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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 10-K
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934
FOR THE FISCAL YEAR ENDED JUNE 30, 2023
Commission File Number 001-36081
NANOVIRICIDES, INC.
(Name of Business Issuer in Its Charter)
1 CONTROLS DRIVE, SHELTON, CONNECTICUT, 06484
(Address of principal executive offices)
203-937-6137
(Issuer’s telephone number, including area code)
SECURITIES REGISTERED PURSUANT TO SECTION 12(b) OF THE ACT: NONE
SECURITIES REGISTERED PURSUANT TO SECTION 12(g) OF THE ACT:
COMMON STOCK, PAR VALUE $0.00001 PER SHARE NYSE AMERICAN
(Title of Class) (Name of exchange on which registered)
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
Yes ☐No☒
Indicate by a check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.
Yes ☐No☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.
Yes☒ No ☐
Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).
Yes☒ No ☐
Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☒
Indicate by check mark whether the Company is a larger accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act.).
Yes ☐ No ☒
On October 10, 2023 there were approximately 11,746,000 shares of common stock of the registrant issued and outstanding.
The aggregate market value of the voting stock held on December 31, 2022, by non-affiliates of the registrant was approximately $12,235,000 based on the closing price of $1.11 per share, as reported on the NYSE American on December 31, 2022, the last business day of the registrant’s most recently completed fiscal second quarter (calculated by excluding all shares held by executive officers, directors and holders known to the registrant of five percent or more of the voting power of the registrant’s common stock, without conceding that such persons are “affiliates” of the registrant for purposes of the federal securities laws).
Table of Contents
TABLE OF CONTENTS
PART I
Item 1. Business 4
Item 1A Risk Factors 52
Item 1B Unresolved Staff Comments 73
Item 2. Properties 73
Item 3. Legal Proceedings 74
Item 4. Mine Safety Disclosures 74
PART II
Item 6. Selected Financial Data 75
Item 7A Quantitative and Qualitative Disclosures About Market Risk 82
Item 8. Financial Statements and Supplementary Data 82
Item 9A. Controls and Procedures 82
Item 9B. Other Information 84
PART III
Item 10. Directors, Executive Officers, Promoters and Corporate Governance. 84
Item 11. Executive Compensation 87
Item 14. Principal Accountant Fees and Services 94
PART IV
Item 15. Exhibits, Financial Statement Schedules 95
SIGNATURES 97
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PART I
SPECIAL NOTE ON FORWARD-LOOKING STATEMENTS
The information in this report contains forward-looking statements. All statements other than statements of historical fact made in this report are forward looking. In particular, the statements herein regarding industry prospects and future results of operations or financial position are forward-looking statements. These forward-looking statements can be identified by the use of words such as “believes,” “estimates,” “could,” “possibly,” “probably,” anticipates,” “projects,” “expects,” “may,” “will,” or “should,” “designed to,” “designed for,” or other variations or similar words. No assurances can be given that the future results anticipated by the forward-looking statements will be achieved. Forward-looking statements reflect management’s current expectations and are inherently uncertain. Our actual results may differ significantly from management’s expectations.
Although these forward-looking statements reflect the good faith judgment of our management, such statements can only be based upon facts and factors currently known to us. Forward-looking statements are inherently subject to risks and uncertainties, many of which are beyond our control. As a result, our actual results could differ materially from those anticipated in these forward-looking statements as a result of various factors, including those set forth below under the caption “Risk Factors.” For these statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. You should not unduly rely on these forward-looking statements, which speak only as of the date on which they were made. They give our expectations regarding the future but are not guarantees. We undertake no obligation to update publicly or revise any forward-looking statements, whether as a result of new information, future events or otherwise, unless required by law.
Glossary of Terms
Nano - When used as a prefix for something other than a unit of measure, as in “nanoscience,” nano means relating to nanotechnology, or on a scale of nanometers (one billionth of a meter or greater).
Viricide - An agent that reliably deactivates or destroys a virus.
Nanoviricide ® - An agent that is made by attaching ligands against a certain virus or family of viruses to a nanomicelle based on the Company's patent-pending and proprietary technologies.
Ligand - A short peptide or chemical molecule fragment that has been designed to specifically recognize one particular type of virus.
Micelle - an aggregate of molecules in a solution, such as those formed by detergents.
Nanomicelle - A term coined to describe the micelles formed from the backbone polymer of a nanoviricide sans attached ligands.
Pendant polymeric micelles - A polymeric micelle forms from a polymer whose chemical constitution is such that even a single chain of the polymer forms a micelle. A pendant polymer is a polymer that has certain units in its backbone that extend short chains branched away from the backbone. Pendant Polymeric Micelles therefore are polymeric micelle materials that are a class of pendant polymers, and naturally form exceptionally well-defined, self-assembling, globular micelles with a core-shell architecture.
Mutations - The ability (of a virus) to change its genetic structure to avoid the body's natural defenses. Mutant viruses are created from a parent virus strain through a process of natural selection under pressure as it replicates in a host.
P-Value - In statistical hypothesis testing, the p-value is the probability of obtaining a result at least as extreme as that obtained, assuming that the null hypothesis is true; wherein the truth of the null hypothesis states that the finding was the result of chance alone. The fact that p-values are based on this assumption is crucial to their correct interpretation. The smaller the p-value, the greater is the probability that the observed study results and the comparison control are distinct, and therefore that the study results are not a result of chance alone.
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More technically, the p-value of an observed value observed of some random variable T used as a test statistic is the probability that, given that the null hypothesis is true, T will assume a value as or more unfavorable to the null hypothesis as the observed value observed. “More unfavorable to the null hypothesis” can in some cases mean greater than, in some cases less than and in some cases further away from a specified center value.
Investigational New Drug Application (Investigational New Drug (“IND”) - The process of licensure of a new drug in the US goes through several steps. A simplified explanation of these steps is as follows. Initially a Company may file a pre-IND application to seek meetings with the United States Food and Drug Administration (FDA) for guidance on work needed for filing an IND application. The Company obtains data on the safety and effectiveness of the drug substance in various laboratory studies including cell cultures and animal models. The Company also obtains data on chemical manufacturing of the drug substance. These and certain additional data are used to create an IND that the Company files with the FDA. After the FDA approves an IND application, the Company may conduct human clinical studies. A Phase I human clinical trial is designed typically to evaluate safety of the drug and maximum permissible dosage level. A Phase II human clinical trial that follows is designed to evaluate effectiveness of the drug against the disease in a small cohort of patients. A Phase III human clinical trial thereafter is designed to evaluate effectiveness and safety in larger groups of patients, often at multiple sites. The Company may then submit an NDA (New Drug Application) with the data collected in the clinical trials. The FDA may approve the NDA. Once the NDA is approved, the Company can sell the drug in the USA. European countries have similar processes under the European Medicines Agency (EMA). Other countries have similar processes.
SAR: Structure-Activity-Relationship study. When an initial lead drug compound is found that has activity, further studies on drug compounds obtained by suitably modifying it are performed with the goal of improving efficacy, safety, or both. Such studies are called SAR studies.
ITEM 1: BUSINESS
Organization and Nature of Business
NanoViricides, Inc. (the “Company”, “NanoViricides”, “we,” or “us”) was incorporated in Nevada on April 1, 2005, and redomiciled to Delaware effective May 30, 2023. Our corporate offices are located at 1 Controls Drive, Shelton, Connecticut 06484 and our telephone number is (203) 937-6137. Our Website is located at http://www.Nanoviricides.com. We do not incorporate by reference into this Annual Report the information on or accessible through our website, and you should not consider it part of this Annual Report.
On September 25, 2013, the Company’s common stock began trading on the New York Stock Exchange American under the symbol, “NNVC”.
We are a clinical stage company with our first drug in Phase 1a/1b clinical trial and several additional drug candidates in various stages of pre-clinical development, including IND-filing stage and late stage IND-enabling non-clinical studies. We have no customers, products or revenues to date, and may never achieve revenues or profitable operations.
