way on getting the public educated about the need for for mass and the need to make sure we don’t use medical mass 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, you know, we see this again and again and again in this crisis, private sector leaders, startups, investors, people you’d never imagine stepping up to because that’s what’s needed.

Nadja

Yeah. Hmm.

Eric

if someone is listening to us right now, and they have a startup, and they think there’s there’s a possibility that they could pivot and go into COVID relief efforts and kind of 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

I think you kind of have to do it. Andrew is really good at talking about a moral obligation. And I think I wholeheartedly agree with him. I think I think of it in a different way. If If we had not pivoted. I wonder to what extent if we were still 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 an unimaginable hours that you know, joke that we didn’t 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

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

Akash

I have an aunt who’s not a physician. But 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 that they’re still I think, you don’t need to be a medical. You don’t need to be a life scientist or a biologist or a in tech tech. help someone because I think this is something that affects everyone in so many different ways.

Nadja

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 bar these homes called elderly care facilities. And first, I thought, Oh, that sounds interesting. And then I realized, but I just don’t have time.

Eric

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. Well, we’ll look up that program and put a link in the show notes. And listen, you did not have 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 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. Yeah. 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

That’s right.

Eric

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 is the new normal look like?

Nadja

So if I just share how, how I personally, try to answer this. I actually don’t know how it’s gonna feel, to take public transportation at some point. Again, to be around 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

I can build on that. And I’d say like, when is it safe to, to go to a bar or a social gathering again? Right, I think, I think maybe a bar is a horrible example. But I just think that as Yeah. I just think when will it be normal again, to just meet up with friends in a in a social setting? at a restaurant or at a Yeah, at a place where you’re closely packed in with other people I think. I think that’s that’s interesting, I think. Yeah, I mean, I to be, I 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 that 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

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

Akash

I think number one is that we need PPE. I also think the next step is that 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 that works, I think, only only time now.

Eric

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 when 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.

I'm building products that build the next generation of companies at LTSE. This blog is where I share my personal thoughts.

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