As a war often accelerates technological innovation, the recent coronavirus pandemic in 2020 provided a big spur to advancements in biotechnology, with the rapid development of vaccines to contain the outbreak.
One company that felt that boost is Connecticut-based firm, NanoViricides Inc (NYSE-A:NNVC), which for 20 years prior to the pandemic had been quietly working on creating special-purpose nanomaterials for antiviral therapy.
Refocusing its expertise for the pandemic and beyond, the company’s lead drug candidate, NV-CoV-2, for the treatment of COVID-19 disease caused by SARS-CoV-2 coronavirus has now just entered Phase Ia/Ib human clinical trials in India.
The company's novel ‘nanoviricide’ class of drug candidates are designed to specifically attack enveloped virus particles and to dismantle them rather than relying on a patient’s immune system to eat them up.
Proactive sat down with Dr Anil Diwan, NanoViricides’ executive chairman and president to find out more.
Proactive: Can you explain the background of developing nanomaterials for antiviral therapy?
Dr Diwan: So, there are two separate questions here. How can we design a surface that looks like a cell? And, can we make it bind to the virus and can we design those ligands that look like the cell surface receptor?
The first question is addressed by the platform - can we design something that mimics a cell membrane? That was relatively simple for me to answer, and it hadn't been done by other people, thankfully, for us. It was very simple for us to design the architecture, what it should look like, and then I had a chemist friend of mine take a look and I literally drew a block diagram. It took almost three years to make the first successful chemicals and I actually got my first patent in 2004, after having started working on this project in 1992.
The other part of it is to make the ligands that will bind to the virus. That was somewhat simpler, because there is a lot of knowledge about some of the viruses influenced by HIV. And those are the ones we went after first - how they bind and where they bind to. We were able to take the molecular mechanics approach, and just do a design in-silico, and come up with a lot of chemical structures. I would design 30 or so structures in a month, and then practically, we would make about 10 or so and test them out to see if it worked right.
In 2005, NanoViricides was founded when Dr Eugene Seymour, who became the initial founder, took an interest in our technology. He had been involved in HIV/AIDS since the very first cohorts, so he was very, very interested in this technology. The nanomedicine approach that we took is strikingly different from what other people are doing with antibodies. What antibodies do is bind to the virus by two points for each antibody to decorate the entire virus surface so it doesn't infect a cell, but that requires more than 8 to 10 antibodies to bind to the virus. And for eight big antibodies to interact with the virus simultaneously, if you write it as a chemical equation, the probability becomes negligible. So that is why antibody approaches don't work that well.
Now, of course, if you use very high concentrations of antibodies you can get there. What happens is that once the antibodies have decorated the virus particle, the immune system has to eat up the resulting particle. But you are dependent on the patient's immune system, which is not functioning right when you have an infection, because the infection would not have taken hold if an immune system was functioning right. We saw that in the case of COVID where in almost 90% of people the infection did not advance - they got infected, they developed antibodies, and a lot of them didn't even notice that they had the symptoms. The remaining 10%, however, saw so many deaths. So, the problem is that you cannot depend upon the immune system.
The other advantage that we had built into our nano-machine approach is that not only does it look like a cell surface, but it can actually go and integrate with the virus surface itself. So, when they come into contact, because there is a lipid inside the nano-machine which gets attracted to the lipid surface of the virus, it starts opening up and integrates into the virus surface pulling out the proteins that the virus uses to bind to the cells. And so, our nano-machine has now made an oil slick onto the virus and the glycoproteins of the virus are neutralized. The virus is then completely non-infectious.
So, this is completely out of the box. We went ahead, and we designed it from scratch, just thinking about the principles of the problem - like Copernicus or Newton. I am not going to put myself in those ranks, but it is like that kind of thinking from the first principles.
The company’s lead drug candidate, NV-CoV-2 for the treatment of COVID-19 disease, is advancing into Phase I/II human clinical trials. Can you give us more details about this?
We licensed the drug to an Indian collaborator, Karveer Meditech Pvt Ltd, which is developing the drug in India towards commercialization. Karveer is sponsoring the Phase 1a/1b clinical trials in India. This open-label clinical trial will evaluate two oral formulations, NV-CoV-2 Oral Syrup, and NVCoV-2 Oral Gummies. The oral syrup is designed primarily for paediatric use, where titration by body weight is usually important or advisable. The gummies are for all other uses where fixed dose forms are desirable from compliance accuracy standpoint. Since it is open label, there is no placebo arm – the Indian regulatory agency would not allow a placebo arm in this situation.
In addition to the usual safety/tolerability and pharmacokinetics (PK) in healthy volunteers, the clinical trial Phase 1b part will also involve obtaining indications of efficacy in additional separate arms of PCR positive COVID cases, mild to moderate/severe, but not at risk of hospitalization within 24-to-48 hours. The design is similar to Phase I/II clinical trials. Phase 1a is single ascending dose. Phase 1b is multiple doses, on alternate days (48 hours) with the first dose being a loading dose, double of the nominal amount. We are trying 10mg/Kg, 20mg/Kg and 40mg/Kg dosing of oral syrup, and in separate cohorts, 500mg, 1,000mg, and 2,000mg dosing of oral gummies.
