Music. Andrew: (Introduction) Welcome to PharmaTalk Radio. I'm Andrew Goldstein. In this podcast, I'll be interviewing Anil Diwan, President and Executive Chairman of NanoViricides, Incorporated listed on the New York Stock Exchange as NNVC, about the science and clinical development of their nanomedicines against viruses. NanoViricides is developing antiviral therapeutics using a patented platform nanotechnology with a novel approach to develop and deliver antiviral drugs. The platform can be used to rescue drugs with delivery and PKPD problems for antiviral and other therapeutics.
Andrew: So to get started, what are you hoping to achieve at the PODD conference this year. Anil: So we like PODD conference because we get to talk to a lot of people in similar areas, like what we are working in the drug delivery aspect, the targeted drug delivery aspect, the oral delivery aspect. These are all very important things, and we learn a lot there, and we also interact with people. We believe that there are a lot of people that come there who have specific needs. They have drugs in mind that they want to have delivered in a different manner, you know. So we want to make connections of that kind. We want to develop collaborations for their developments to help their drugs.
We also want to develop collaborations that will take and help us with getting all these multiple phase two clinical trials that we really have in front of us. Andrew: Regarding your lead drug, NV ti87, in a recent press release, you stated that three of the viruses addressed by it, namely Influenza, RSV and COVID account for over $8 billion in estimated market size for 2024 growing to an estimated $12 billion in three years. I understand you just finished phase one trials on the lead drug. Can you talk about that? Anil: So the NV-ti87, is the drug that we developed during the covid pandemic that I was talking about earlier. We use the abashment receptor decoys as the ligands that will bind to the virus that are decorating and covalently attached to the nanoviricide micelle surface. So what that does is two different things. One is, I was alluding to that before that, SARS_CoV-2 was a BSL-ti or 4 class virus. We could not directly use it. We did use pseudovirions of that, and we did demonstrate that NV-ti87 does work in that system. But what we really need is a physiological approach, that is, animal studies. So for that, like I said, we use the model virus, and in order for developing a drug that works against a model virus and the native virus, both of them, we had put ourselves to the task that the ligand we choose has to be broad spectrum, so that (A) the virus will not drift away from it. There will be no escape resistance, and (B) it will work across the entire family of coronaviruses.
What happened beyond that? What we did, and it was a pleasant surprise, we mimicked what are called sulfated proteoglycans. It was a fortunate coincidence that that particular mimic was excellent at decoying the virus’s landing site. Heparan sulfate - it's sort of like there are several sulfates that come up off the plane of the sugar on one side. And our ligand matched that kind of stereochemistry fairly well. So that was very good. And because of that, we thought, okay, then maybe it can also work against other viruses that also use heparan sulfate proteoglycan or other sulfated proteoglycans for viral attachment, the initial step. And you may not know this, but it has been well established that more than 90 to 95% of viruses that are human pathogens, they all bind to heparan sulfate proteoglycans or some other sulfated proteoglycan. Now that's huge when you have one drug against viruses, almost like penicillin was against bacteria. Penicillin can aback almost every bacterium, except some of the bacteria have become resistant, and so on, so forth. But that kind of broad spectrum activity we were able to achieve against viruses.
So when we started expanding on discovering which viruses this particular drug, NV-ti87, works against, we went after influenza, we went after RSV, and, of course, coronaviruses, we tested many different viruses.
And in addition to that, you probably remember in 2022, the mpox epidemic happened, and people were expecting that it might spread. The pox viruses also use HSPG. So we decided to develop something and see if it works against that. Because there is no drug against Pox viruses right now, the only drug that is developed and stockpiled is called TPOXX. (tecovirimat), which was actually mobilized during the 2022 Mpox pandemic.
Unfortunately, it has no activity against Mpox as was shown in a clinical trial supported by NIAID/NIH that was just recently concluded. So I think that our drug now has a very good chance of attacking that MPox in the current epidemic in Central Africa.
So going back to where you are asking me, phase one trial of NV-ti87 was completed. There are absolutely no serious adverse events, no adverse events at all, practically. And so it is a very, very safe drug. And we knew that going in from animal studies already, the what is called maximum tolerated dose (MTD) and no observed adverse event level (NOAEL) dose in animals was extremely high, you know, 1200 milligram per kg in NOAEL, 1500 milligram per kg in MTD, in rats for injectable NV-ti87; that's huge, because when you give it orally, it's even safer than that.
So because of that, we started working on, like I said, Mpox. We did two different kinds of studies on Mpox. We did a skin to skin infection type of study. We did an aerosol type of infection study, and in both of them, NV-ti87 matched the activity of tecovirimat, and also when they were given together, there was substantial improvement in the activity. What that means is that what we thought that the two drugs are acting by orthogonal mechanisms, mechanisms that are independent of each other, is true.