The Company’s novel nanoviricide® class of drug candidates are designed to specifically attack enveloped virus particles, on the same sites that they use to bind to cells and dismantle them. Our unique biomimetic approach promises that a virus cannot escape our nanoviricide drugs due to mutations, if the virus-binding ligands perform as designed. The Nanoviricides Platform provides for modalities that can result in potentially cures for viruses that do not establish latent virus infection in humans.
NV-CoV-2, Our First Nanoviricide Drug that has Entered Phase 1a/1b Human Clinical Studies
NV-CoV-2, the drug we developed in response to the COVID-19 pandemic, has entered Phase 1a/1b human clinical trials sponsored by our licensee and collaborator, Karveer Meditech Private Limited (“Karveer”), in India, around June 19, 2023.
Nanoviricides Platform Has Enabled Industry-Leading Orally Available Nanomedicines And Multiple Routes of Administration
We found that unlike almost all other nanomedicine platforms, our nanoviricide NV-387, the active pharmaceutical ingredient (API) of NV-CoV-2, demonstrated strong antiviral activity when administered orally in multiple animal models. Most nanomedicines do not possess significant oral bioavailability and therefore have to be administered as injections or infusions. This oral bioavailability of our nanoviricides distinguishes our technology from almost all of the rest of the nanomedicines world.
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We developed two different oral formulations of NV-387, namely “NV-CoV-2 Oral Syrup”, and “NV-CoV-2 Oral Gummies”. The latter is a semi-solid fixed-dose form. The oral syrup enables body-weight-based dose titration as is required for pediatric cases. Both of these are in the Phase 1a/1b human clinical trial.
The oral dosage forms are expected to provide wide-spread adoption across the entire population from children to senior citizens, and special cases such as immune-compromised patients outside the hospital. The Oral Gummies fixed dosage form has the advantage that it is suitable even for patients that cannot swallow the usual hard tablets or capsules, because it slowly dissolves in the mouth as it is absorbed.
We have also developed a NV-387 formulation called “NV-CoV-2 Solution for Injection, Infusion and Inhalation”. We believe treatment of severe cases that are not yet hospitalized would be best performed by an injection. Hospitalized patients would benefit most from the 100% bio-availability of the injection route, and may be dosed with an infusion if larger quantity dosing is warranted.
Importantly, the same injectable solution can be readily delivered directly into the lungs as a fog created using standard portable battery operated nebulizer devices. This enables direct and quick action at the most important site of infection by a respiratory virus such as coronaviruses, RSV, influenzas, human meta-pneumovirus (hMPV), certain adenoviruses, and others, that can lead to severe pneumonia.
The Nanoviricide Platform Technology in Brief
NanoViricides, Inc. is engaged in the application of nanomedicine technologies to the complex issues of viral diseases. We are developing a class of drugs, that we call nanoviricides®, using a platform technology. This approach enables rapid development of highly effective and safe new drugs against a number of different viruses.
A nanoviricide is a “biomimetic” - it is designed to appear to the virus like the cell surface bearing the sites that the virus binds to. The nanoviricideTM technology enables direct attacks at multiple points on a virus particle.
Since the cellular binding sites for a given virus do not change despite mutations and other changes in the virus, we believe that the virus would be highly unlikely to escape our drug candidates even as a virus changes rapidly as it evolves.
A nanoviricide exposes a very high density of virus binding sites on its surface, in contrast to a human cell. Thus, a virus would be more likely to be captured by the nanoviricide than to bind to a cell. As the nanoviricide polymeric micelle interacts with the virus particle, the nanoviricide is capable of binding to the virus at multiple points, and while doing so, wrapping itself around the virus by virtue of an effect called “lipid-lipid mixing”. In the process, the specific glycoproteins that the virus uses for binding to the cell (for example, the coronavirus “Spike” protein) are expected to be neutralized and dismantled. It is believed that such attack would lead to the virus particle becoming ineffective at infecting cells. Therefore we call this novel mechanism of action “Re-Infection Inhibition”.
A nanoviricide is made by chemically covalently linking a “nanomicelle” - a globular polymeric micelle with pendant lipid chains inside - to one or more different small chemical ligands designed to mimic the cellular receptor to which the virus binds. In addition, the nanoviricide can carry additional active pharmaceutical ingredients (APIs), which may be chosen to affect the intracellular virus life cycle. Thus, the nanoviricide platforms enables construction of complete virus-killing nanomachines that block the virus from entering the cell as well as that block further production of the virus inside the cell.
Nanoviricides are designed to work by binding to and eliminating virus particles from the blood stream, just as antibodies do, only potentially much better. Treating a patient that has a viral infection with a nanoviricide against that virus is expected to result in reduction in viremia. Reduction in viremia is an important goal in diseases caused by all viral infections. Nanoviricides are designed to accomplish this using a “Bind-Encapsulate-Destroy” strategy to eliminate the free virus.
It is important to realize that the flexible, “shape-shifting” nanoviricides nanomedicines show substantial advantages over hard sphere nanoparticles in this antiviral drug application as the nanoviricides enable lipid-lipid mixing with the viral envelope and can wrap around or merge with the virus surface. Hard sphere nanomaterials such as dendritic materials (dendrimers), nanogold shells, silica, gold or titanium nanospheres, polymeric particles (such as PLA-PLGA, others), etc., were never designed to be capable of completely enveloping and neutralizing the virus particle.
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This powerful Nanoviricides Platform technology has enabled us to develop several drug candidates against a large number of different viruses that could be further improved into clinical drug candidates, thus building a very broad drug pipeline that may lead to exponential growth of the Company upon the approval of our first drug candidate. While our first drug candidate, NV-CoV-2, is now in human clinical trials, and another one, NV-HHV-1, is awaiting to go into the clinic, over the years we have developed more than ten drug candidates that, we believe, can be rapidly moved into the clinical stage, from nearly forty different antiviral drug development programs. Our progress to clinic is limited by our resources. We anticipate that once our first drug goes successfully through Phase 1 and Phase 2 clinical trials thereby proving our capabilities and our Nanoviricides Platform technology, the Company, assuming it acquires the necessary financings, could enter a phase of exponential growth and rapid clinical development of additional candidates thereby transforming the way viral infections are treated.
Nanoviricides Represent the Next Generation Development Beyond Immunotherapeutics
Our nanoviricide technology relies on copying the human cell-surface receptor to which the virus binds, and making small chemicals that are called “ligands” that will bind to the virus in the same fashion as the attachment receptor or the cognate receptor (see below). These ligands are chemically attached to the base polymer or “nanomicelle”, to create a nanoviricideTM.
A class of small molecules called entry inhibitors exists. These drugs are designed to bind to the virus to stop it from binding to cells. A very large number of these small molecules must simultaneously attack the virus particle for the particle to be fully inhibited – a task that has very low probability in vivo (“kinetic hurdle”). Additionally, similar to antibodies, entry inhibitors are also rapidly rendered ineffective as the virus changes.
In contrast to a nanoviricide that is expected to bind to the virus at multiple points, antibodies can bind a virus particle at only a maximum of two attachment points per antibody. Several antibodies are required to simultaneously bind to the virus particle to neutralize it. Additionally, the human complement system and immune systems are required to work properly to clear the resulting complex.
“Resistance is Futile” – NanoViricides Has a Unique Technology Designed So That Viruses Would Not Readily Escape Our Drugs
The Nanoviricide Platform has built into it cognitive elements that the virus recognizes and binds to, no matter how much it mutates, provided we have mimicked the virus-binding site on the attachment or cognate cellular receptor properly. This is because no matter how often a virus mutates, generating myriads of variants as it evolves, the specific binding sites to which virus attaches and gains entry into cells does not change.
In contrast, antibodies are extremely specific and therefore even minor changes in the virus tend to make them ineffective. Antibodies and vaccines are readily evaded by viruses under the evolutionary pressure in a natural process itself. This has become starkly evident in the COVID-19 pandemic.