A total of 72 people will be in the clinical trial, with 36 healthy volunteers in Phase 1b healthy part, and another 36 COVID patients in Phase 1b COVID part. There are 6 persons in each cohort. The 48 hour interval between dosings is supported by pre-clinical PK and will allow us to make more detailed observations about how the dose affects the disease. PK in rats and cynomolgus monkeys both showed sustained plateau level in the 4-to-8 hour range, with a slow decline to 24 hours, and baseline attainment at around 48-to-60 hours or longer, depending on the dose.
So this is a drug that sustains itself for a long period of time, enabling once-daily dosing. Our expectation is Phase II will involve dosing at the mid-level (20mg/Kg or 1,000mg nominal) but daily, with two doses on day 1, followed by a single daily dose, until resolution - I know regulatory systems have not come up to this “until resolution” basis, but the World Health Organisation (WHO) is already suggesting such approaches, and doctors have been following such approaches. Thus, a mild case may require 1 day of treatment while a severe case may require five days of treatment.
NanoViricides’ other advanced candidate is NV-HHV-1 for the treatment of Shingles. What is the status of this treatment?
We are currently focused on NV-CoV-2. Its active pharmaceutical ingredient (API), NV-387, we believe should be a promising antiviral against other viruses of interest as well. We have begun the work for indication expansion to other virus families. In fact, we have found NV-387 to be highly effective in an animal model of RSV infection. So, the same drug would go into Phase II/III clinical trials for RSV, and possibly later for additional expanded virus families, enabling significant return on investment (ROI).
After initiating what we believe will be at least two Phase II/III clinical trials based on NV-387 we plan on going back to the HerpeCide program. NV-HHV-1 is the first drug in that program, and has completed safety/toxicology studies as well as efficacy model studies. We also have drug candidates behind it that are effective against HSV-1 (cold sores) and HSV-2 (genital herpes) in cell cultures and animal models. NV-HHV-1 is topical. It is also expected to work topically against HSV-1 cold sores, and possibly HSV-2 genital ulcers.
This again will be a single drug with multiple indications case. Additionally, we have developed systemically deliverable drug candidates for herpesvirus family. These are expected to be useful for HSV-1, HSV-2 as well as EBV, CMV and other herpes viruses. We also have a drug candidate that was highly effective in preclinical studies against HIV. We are working on improving our influenza drug candidate. These projects even if run concurrently would take several years.
The company's business model is based on licensing technology from TheraCour Pharma Inc for specific application verticals of specific viruses. What risks does this hold?
TheraCour is owned and managed by me. So anytime NanoViricides wants antiviral work or a project to be engaged with, it is able to do it. There is no risk. The licenses are extremely broad — NanoViricides does not license a specific drug but licenses all developments applicable to a specific virus or virus family (an entire application vertical domain) as per the scope of the license agreement.
The advantage to NanoViricides is that it can look at the solution developed, and if it is suitable for further drug development, then it may proceed with licensing the application vertical. But TheraCour cannot develop the same drug for any other company. Only NanoViricides can license these drugs out into collaborations.
At the end of fiscal 3Q on March 31, 2023, NanoViricides had a healthy cash and equivalent assets balance of $9.9 million. What sort of runway does this offer the company?
In addition to $9.9 million cash, we also have a cGMP-compliant manufacturing facility where we already have manufactured drug products for clinical use. Replacement cost for this facility is upwards of $25 million or more. We only spend about $6-to-7 million per year in cash.
So we have sufficient cash for a whole year and a little more in hand. We are managing our money carefully. Besides, I have personally supported the company previously with $2 million via a loan, of which the company had accessed just about $1.1 million.
What do you think you bring to the company as its executive chairman and president?
Other than as a scientist and engineer who has developed completely out-of-the box novel nanomedicine technologies to attack viruses, you mean? With the help of our CFO Meeta Vyas, I have been managing all the affairs of the company. I am involved day-to-day in the scientific work. I am also at present the lead person for developing external collaborations, with governmental agencies and non-governmental commercial pharma companies as well. I must add that Meeta has extensive business development experience, having served in various C-suite and management consulting roles before joining us, so she handles the finances as well as business development management.
We are a very lean team, but we have been highly productive. We went from a concept to a drug product in clinical trials for COVID in about three years (IND-enabling GLP safety/tolerability was completed in just a year). As a small company, we faced a lot of difficulties and hurdles in getting into clinical trials. We solved the issues by developing collaborations in India.
What should NanoViricides’ investors expect in the near to medium term?
Our focus is on NV-CoV-2. In the near term, we expect Phase 1a/1b data and initiation of Phase II/III aimed at COVID Thereafter, we can expect initiation of a Phase II/III for the same drug against RSV infection. In the medium term, we expect to commercialize and begin producing revenue from one or more of the drugs in the pipeline.
As the first drugs move forward, we plan on developing the other programs. We are also working to develop total cures for viral infections of viruses that do not go latent — all herpes viruses become latent as extrachromosomal factories in the cell nucleus. One of them also integrates itself into the human genome. HIV becomes latent by copying the complementary DNA corresponding to its dsRNA genome and integrating it into the human genome.
Additionally, there are ‘HERVs’ - these are human endogenous retroviruses, that exist in our genomes. They can cause diseases like multiple sclerosis (MS), which is also linked to EBV. And many cases of Alzheimer’s disease are linked to persistent HSV-1 infection. Other than these known cases, all other human pathogenic viruses do not become latent, and can be cured by our existing technology!
Contact the author at jon.hopkins@proactiveinvestors.com