So one more thing like now that tecovirimat has failed, of course, NV-ti87, can be deployed. We would really like it to be helpful to people, patients in the world where it is needed, we are open to it, and we are also trying to access our contacts for doing that.
In the case of RSV, you probably know now RSV is in the news a lot because two different RSV vaccines were recently approved and a new antibody was also recently approved. That antibody was approved as a prophylactic in infants. And what that means is that if the infant is gauged to be at risk of get catching an RSV infection, then that antibody is to be prescribed, and it will protect the infant for about between three and six months, and after that, you may have to do the same course again, or whatever. But there is no drug. The only drug is ribavirin, which is highly toxic, only given in very late stage. You know, all hopes, like Hail Mary type of approach.
So, we wanted to aback that and in fact, we did animal studies with RSV infection, lung infection, lethal studies. We always do lethal studies, because with these studies you can develop objective metrics of actual numbers, which you can compare for the effectiveness of different approaches of treatment. So, in the case of RSV, we actually were able to get the animals completely cured. There was no lung pathology seen in micro-histopathology, and they survived through the entire course of study, ti0 days that we followed them. At ti0 days, because of the protocol that was in place, we had to sacrifice them, but they were completely healthy. So that is amazing. Now you know RSV, a lot of drug development has been taking place, and a lot of drugs have failed in clinical trials. Those antibodies were originally developed hoping to be actually therapies, and they were not therapies, so they were then promoted to be prophylactics. Vaccines are there for adults right now, vaccines for infants and pediatrics are not yet approved. They might get approved too, but there is no drug. So that's a huge thing that is a challenge, and unmet medical need. And we have actually something that cured that RSV infection, which has not happened before. So we are very, very hopeful that NV-ti87 is a very good drug against RSV.
Like I said, Mpox is there. RSV is there. In the case of influenza, we did similar lethal studies. In those studies, we used three different drugs that are already approved, Tamiflu. , Repivot. and Xofluza. , in three different groups, separate groups, and our drug in another group, and our drug beat them by 100% more increase in survival in those studies. That is amazing. So it does work, and it is excellent in terms of efficacy, as far as what you can see in animal studies. So of course, it should be promoted into human clinical trials and tested there. We are planning to do that.
One of the things that we would really like to do is, because it's such a broad spectrum drug, we would like to evaluate it against multiple viruses. That kind of approach is being talked about right now, but it is not something that fits within the current, let's say, mold of regulatory development. So we are talking about it. If we can make that successful, we would probably have a single drug NV-ti87 that works against most, if not all, respiratory viruses. That means it is broad-spectrum, just like penicillin. Penicillin was the antibiotic for bacterial infections that your doctor prescribes when you come in and he assumes that it's a bacterial infection without having to test which bacterium it is. Same thing will happen with NV ti87, it can be given to the patient when viral infection is suspected without having to test which viral infection it is. THAT would be revolutionary in this field. And with that in mind, with that as our vision and goal, we are trying to develop phase two protocols of different kinds. And we are, like I said, connecting with regulatory agencies in Africa for phase two in Mpox, in the current epidemic that's going on there. We are also talking to our own consultants in India for developing a broad clinical trial of the kind that I was discussing that will take NV-ti87, as a respiratory virus drug. And then we are also developing, in the USA, with our consultants, a phase two clinical trial for RSV.
Andrew: How can the nanoviricide planform interact with other different APIs? Anil: That’s a very interesting question. I just talked to you about tecovirimat. Like that, there are other APIs that are typically orthogonal to our drug, except for antibodies. Almost all the antivirals that have been developed to date are orthogonal in mechanism to our drug. So we can combine those two together and give them as therapies, and they will be much beber than single therapy, just like what is known in HIV that you are giving now three or four drugs, but they are all against replication cycle. Together, it will be that the Reinfection cycle is inhibited by NV-ti87 and the Replication cycle is inhibited by the other API, which means the entire life cycle of the virus is inhibited, and that would produce a cure.
So that is one thing. The second thing, which is also important, and that's probably a lot more important for the folks that come to PODD, is that we actually have the ability to encapsulate drug cargo inside the nanoviricide nanomicelle, and we have done that with using NV ti87. We have done that with remdesivir. We developed a pro-drug of remdesivir to improve on its properties. We also did that with a pro-drug of ribavirin. We were able encapsulate these drugs within NV-ti87 nanomicelles. And with tecovirimat, we just mix the two drugs (tecovirimat and NV-ti87) together.
What we were able to do with the remdesivir approach, the pro-drug, as well as the remdesivir itself, is that we were able to convert that API from an injection infusion to an oral drug!
Mind you that NV ti87 itself is orally bioavailable, and that is probably the first in nanomedicines. Almost all nanomedicines to date are injectables or infusions. This NV-ti87 nanoviricide is probably the first one that is actually orally bioavailable.