Even as new virus variants develop that evade exiting antibodies and vaccines, the variants continue to bind to their cellular attachment receptor(s) and the cellular cognate receptor(s) at the same sites and in the same manner, despite changes in the viral glycoprotein itself. Thus if we design the ligands correctly, the nanoviricide would continue to be effective even as the virus keeps changing in the field, in stark contrast to antibodies and vaccines that readily lose effectiveness as the virus evolves.
We believe that our platform technology enables development of drugs that viruses would not escape from. In fact, we have successfully screened our COVID-19 drug candidates to be able to protect cells against infection by distinctly different coronaviruses. This broad-spectrum drug development approach was adopted to ensure that our drug candidates should remain effective even as future variants of SARS-CoV-2 evolve in the field, as was already anticipated by us at the very beginning of the pandemic.
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Beyond Antibodies or “Post-Immunotherapeutic” Approach: A Nanoviricide in Its Design is a Nanomachine Built to Destroy Viruses
Once bound to the virus, it is thought that the nanoviricide would wrap itself around the virus, and the interior lipidic chains of the nanoviricide would merge into the lipid envelope of an enveloped virus, thus destabilizing the virus. This attack is expected to result in loss of the viral glycoproteins that it uses to bind to cell and to fuse with the cell membrane, thus rendering the virus particle non-infectious. In contrast, for an antibody to be successful as a drug, as many as ten to fifteen antibodies must bind to saturate the virus surface. The resulting antibody-virus complex then may be subject to the complement protein system in the bloodstream, or it may bind to antibody-receptors on human immune cells. Thus the human immune system needs to be functional for an antibody to be effective as a “drug”. In a sense, antibodies only “flag” the virus particle as foreign. In contrast, a nanoviricide would complete the job of making the virus particle non-infectious, without any help from the human immune system.
Almost any virus that causes pathology in humans is able to do so because it has developed intelligent and complicated pathways for disabling the human immune system at one or more points. This may be one of the reasons why many antiviral antibodies fail in the field use. Additionally, viruses readily escape antibodies by mutations, and, in some cases, reassortment. Such viral escape from antibodies has been witnessed in almost every viral epidemic, be it HIV/AIDS, the Influenza pandemic of 2009, or the Ebola epidemic of 2014-15. In contrast, despite mutations and other changes, a virus is unlikely to escape a nanoviricides drug designed against it.
It is anticipated that when a virus comes in contact with the nanoviricide, not only would it land on the nanoviricide surface, binding to the copious number of ligands presented there, but it would also get entrapped because the nanomicelle polymer would turn around and fuse with the virus lipid envelop, harnessing a well known biophysical phenomenon called “lipid-lipid mixing”. In a sense, a nanoviricide drug acts against viruses like a “venus-fly-trap” flower does against insects. Unlike antibodies that tag the virus and thereafter require the human immune system to take over and complete the task of dismantling the virus, a nanoviricide is a nanomachine that is designed to not only bind to the virus but also complete the task of rendering the virus particle ineffective.
Thus the Nanoviricide Platform technology can be viewed as the next step in evolution of antibody-based approach, taking into account and eliminating the limitations of antibodies.
Uniform Polymer Nature Enables Simplified Nanomedicine Manufacturing Quality Assurance
A major problem in the field of nanomedicines has been that most nanomedicines have been found to be notoriously difficult to manufacture in a consistent manner from batch to batch. This is because of the complexity inherent in making large molecules, the very nature of polymer and particle making processes, particularly in the case of block-copolymers that are commonly employed, and the fact that many nanomedicines are mixtures of multiple components.
The Nanoviricide Platform technology has been designed from the ground up to enable consistent manufacture and control. Thus, the nanoviricide backbone is a “homopolymer” (i.e. it is made up of a single repeating unit or monomer), which enables a naturally uniform structure. This is unlike block-copolymers wherein there is structural heterogeneity along the polymer chain that is often difficult to control. In addition, the nanoviricide polymer is designed to dynamically and naturally self-assemble into micelles in a solution. Also, the virus-binding ligands are chemically attached to the polymer. The extent of attachment can be assessed by analytical techniques that we have developed and continue to develop as needed. Further we use specialized techniques in the polymer processing to minimize any contamination with endotoxins or other foreign particles as well as to remove impurities. The final nanoviricide solutions are sterile filtered using standard membrane filtration processes. The resulting solutions can be concentrated in a non-contaminating environment in our Process Scale-Up Lab or our cGMP-capable Manufacturing Facility.
Formulation is Inherent in the Design Aspect of a Nanoviricide
Since developing our API NV-387 in the COVID drug development program, development of its formulations, injectable, infusion, inhalation, oral syrup, and oral gummies (semi-solid form) was relatively quick, accomplished within months, including formulation design and scale-up with cGMP manufacturing considerations. Similarly, since declaring our shingles clinical candidate, NV-HHV-1, its formulation as a skin cream for topical treatment of shingles rash, and scale-up, and cGMP-compliant manufacture was accomplished relatively rapidly, within a few months. Formulation development for novel drugs in normal pharmaceutical paradigm often takes years. However, in the nanoviricide approach, the nanomicelle polymeric backbone itself takes care of the formulation aspects. The nanomicelle is designed to optimize the drug for its intended route of administration, be it injectable, skin cream, eye drops, or even oral. Thus, no specific or extensive formulation development is expected to be required after clinical candidate declaration.
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Thus the Nanoviricides Platform has been designed from the ground up to enable simplifications in processes and analyses that need to be implemented in order to develop robust, reproducible, and scalable processes.
The Nanoviricides Platform’s capabilities can be harnessed in multiple modalities, and we are working on a number of drugs based on these modalities to enable cures for viral diseases.
Nanoviricides Platform Modality #1: Broad-Spectrum Antiviral “Reinfection Inhibitors”
There are certain classes of cellular features that a very large number of viruses commonly use to get access to cells. As a first step, the virus binds to one so called “Attachment Receptor(s).” This allows the virus to concentrate near the target cells, and enables the virus particles to latch onto more specific receptors on the cell surface itself that are termed “Cognate Receptor(s)”. Some viruses can directly fuse with the cell membrane without such a cognate receptor.
The attachment receptors employed by most viruses fall into very few families. One such family is “Sulfated Proteoglycans (S-PG)”, or “Glycosaminoglycans (GAGs).” We loosely include a number of sulfated proteoglycan types in this “S-PG class”. They differ in exact structures but share a number of commonalities. This family includes heparan sulfate (HSPG), dermatan sulfate (DSPG), chondroitin sulfate (CSPG), and keratan sulfate (CSPG). Over 90% of known pathogenic viruses bind to one or more of these S-PG class attachment receptors. These viruses include Coronaviruses, Paramyxoviruses (RSV - Respiratory Syncytial Virus, and HMPV- human Metapneumovirus), Dengue Viruses, Herpesviruses, Human Papillomavirus (HPV), HIV, Hendra and Nipah Viruses, Ebola and Marburg Viruses, among others.
Many of these viruses have no available antivirals or have antivirals with limited applicability. Nanoviricides that mimic S-PG can be expected to be capable of attacking many of these viruses, enabling very broad-spectrum antiviral agents. This is reminiscent of the development of beta-lactam antibiotics, that have broad-spectrum antibacterial properties because they attack a common feature of a large number of bacteria; the peptidoglycan cell wall.
NV-387 was designed using our knowledge of the commonalities in this S-PG class of attachment receptors for mimicking it with small chemical ligands. Thus, NV-387 is designed as a broad-spectrum antiviral agent. After its success in attacking multiple unrelated coronaviruses, we have undertaken a program to expand the potential indications of NV-387. Effectiveness in any of these additional indications would enable direct entry into Phase II/III clinical trials for that indication after completion of the current Phase 1 clinical trials of the NV-387 containing drug NV-CoV-2.
We reported in July 2023 that NV-387 was highly effective against a lethal RSV infection in a mouse model study. In light of the recent Nipah virus cases in Kerala, India, it would be interesting to explore if NV-387 can be an effective drug against Nipah and the related Hendra viruses. Such expansion of use of NV-387 would significantly expand the market size and substantially improve the return on investments (ROI).
Another important class of attachment receptors is Sialic Acids (SA). We are working on developing broad-spectrum antivirals mimicking SA. SA is well known as the initial site of binding for Influenza viruses, as well as many of the infectious Adenoviruses and many other viruses.
It would be very difficult for a virus to become resistant to a nanoviricide that mimics the virus’ attachment receptor. This is firstly because the nanoviricides based on mimicking attachment receptors are broad-spectrum in nature, capable of antiviral effect against not just a specific virus type or subtype, strain or variant, but entire families of viruses (as defined in the virus classification system), and secondly, because, no matter how much a virus mutates or changes, its binding to the cellular receptor does not change.
Nanoviricides Platform Modality#2: Specific, Highly Effective, Antiviral “Reinfection Inhibitors”
Instead of developing bio-mimetics of the broad-spectrum attachment receptors, we can also develop nanoviricides that mimic the specific cognate receptor(s) used by a virus to develop highly specific drugs against that virus.
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Our antiviral drug candidate NV-HHV-1 is based on mimicking the cognate receptor HVEM (“herpesvirus entry mediator”). It has shown strong activity against VZV (Varicella Zoster Virus). VZV causes chickenpox in children and immune-compromised persons, and its reactivation causes Shingles in adults. NV-HHV-1 has completed pre-clinical IND-enabling studies for VZV. NV-HHV-1 was also effective against HSV-1 and HSV-2. We plan on exploring its activity against other herpesviruses such as CMV and EBV as well.
Further, we have developed drug candidates in the HIVCideTM Program that mimic the cellular CD4 binding site used by HIV to gain cell entry. Another important HIV cognate receptor is CCR5. The Nanoviricides Platform enables using mimics of one or more cellular receptors attached into a single nanoviricide drug. Thus this platform has the capability of mimicking both the CD4 binding site and the CCR5 binding site of HIV on one nanoviricide, which is expected to enable the most effective drug against HIV. The only countable number of patients that have been “cured” of HIV were recipients of stem cells that possess a modified CCR5 lacking its HIV-binding region, attesting to the importance of mimicking both CD4 and CCR5 simultaneously.
Attacking the “Achilles Heel” of the Virus- Unchanging Ability of the Virus to Bind to Its Cognate Receptor on Cell
We strive hard to develop virus-binding small chemical ligands that mimic the cognate cellular receptor of the virus, using rational design and molecular modeling strategies and our internal, accumulated expertise. Some viruses use more than one receptor. The nanoviricide® platform technology allows use of different ligands on the same nanoviricide drug to be able to attack such difficult viruses.
It would be very difficult for a virus to become resistant to a nanoviricide that mimics the virus’ cognate cellular receptor. This is because, no matter how much a virus mutates or changes, its binding to the cellular receptor does not change. If the virus does not bind to the nanoviricide efficiently, it would likely have lost its ability to bind to the cellular receptor efficiently as well, resulting in an attenuated version with limited pathogenicity.
Nanoviricides Platform Modality #3: Nanoviricides Platform Enables Cures for Viruses that Do Not Become Latent
To date most viral infections do not even have effective drugs, let alone cures.
Most viruses do not become latent in the human body. Such viruses have a relatively simple life cycle: After a virus is transmitted to the person and infects some cells, it replicates inside the infected cell (the replication part), thereafter the new virus copies exit the cell and then infect new cells (the “re-infection” part) thus starting the cycle over again. If both parts of the life cycle can be blocked effectively, then such a virus infection can be readily cured. The Nanoviricide Platform Modality #3 enables such cures.
In this modality, the nanoviricide technology simultaneously enables attacking the external virus particle, as well as blocking the rapid intracellular reproduction of the virus by incorporating one or more APIs within the “belly” of the nanoviricide. The nanoviricide® technology is the only technology in the world, to the best of our knowledge, that is capable of both (a) attacking extracellular virus, thereby breaking the reinfection cycle, and simultaneously (b) disrupting intracellular production of the virus, thereby enabling complete control of a virus infection.
The nanoviricides built using Modality #1 as well as Modality #2 can be employed to add the replication-inhibition capability in this manner.
NV-CoV-2-R, our other drug in development for treatment of coronaviruses contains the API NV-387-R. This API is made up of remdesivir encapsulated within the belly of the polymeric micelles of NV-387. While NV-387 is designed to directly attack the virus outside the cell, the remdesivir component is known to block the virus replication inside the cell. By blocking both of these pathways, NV-387-R would result in a cure of the viral infection. Remdesivir is a broad-spectrum antiviral agent that has been approved for COVID and has shown strong pre-clinical activity against many RNA viruses. Its clinical activity is limited by its rapid metabolism in the bloodstream. NV-387 holds remdesivir like in a bottle and releases it slowly, thus limiting the metabolism and enhancing the pharmacokinetics and thereby the effectiveness of remdesivir.
Note that Remdesivir, sponsored by Gilead, is a known antiviral drug that has received full FDA approval for treatment of COVID-19 and has received Emergency Use Authorization (“EUA”) in many countries. We are developing NV-CoV-2-R on our own, independent of Gilead.
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We have also developed other drugs based on this concept of curing the viral infection.
One of these is NV-387-Rp, which contains a modified and improved form of Remdesivir. Another one is NV-387-Ribvp, which contains a prodrug of Ribavirin. Ribavirin is a highly toxic but highly effective antiviral drug. It is approved in the USA only for the treatment of RSV infection as a drug of last resort. However, it is used in the case of many viral infections for which no antivirals are known in severe hospitalized cases. NV-387-Ribvp is expected to enable cures for such viruses by combining the Re-Infection Inhibition activity of NV-387 with the Replication Inhibition activity of Ribavirin, while at the same time enabling lower doses of Ribavirin to stay well below its toxicity level.
Nanoviricides Platform Modality #4: Nanoviricides Platform Has the Capability to Enable Cures for Viruses that Do Become Latent
HIV and many viruses in the herpesviridae family form “latent reservoirs” in human cells making them difficult to cure. HIV and the class of lentiviruses achieve this by directly copying its genomic information into the human chromosomal DNA itself. Two of the herpes viruses, namely HHV-6A and HHV-6B, are known to copy their genetic information into the telomere region of the chromosome, shortening the number of cell divisions the modified cell can undergo, effectively a phenomenon of aging. All other herpesviruses create episomal islands in the cell’s nucleus which are their own “factories” for making progeny copies. The nanoviricides technology platform can be harnessed against these viruses in another different modality that can potentially produce cures. We are working on such cures of latent viruses in our research and development (“R&D”) projects.
Broad and Expanding Pipeline Based on the Nanoviricide Platform Technology – in Brief
We have several drugs in our pipeline, enabled by our strong and extensive nanoviricide technology platform. Of these, NV-CoV-2 is in Phase 1a/1b Clinical Trials for the COVID indication and is the farthest along in the regulatory pathway. The need for the broad-spectrum nanoviricide SARS-CoV-2 drug cannot be overstated in the current circumstances and the present status of the pandemic with continuous evolution of variants of the virus and a constant threat of the possibility that a substantially more pathogenic virus compared to the current omicron variants may readily emerge. The current set of tools available for combating the COVID-19 pandemic is not robust enough to allow a “Living with COVID” attitude.
Following completion of the Phase 1a/1b clinical trials of NV-CoV-2, we plan on moving this drug into Phase 2 Efficacy Clinical Trials. We have currently associated the treatment indication of COVID for this drug. The same API, NV-387, was also highly effective against a lethal infection of RSV in a mouse model. Thus, we plan on entering this drug into Phase 2 Efficacy Clinical Trials for the RSV indication, in addition to COVID, depending upon our financial resources.