And now on top of that, we can also put a cargo inside, and that cargo also becomes orally bioavailable, and that's a huge thing. So in terms of acting together with other antivirals or other drugs in general, this is the thing that we can provide, that it's a delivery mechanism. Not only that, it is a delivery mechanism that protects the cargo against bodily metabolism of the cargo drug. It also has the ability to do a zip-code level, addressing to specific cell types. In the antiviral space, what we are doing is we are going to address the specific virus type or a class of viruses, or a broad spectrum antiviral, that are different ways of choosing the ligand, and we go afer the viruses.
In the case of cells, we can do the same thing. We can go specifically to specific types of cells, we can go to specific types of tissues and deliver the cargo there. So that is important. The protection of bodily metabolism of the cargo is also very important. And rescue of non-Lipinski drugs, which has been talked about quite a bit, as you know, and that also is automatically built into this planform.
Andrew: Are there applications for this platform outside of antivirals?
Anil: Yes, practically any non-Lipinski drug we can encapsulate into an appropriate nanoviricide planform polymeric micelle and it will be either available as an infusion, injection therapy, or hopefully, it can also become bioavailable as an oral therapy. So that's a huge application for almost anything that is stuck in the pipeline because of improper PK kinetics, PKPD properties, or for the drug that is going to wrong sites, or for a drug that is highly toxic and you want to truly zip-code-like targeted delivery: we have done preliminary work in those areas.
Some data is also available. I think we have published some of it too. Andrew: What are the challenges to the current model of antiviral drug development, and how does the Nanoviricide planform overcome those challenges? Anil: So as you know, vaccines were successful against viruses before anything else was and that became the mainstay of antiviral modicums of countermeasures. So afer that, eventually small chemicals were developed. Unfortunately, most of the small chemicals that are developed, they work inside the cells, so they tend to be toxic. And in addition to that, what was clearly easily found and determined was that what vaccines do is develop antibodies, or help the body create antibodies when the actual invasion by the virus occurs. So because of that, a lot of focus was given on development of antibodies, both as prophylactic, which means before infection as a protection, as well as as therapeutic, which means afer the infection has already occurred. So you have seen these three modalities, small chemicals that interact with the virus life cycle, primarily in the replication, entry, and exit, those three parts, and antibodies that can block the entry of the virus, and you have the vaccines which can create antibodies. The problem is that all of these specific countermeasures are highly specific to a particular virus, and the viruses are very, very mutable, as you have now seen from covid. Everybody knows that the COVID virus has changed constantly. So that happens, and then the vaccines will lose efficacy substantially with every round of new viral variant development, antibodies almost completely lose their efficacy, and often times the virus will generate mutants that are going to be resistant to any small chemical that is deployed. So it is the drug escape that is the huge problem in antiviral medicines, and so we saw that as a major challenge, and we started looking at that problem from a different angle.
I'm a chemical engineer, so for me, it's a lot easier to think about systems and machines, rather than to think about small chemicals that make a small difference, in particular, like a biochemist would do for enzyme inhibition or protein aback. So we started thinking about that. And how will we make a drug that the virus cannot escape? And when we're thinking about it, the first thing that became evident afer a lot of research, of course, and there was thankfully a lot of research accumulated by that time, the thing that became evident is that no matter the virus how much it changes, the entry point that it uses, those feet, let's say that it uses where it lands with those feet of the virus onto the cell, those landing points do not change no matter how much the virus changes. And there has been lot of work done in those landing points on cells also. And what happens is that there are two different classes of those landing points. One is called attachment receptors, and the second is called cognate receptors. And what happens is the viruses use the attachment receptors, which are copious in the body, but they are very, very general, and the viruses use those to concentrate next to cells. And once the viruses have concentrated next to the cell, now the aback on the cell becomes feasible. And then whatever the cell surface protein that it uses as the cognate receptor, the virus binds to that and what the virus has done, is it has evolved so that it can use that binding for internalizing itself into the cell. It will fuse with the cell membrane, then it will go inside, then it will go into wherever the domain of its activity is, dump out the genome and start copying, make replicas, and then come out, aback another cell (called “Re-infection”) and the cycle starts again. That's called the reinfection part, which is virus particles coming out, and virus particles that have come out now go through the bloodstream or plasma or whatever, and go into new site, aback a cell and start infection. So that is where we came into looking at how we can make an approach that will be effective. Now there are a lot of people doing research. This is not our own invention, like I said, that there are these abachment receptors and cognitive cognate receptors. So there are a lot of people, we are walking on their shoulders, essentially, and they had done lot of work that was done in that kind of area. That is how the entry inhibitors concept