We plan on continuing additional exploratory studies to evaluate the effectiveness of NV-387 against other viruses that use S-PG class of attachment receptors. We have also completed pre-clinical development of a nanoviricide drug showcasing Modality 2, namely NV-HHV-1. We plan on undertaking Phase 1 and further clinical development of NV-HHV-1 as and when enabled by our financial resources. NV-HHV-1 is currently formulated as a Skin Cream for the treatment of Shingles.
We also have several additional pre-clinical drug development programs including Herpes Simplex Viruses (HSV-1 that causes cold sores, and HSV-2 that causes genital ulcers), HIV/AIDS, Influenza, Dengue viruses, and Ebola/Marburg, that we plan to advance further towards clinical drug candidates as they progress further. Thus we have a strong and broad pipeline that is expected to continue to result in highly effective drug candidates against a number of viral diseases.
We are now at the stage of clinically harnessing the development of Modality #1 and Modality #2 nanoviricides drugs. To recap, Modality #1 drugs mimic Attachment Receptors and possess a very broad spectrum of antiviral activity that includes a large number of different types of viruses. Modality#2 drugs mimic Cognate Receptors and possess a very strong antiviral activity against a set of specific types of viruses. In both cases, the targeted viruses are highly unlikely to escape the drug by evolving variants. NV-387 is an example of Modality #1 nanoviricides, and NV-HHV-1 is an example of Modality #2 nanoviricides. NV-387 is now in Phase 1a/1b clinical trials with COVID as indication. We are in the process of completing the IND-enabling studies for NV-387 to enter Phase 2 clinical trials for the treatment of RSV in addition to COVID. NV-HHV-1 has completed IND-enabling studies as a Skin Cream for the treatment of Shingles.
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We have also continued R&D on Modality #3 nanoviricide drugs that promise potential cures for non-latency viruses. NV-387-Rp and NV-387-Ribvp have shown strong effectiveness against Coronaviruses and RSV in animal models respectively, and are expected to be highly active against a number of other viruses based on the known activities of the components. We plan on developing these Modality #3 potential cures of a number of viral diseases after the Modality #1 and Modality #2 drugs.
Overall, since our founding, we have worked on development of about 40 different drugs against a number of different viral diseases in a number of drug programs. In the process, we have built an extensive library of both the (i) Nanoviricides Platform know-how and (ii) the actual synthesized chemical drugs. This enabled us to rapidly respond to the COVID-19 pandemic. We were able to announce that our early COVID drug candidates demonstrated strong antiviral effectiveness in animal studies as early as May 2020. We have diligently continued to progress these drug candidates with the culmination of the start of human clinical trials of the API NV-387 (the drug products are called NV-CoV-2) recently.
Additional details of our drug pipeline can be found in the section “NanoViricides Drug Pipeline” further below.
NanoViricides Drug Development Process
Our drug programs begin from initial R&D to understand the virus and advance to design antiviral medical countermeasures. Then we chemically synthesize selected potential small molecules to act as the ligands that mimic the cellular receptor(s) of both Modality #1 (broad spectrum) type as well as Modality #2 (specific to the virus family) type to bind to the virus. Separately we have been engaged in evolving and optimizing various versions of the nanoviricide backbone polymer. We then choose some of the select polymers and attach the selected antiviral ligands chemically to the polymer providing a library of antiviral nanoviricides. We then evaluate these antivirals in cell cultures against the target viruses. We further evaluate selected antiviral ligands from this screen in animal model studies. We then down-select from the effective drug candidates about five to seven candidates for further development based on a number of considerations including level and spectrum of activity, any likely issues with safety/tolerability, drug stability, pharmacokinetics, pharmacodynamics, ease of manufacturing, ease of formulations, and the desired routes of administration.
Along the way, we refine the methods of preparation of these drug candidates, from chemical synthesis all the way to formulation and packaging of the final drug product, developing and implementing the Chemistry, Manufacture and Controls information for the resulting drug substances as well as the potential drug products.
The selected candidates then undergo additional studies. Typically about two of them are advanced into IND-enabling GLP Safety/Tolerability studies. One of these is then selected for further evaluation in human clinical trials.
NanoViricides, Inc. is a Fully Integrated Pharma Company
We have strived to minimize the risks inherent in the drug development process. One of the major risks is the manufacture of our nanoviricide drug candidates in a manner to produce consistently quality drugs.
NanoViricides c-GMP-capable Kilogram-Scale Manufacturing Facility for Drug Substance and Drug Products
Manufacturing of drug products for sale, as well as for late stage clinical trials is required to be performed in FDA-registered cGMP manufacturing facilities. Manufacture of drugs for earlier stage clinical trials as well as for IND-enabling GLP Safety/Toxicology studies needs to be performed in a c-GMP-compliant manner.
We discovered early in our development that the existing contract manufacturing operations in the pharmaceutical industry have very limited expertise that would be applicable to our kind of drugs. In order to speed up nanoviricide drug development, save on costs, and ensure quality, we have set up our own manufacturing facility that can scale from discovery qualities of a few grams to clinical trials quantities of a few kilograms.
We believe we are one of the very few small pharmaceutical drug innovators that possess its own cGMP or cGMP-capable manufacturing facility. With our Shelton, Connecticut campus and pilot-scale cGMP-capable manufacturing facility, we have now demonstrated that we are in a position to rapidly advance our drug candidates into clinical trials, produce the pre-clinical “tox package” batches, and the clinical drug substance batches.
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We have produced and plan to continue to produce our nanoviricide drugs for clinical trials in this facility. We have the capability to produce sufficient drugs for about 1,000 patients in a single batch of production, depending upon dosage. This production capacity is anticipated to be sufficient for the clinical trials of our anti-coronavirus drug, as well as for the anticipated clinical trials of NV-HHV-1 skin cream for the treatment of Shingles. Further, this cGMP-compliant manufacturing capacity is anticipated to be sufficient for commercialization of our RSV drug candidate subsequent to required regulatory approvals thus enabling rapid market entry and revenue generation.
Our cGMP-compliant manufacturing facility is equipped with Class 100 (ISO 5), Class 1000 (ISO 6), and Class 10000 (ISO 7) clean room suites for injectables and other manufacturing operations.
We have in-house all the capabilities necessary for formulation, filling and finishing of our drug products in the following forms: (i) oral syrup, (ii) oral gummies (semi-solid form), (iii) skin creams and (iv) ointments. We plan to employ an external Contract Manufacturing Organization (CMO) for our injectable drug products for the clinical trials as and when required.
We believe that we are in compliance with all material environmental regulations related to the manufacture of our products.
NanoViricides State-of-the-Art Nanomedicines Characterization Lab Supports In-Process QC, Release Testing of Manufactured Drug Substance, Drug Products, as well as R&D
We have a state of the art nanomedicines characterization facility in-house in the same campus that has all the capabilities necessary for in-process quality control as well as release testing and quality assurance of our drug products and for supporting our manufacturing operations as well as our R&D operations. We also have a Bio-Analytical laboratory that we use for various quantitative and semi-quantitative analyses.
NanoViricides BSL2 Virology Lab for Evaluation of Drug Candidates in Cell Culture Studies
In addition to the cGMP-capable manufacturing facilities, we have also brought in-house the capability for testing of our nanoviricide drug candidates against a number of viruses in cell culture studies for early evaluation. We have built a Biological Safety Level-2 (BSL2) Virology Laboratory with attendant cell culture and biochemistry capabilities in our campus in Shelton, CT, certified by the State of Connecticut. We are able to perform drug efficacy and safety studies in cell cultures for multiple different viruses at the same time in this facility, in isolated lab rooms.
We can also study antivirals against certain BSL3 and BSL4 viruses in this facility by developing what are called “pseudovirions”. Pseudovirions are virus particles that cannot replicate, but that have the coat protein of the virus that we want to study (e.g. SARS-CoV-2, Ebola, Marburg etc.) on a viral backbone that is a BSL2 compatible virus. We only require and employ pseudovirions technology where the resulting virus particles cannot replicate. The pseudovirion systems allow evaluation of drug candidates that block the entry of the virus particle into cells, such as entry inhibitors, antibodies, and nanoviricides.
We have developed in-house cell culture screening capability for developing drug candidates against human Coronaviruses (h-CoV) including SARS-CoV-2 pseudovirions, VZV, HSV-1 and HSV-2, Influenzas, HIV, RSV, Ectromelia Mousepox Virus (a model for MPox and Smallpox viruses), and pseudovirion technology for Ebola/Marburg viruses, among others. We believe that this internal screening enables speedy evaluation of a much larger number of candidates than external collaborations allow. We believe this has significantly improved our ability to find highly effective ligands and performing structure-activity-relationship studies of the same in a short time period.
External CROs for GLP and Non-GLP Animal Model Studies, Regulatory Affairs Support, and Clinical Trials
We depend upon external collaborators and Contract Research Organizations (“CROs”) for all of our animal studies that include antiviral efficacy studies, safety and tolerability studies, in both GLP and non-GLP practices. We also depend upon external collaborators and CROs for completing our regulatory filings, designing suitable clinical protocols, as well as for conducting human clinical trials, compiling the resulting data, biostatistics evaluations, and preparation of reports for regulatory filings. We plan on bringing some of the regulatory affairs capabilities in-house in the near future in order to speed up our regulatory processes.
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NanoViricides Campus – Fully Owned Asset Group
All of the facilities described above, the land, building, construction, and equipment, are fully owned by NanoViricides, Inc. with no mortgages or liens. This forms a significant and stable part of our long term assets, accounting for over $8 million in long term assets post-depreciation and amortization. The replacement cost of this asset is estimated to exceed $25 million.
We believe NanoViricides, Inc. is one of a few innovation-led small pharma companies that has or is close to having a fully integrated pharmaceutical operation from drug discovery to drug product manufacturing. This sets us apart in the field by substantially de-risking our development programs as well as enabling time and cost savings in the new drug development process.
Fiscal Year 2022 - 2023 in Review
NV-CoV-2 Phase 1a/1b Clinical Trial Encompassing both Safety and Effectiveness Indications for COVID Treatment, and Interim Update on Phase 1a/1b Human Clinical Trial of NV-CoV-2
In the reported year and subsequently to date, we have been working towards the goal of conducting human clinical trials for NV-CoV-2.
The API in NV-CoV-2, namely NV-387, is a broad-spectrum antiviral designed to destroy the virus particle so it cannot infect cells. We believe that NV-387 has broad-spectrum pan-coronavirus activity, and should be effective against the deadly MERS-CoV and SARS-CoV-1 infections, as well as the SARS-CoV-2 and seasonal coronavirus infections, some of which, including hCoV-NL63 and hCoV-OC43 can be deadly.
We previously completed pre-clinical IND-enabling studies on our novel SARS-CoV-2 drug candidate NV-CoV-2 around May, 2021, and thereafter engaged in efforts to enter the drug into clinical studies.
NV-387 was found to be statistically effective in multiple unrelated coronaviruses in cell culture studies, including hCoV-229E and hCoV-NL63. It was also found to be statistically effective in blocking cell infection by pseudovirions of bearing the SARS-CoV-2 Spike protein on their surface. Further, in multiple animal studies of lethal lung infection by hCoV-NL63, NV-387 given by injection, as well as given orally was statistically effective. h-CoV-NL63 produces pathology similar to SARS-CoV-2 in humans and they both bind to the same attachment receptor(s) (S-PG class), as well as the same cognate receptor, namely ACE2. Therefore hCoV-NL63, which requires BSL2 lab, has been widely used as a surrogate for SARS-CoV-2, which requires BSL3/4 labs.
We found that NV-387 was safe, with a No-Observable-Adverse-Event-Level (NOAEL) of 1,200mg/Kg and a Maximum-Tolerated-Dose Level (MTD) of 1,500 mg/Kg in rats. In GLP Safety/Toxicology Studies, NV-387 was found to be safe and no observations (i.e. no adverse events) were reported in cardiotoxicity as well as respiratory and neurologic studies.
We have also found that NV-387 is non-immunogenic, non-mutagenic, and non-genotoxic in appropriate IND-enabling studies. There were no injection-site reactions in any of our studies. NV-387 was therefore presumed non-allergenic; accordingly, allergenicity testing was not required.
Additionally, the pharmacokinetics (PK) of NV-387 in rats as well as in a primate (i.e. human-like species) model, namely, cynomolgus monkeys, was found to produce a plateau in the blood stream in at least the 4-8hr range, after a maximum around 0.5-2 hr range. Further, the PK profile upon multiple repeated dosings over a period of several days suggested accumulation of the drug with clearance extended well beyond 24 hrs. This PK profile is unlike that of most small chemicals, and is reminiscent of sustained-drug-release approaches. This profile enables once daily dosing of NV-387.
We faced substantial difficulties in our efforts to take NV-CoV-2 into clinical trials while the pandemic was raging due to the on-going pandemic restrictions, the saturation of clinical sites, consequent unavailability of CRO’s, and the clinical market dynamics. We were pursuing both US and international possibilities for starting clinical trials with our limited resources. In September 2021, we signed an agreement with Karveer to evaluate the possibility of them sponsoring our COVID drugs for clinical trials in India.
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We, in collaboration with Karveer, the Drug Sponsor in India, and PristynCR, a Clinical Research Organization (“CRO”) in India, completed medical writing of the IND-enabling studies including Chemistry, Manufacture and Controls (CMC) and Pre-clinical Safety/Toxicology, Pharmacology, and Animal and Cell Culture Effectiveness Studies. We, together with our collaborators, Karveer, and PristynCR, completed developing the full-fledged Clinical Protocols rapidly and thereafter a complete Clinical Trial Application was submitted by Karveer in India around November, 2022. Karveer received a conditional regulatory approval from the Central Drugs Standard Control Organization and the Drug Controller General of India (“CDSCO/DCGI”) to proceed at the end of January, 2023. The conditions pertained to local clinical trial site related arrangements and approvals. The processes for satisfying these conditions were completed around March/April, 2023.
In March 2023, we consummated a License Agreement with Karveer pursuant to which we outlicensed to Karveer the two COVID drugs namely NV-CoV-2 and NV-CoV-2-R for further development and commercialization in India, as anticipated with the September 2021 engagement. Karveer has retained a local CRO, PristynCR Solutions, Pvt. Ltd., that developed the clinical trial protocols and clinical trial applications. PristynCR is performing the clinical trials at Mahatma Gandhi Mission Medical College and Hospital in Aurangabad, India (MGM). Karveer is managing the entire clinical trial process.
Around March/April, 2023, we completed cGMP-compliant manufacture of the clinical drug products at our own facility and shipped them to Karveer. The clinical process documentation was prepared by the CRO in collaboration with Karveer and the clinical trial site, MGM. Subsequently, initial enrollment work began. On or about June 19, 2023, the first healthy volunteers were dosed in the clinical trial. The clinical trial has continued with interim data reviews and further enrollments as planned.
On June 29, 2023, we announced that the clinical trial of NV-CoV-2 Oral Syrup and Oral Gummies has started. The clinical trial is designed to assess the safety and tolerability of the two drug products in healthy volunteers as well as in PCR +ve COVID patients. The Phase 1a part is a single-ascending dose (“SAD”) protocol study in healthy volunteer subjects and includes three cohorts for each of the drug products with six subjects per cohort. The Phase 1b part is a multiple ascending dose (“MAD”) protocol study. Phase 1b has two subparts. The healthy volunteers subpart of Phase 1b includes three cohorts for each of the drug products with six subjects per cohort. Additionally, the COVID patient subpart of Phase 1b includes three cohorts for each of the drug products with six subjects per cohort. Karveer intends to enroll PCR positive COVID patients with mild-to-moderate disease. All enrolled subjects will be sequestered in a hospital ward set aside for this purpose for the duration of the study in that subject. Clinical observations, Blood Chemistry, and Organ Function Tests are included at different time points and at a follow-up visit post-discharge. In addition, pharmacokinetics of the drug will be studied in the healthy volunteers cohorts. In the COVID cohorts, PCR tests will be conducted to determine when the virus clears. This part is designed to provide information on effectiveness of the drug and also to provide guidance on selection of dosing regimen for Phase II/III clinical trials.