came out. Unfortunately, as small chemicals, entry inhibitors were, again, something that the virus could easily overcome by simple mutations. So that is why those failed. Then there were approaches where fragments of the cognate receptors were used as the decoys for the virus to bind and somehow get eliminated from the body. That didn't work very well, because often times such protein fragments will be immunogenic in humans, that is one thing. And second thing, they don't fully decorate the virus. They simply tag the virus, just like the antibodies. Antibodies also just tag the virus. You know, it is after the antibodies that have tagged the virus that the complement system, the other parts of the immune system, they come together, and then they have to dismantle and destroy the virus. So what we saw is that there is a deficiency in all these approaches. That, one thing, the escape resistance is not there, and second thing that these drugs do not complete the task of dismantling the virus particle. So what we decided to develop is something that can do both of those things. And fortunately, since 2005 to 2012 we worked over many different viruses, and we were getting small successes all the time, Influenza, H5N1 Bird Flu, HIV, herpes viruses. And once we got to the herpes viruses, we developed a drug against shingles called NV-HHV-1, we went to non-clinical studies of that. And then in 2019, at the end of 2019 when we were actually looking for clinical sites for doing the shingles phase one clinical study. At that time, something happened in the world. It was the biggest thing that has happened in our lifetimes. It was the COVID pandemic. We saw some articles about it, and then we decided to switch to COVID drug development. We had done drug development against MERS and SARS before, so we had a starting point. And unfortunately, during because of the pandemic, the nature of the pandemic, SARS-CoV-2 was considered a high threat virus, requiring BSL three, BSL four facilities. We Our facility is BSL two. And when you are looking for developing drugs that will work in humans, what you really have to do is you have to make them work first in animals. So the animal studies we had to do in BSL two that we had. So we developed a model system that used the same kind of receptors as SARS-CoV-2 does, with hCoV-NL6ti virus in coronavirus family itself, and this model virus has the same exact modalities as SARS-CoV-2, except it is less pathogenic. So we were able to use that one, and we used that to develop a drug against COVID.
So we wanted to develop a complete nanomachine that can do the task of completely unwrapping the virus particle. And to do that, we develop something that looks like a cell membrane, and we decorate it with the same things that the virus uses as its landing sites, in the case of covid drug, we use the attachment receptor decoys. In the case of the Shingles drug, we use the cognate receptor decoys. So we have the tailoring ability to do whatever we want with those things and we made them like they were cell membrane like materials, so that they had lipid chains that are hanging just like the cell membrane has hanging lipid chains, and that gives them the shape-shifting ability so that once the nanoviricide nanomachine binds to the virus particle, unlike the classical nanomedicines, which are hard particles that are ofen times characterized using electron micrography as balls of different particle sizes, unlike that, when our drug has initial interactions with the virus particle, multiple interactions happen between the two entities, our drug and virus particle, that leads to a Velcro type of effect, nanoscale velcro effect, and that leads to our drug covering up the virus surface. Then, because of the proximity the lipid chains that are inside our micelles, the nanoviricide micelles, they interact with the lipid surface on the virus, and that essentially pulls the lipid together. We actually saw that in electromyography, that it does happen that way. And because of that, the glycoproteins that the virus uses to bind to the attachment receptors or to bind to the cognate receptors, they get uprooted. Once those are uprooted, the capsid of the virus is essentially non-infectious because it cannot bind and cannot enter cells. So basically, the task is achieved there, and that is the major difference from what we are doing and what other people are doing. It's not just a decoy. It's a complete nanomachine that goes and grabs the virus particle like a Venus fly-trap and then pulls it apart. That was the thought process that essentially, because I am a chemical engineer, and I have a virological background, and I also have chemistry background, biophysical background, so and so forth, so because of that, it all came together. Andrew: Anything else that you'd want to say to the PODD audience, or anything else you want people to know about? Anil: Yes, so I am going to be talking at PODD on day one, October 28 at ti45pm on Track Three A.
The title of the talk is: “Revolutionizing antiviral treatments, Phase 2-ready, orally available nanomedicines that can deliver difficult APIs and improve PK.” That is in the Track Three A, Oral, Mucosal, Transdermal and Other Non-injectable technologies. And I hope to see a lot of the people that are listening to this to come and visit me there, and hopefully we can move this entire field of drug delivery, drug development and new medicines for intractable diseases forward with new collaborations. Thank you so much for your time.
Andrew: Anil, thank you very much. I appreciate it.
Andrew: (Closing) We hope you enjoyed the podcast you were listening to. Anil Diwan, President and Executive Chairman of NanoViricides, Incorporated, listed on the New York Stock Exchange as NNVC, about the science and clinical development of their nanomedicines against viruses. For more information about NanoViricides and their NV-ti87 technology, please visit nanoviricides.com . For more information about the PODD conference, editorials, podcasts or webcasts, please visit podconference.com or drugdelivery.org .
Thanks for listening.