On August 21, 2023, we reported interim communication that 26 out of the target of 36 healthy volunteers in the various cohorts in the Phase 1a Single-Ascending-Dose (“SAD”) have already completed the study. Additionally, 17 of the target of 36 healthy volunteers in the various cohorts in the Phase 1b Multiple-Ascending-Dose (“MAD”) part of the clinical trial had already completed the study by then. As of the date of this report, 26 out of 36 healthy volunteers in the various cohorts in the Phase 1b MAD study have completed the study, and an additional 10 healthy volunteers are expected to be recruited soon. Additionally, PristynCR has requested the Ethics Committee for permission to begin enrolling COVID patients.
No adverse events or serious adverse events were found in the SAD or MAD studies to date, in either the NV-CoV-2 Oral Syrup or the NV-CoV-2 Oral Gummies administration cohorts, even at the highest doses administered. These results are consistent with our pre-clinical safety toxology studies.
Bringing Clinical Programs into FDA Regulatory Processes
While our collaborator Karveer has progressed NV-387 into Phase 1a/1b clinical trials in India, we are now working on how to bring over the results of the clinical trial to the FDA once the reports become available. This would enable us to qualify to begin Phase II or Phase II/III clinical trials of the same drug in the USA for COVID and presumably, for RSV, as well as other potential indications that NV-387 may be a good candidate for their treatment.
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Expanding Indications of NV-387: RSV, Other Viruses
Additionally, knowing that NV-387 has broad-spectrum antiviral activity, as mimic of the attachment receptor S-PG class, we began exploration of its antiviral activity against other respiratory viruses.
The first of the target respiratory viruses we chose is RSV. We chose RSV because it is an important life-threatening infection particularly for newborns and children which leads to pneumonia in infants and children, and can result in deaths.
RSV is an Acute Lower Respiratory Infection (ALRI; includes Pneumonia). RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children. Each year in the United States, an estimated 58,000–80,000 children younger than 5 years old are hospitalized due to RSV infection. Globally, in 2015, 33 million episodes of RSV-ALRI resulted in about 3.2 million hospital admissions, and 59,600 in-hospital deaths in children younger than 5 years. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months.
Yet there is currently no drug for the treatment of RSV infection, which represents a multi-billion-dollar unmet medical need. GrowthPlus Reports, in June 2023, said the market size for RSV therapeutics was worth $1.8 Billion in 2022, and is expected to grow at a CAGR of 18.9%, reaching $8.73 Billion by 2031.
We reported in July 2023, that NV-387 was almost as effective against lethal RSV infection in an animal model as the only known drug active against it, namely, ribavirin, which is a highly toxic drug. More importantly, both oral dosing of NV-387 as gummies, as well as dosing as an injection were successful in combating the RSV infection. Further, the oral bioavailability of NV-387, when comparing for equivalent clinical effect, was found to be quite high, approaching 50%. If the Phase 1a/1b clinical trials of NV-CoV-2 are acceptable then we would be able to engage into Phase II/III clinical trials of NV-387 oral formulations under the RSV indication. These oral formulations, currently named NV-CoV-2 Oral Syrup and NV-CoV-2 Oral Gummies, are likely to be renamed because of their broad-spectrum activity beyond coronaviruses.
We are also continuing additional work on other viruses that are likely to be susceptible to NV-387, that is, viruses that are known to use S-PG class of attachment receptors for infecting cells. This is a huge list that covers many of the viruses we are already working on and many new ones.
Our IND-Ready Drug Candidate, NV-HHV-1 Skin Cream for the Treatment of Shingles
We have previously developed NV-HHV-1 and formulated it as a skin cream for the treatment of Shingles rash, NV-HHV-1 has completed IND-enabling studies. We plan on undertaking further development of NV-HHV-1 into human clinical trials once our NV-387 based drug candidates progress further in clinical trials.
Licenses, Patents, Trademarks, Proprietary Rights: Intellectual Property
Licenses from TheraCour
Our drug development business model was formed in May 2005 with a license to the patents and intellectual property held by TheraCour Pharma, Inc. (TheraCour) that enabled creation of drugs engineered specifically to combat viral diseases in humans. This exclusive license from TheraCour serves as a foundation for our intellectual property. We have a worldwide exclusive license to this technology for several field of application verticals with specific targeting mechanisms for the treatment of a number of human viral diseases. TheraCour owns approximately 21% of our voting capital stock and, Anil Diwan, our Founder, President and Executive Chairman, owns approximately 90% of TheraCour’s capital stock.
Our drug candidates are licensed from TheraCour, and are developed by TheraCour for the Company on the basis of several patents, patent applications, provisional patent applications, and other proprietary intellectual property know-how held by TheraCour. Unlike usual pharma industry licenses that are specified for single chemical entities or for groups of similar chemical entities, our licenses are specified for the vertical application field of use, thereby providing us with a large universe of diverse development candidates under the same umbrella. Further, the licenses are held by NanoViricides for worldwide use and can be sub-licensed. The licenses can revert only in the case of a default by NanoViricides. The terms of default are such that, effectively, TheraCour would be able to take the licenses back only in the event that NanoViricides declares insolvency and inability to conduct its business.
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We have exclusive licenses from TheraCour for drug candidates derived from and based on TheraCour’s technologies for several viruses. In 2005, we obtained a license from TheraCour for the treatment of the following human viral diseases: Human Immunodeficiency Virus (HIV/AIDS), Influenza including Asian Bird Flu Virus (INF), Herpes Simplex Virus (HSV-1 and HSV-2), Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), and Rabies. Thereafter, on February 15, 2010, we entered into an Additional License Agreement with TheraCour granting the Company the exclusive licenses for technologies developed by TheraCour for the additional virus types for Dengue viruses (DENV), Japanese Encephalitis (JEV), West Nile Virus (WNV), viruses causing viral Conjunctivitis (a disease of the eye) and Ocular Herpes Keratitis, and Ebola/Marburg viruses. While herpes simplex viruses were already specified as licensed previously, the term “ocular herpes keratitis” was added to this additional license agreement at the specific request of the Company for clarity only. In addition, we completed the process of licensing the VZV (shingles, chicken pox virus) field from TheraCour in November 2019. We further completed the process of licensing antivirals for the field of human coronavirus indications in September 2021 under the COVID agreement. As in the past, as and when advised by counsel, we will seek additional licenses to verticals of antiviral fields from TheraCour. To date, TheraCour has not withheld any licenses for antiviral nanomedicines that NanoViricides has requested.
We retain worldwide exclusive rights to commercially develop, commercialize, and market the licensed products. We pay TheraCour for the R&D work asked to be performed by the Company to develop these drugs, their chemistries, formulations, and manufacturing processes, substantially at cost, with a certain fee as specified in the license agreements. We may perform initial developmental testing by ourselves and through third parties, such as academic labs, government institutions, contract research organizations, for safety and effectiveness, among other tests. The Company may perform further IND-enabling advanced pre-clinical studies using third parties, such as contract research organizations, usually on clinical drug candidates. We expect to perform human clinical trials using contract research organizations with expertise in such clinical trials. We intend to sponsor the drugs for commercialization activities and obtain the rights of commerce under various regulatory authorities for its own use.
We focus our research and clinical programs on specific anti-viral therapeutics and are seeking to add to its existing portfolio of products through our internal discovery and clinical development programs and through an in-licensing strategy. To date, we have not commercialized any product.
For all the licensed fields, we control the research and work TheraCour performs on our behalf and no costs may be incurred without the prior authorization or approval by us.
The TheraCour technologies and patents required for execution of our work in the licensed fields and licensed products are automatically licensed to us even if such technologies and patents are developed after the license agreements themselves.
Patents, Patent Applications, Proprietary Rights
Patents and other proprietary rights are essential for our operations. If our drugs are protected by a properly designed and enforceable patent, it can be more difficult for our competitors to use our technology to create competitive products and more difficult for our competitors to obtain a patent that prevents us from using technology we create. As part of our business strategy, in conjunction with TheraCour, we actively seek patent protection both in the United States and internationally and intend to file additional patent applications, when appropriate, to cover improvements in our compounds, products and technology. We also rely on trade secrets, internal know-how, technological innovations and agreements with third parties to develop, maintain and protect our competitive position. Our ability to be competitive will depend on the success of this strategy.
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A new international PCT patent application regarding coronavirus drug candidates, PCT/US21/39050, entitled “Self-Assembling Amphiphilic Polymers As Anti-Covid-19 Agents,” was filed under the Patent Cooperation Treaty (PCT) on June 25, 2021. An additional international PCT patent application that builds on this application regarding coronavirus drug candidates, PCT/US22/35210, entitled “Self-Assembling Amphiphilic Polymers As Anti-Covid-19 Agents,” was filed on June, 28, 2022, with a requested priority date of the 2021 application. Our anti-COVID drugs are based on polymeric micelle nanomedicine technologies developed by TheraCour and its affiliate, AllExcel, Inc. (“AllExcel”). The inventors at AllExcel have filed these two broad PCT patent applications that form the basis of our two lead drug candidates, namely, NV-CoV-2 and NV-CoV-2-R. These new patent applications cover the new technologies, compositions, formulations, processes, manufactured products, and methods of use, among other specifics.
The nominal expiry date for patents resulting from these two PCT applications would be 20 years, after filing and if issued, i.e. June 24, 2041, and could be extended in certain countries under regulatory extensions to as late as into the year 2043, providing a significant commercial runway.
We believe that our drugs by themselves may be eligible for patent protection. We, in conjunction with TheraCour, plan on filing patent applications for protecting these drugs when we have definitive results that enable clinical drug development. We believe this strategy would maximize the available commercial patent life for many of our future drugs well beyond 2043. We intend to file the patent application for HerpeCide before entering human clinical trials, as we have done for our Coronavirus program. The estimated expiry date for the HerpeCide patents, if and when issued, would be no earlier than 2044-2049.
The Company has licenses to key patents, patent applications and rights to proprietary and patent-pending technologies related to our compounds, products and technologies (see Table 1), but we cannot be certain that issued patents will be enforceable or provide adequate protection or that pending patent applications will result in issued patents.
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We have previously announced certain important issuances of patents on the TheraCour® technology underlying our Nanoviricides® drugs. A total of at least 61 patents have been issued globally, on the basis of the first two international PCT patent families that cover the fundamental aspects of the platform technology we license from TheraCour. Additional patent grants are expected to continue as the applications progress through prosecution processes. All of the resulting patents have substantially broad claims. These patents have nominal expiry dates in 2026 to 2029.
The patent expiry dates can be further extended in several countries and regions for the additional allowances due to the regulatory burden of drug development processes, or other local considerations, such as licensing to a local majority held company. Many countries allow up to five years extension for regulatory delays.
We believe that the novel compositions disclosed in these patent applications, and additional proprietary intellectual property provide the necessary features that enable the development of nanoviricides. We believe that no other published literature materials or existing patents are capable of providing all of the necessary features for this development, to the best of our knowledge. However, we have no knowledge of the extensive active internal developments at a number of companies in the targeted therapeutics area.
TheraCour may obtain patents for the compounds many years before we obtain marketing approval for them. Because patents have a limited life, which may begin to run prior to the commercial sale of the related product, the commercial value of the patent may be limited. However, we may be able to apply for patent term extensions, based on delays experienced in marketing products due to regulatory requirements. There is no assurance we would be able to obtain such extensions. Patents relating to pharmaceutical, biopharmaceutical and biotechnology products, compounds and processes such as those that cover our existing compounds, products and processes and those that we will likely file in the future, do not always provide complete or adequate protection. Future litigation or reexamination proceedings regarding the enforcement or validity of our licensor, TheraCour’s existing patents or any future patents, could invalidate TheraCour’s patents or substantially reduce their protection. In addition, the pending patent applications and patent applications filed by TheraCour, may not result in the issuance of any patents or may result in patents that do not provide adequate protection. As a result, we may not be able to prevent third parties from developing the same compounds and products that we have developed or are developing. In addition, certain countries do not permit enforcement of these patents, and manufacturers are able to sell generic versions of our products in those countries. We also rely on unpatented trade secrets and improvements, unpatented internal know-how and technological innovation. In particular, a great deal of our material manufacturing expertise, which is a key component of our core material technology, is not covered by patents but is instead protected as a trade secret. We protect these rights mainly through confidentiality agreements with our corporate partners, employees, consultants and vendors. These agreements provide that all confidential information developed or made known to an individual during the course of their relationship with us will be kept confidential and will not be used or disclosed to third parties except in specified circumstances. In the case of employees, the agreements provide that all inventions made by the individual while employed by us will be our exclusive property. We cannot be certain that these parties will comply with these confidentiality agreements, that we have adequate remedies for any breach, or that our trade secrets will not otherwise become known or be independently discovered by our competitors.
Out-Licensing to Karveer Meditech Private Limited, India
On March 27, 2023 we entered into a License Agreement with Karveer wherein we granted to Karveer a limited, non-transferable, exclusive license for the use, sale, or offer of sale in India of the two clinical test drug candidates titled as NV-CoV-2 and NV-CoV-2-R for the treatment of COVID in patients in India. Karveer has engaged in further drug development in India including sponsoring of drug candidates for human clinical trials in India and has acted as clinical trials manager for such clinical trials. Karveer shall provide NanoViricides with all reports of the clinical trials and the Company can use such reports for further advancement of the drug candidates with regulatory authorities outside India. In consideration, Karveer will be reimbursed by us for all direct and indirect costs incurred for the clinical trials and development activities with a customary clinical trials manager fee of thirty (30)% of such costs and applicable taxes. Upon commercial sales of any resulting approved drugs, Karveer will pay the Company a royalty of seventy (70)% percent of the final invoiced sales less costs to unaffiliated third parties. Diwan, our Founder, President and Executive Chairman, is a passive investor in Karveer. His ownership interest does not provide him with control or significant influence over Karveer.
Trademarks
The Company currently has no registered trademarks.
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Corporate Events - Financing
We had approximately $8.1 million cash in hand as of June 30, 2023, the end of the reporting period. We spent approximately $5.7 million in cash on operating activities in the reported year, although our expenditures are expected to increase upon commissioning of additional human clinical trials. Additionally, we have long term assets of $8.1 million post-depreciation and amortization that represent our facilities.
We believe we have sufficient financing to complete at least the initial set of human clinical trials for our most advanced drug candidate, namely, NV-CoV-2, which is anticipated to occur during the coming fiscal year.
On July 8, 2020, we entered into an underwriting agreement (the “Underwriting Agreement” or “Offering”) with Kingswood Capital Markets, a Division of Benchmark Investments, Inc. ( now EF Hutton Group). The Offering was consummated on July 10, 2020, whereby we sold 1,369,863 shares of common stock and a fully exercised underwriters’ over-allotment option of 205,479 additional shares at $7.30 per share. No warrants were issued in this Offering. The net proceeds to us from the Offering was approximately $10.4 million after deducting underwriting discounts and commissions and other estimated offering expenses payable by us.
On July 31, 2020, we entered into an At Market Issuance Sales Agreement (the “ATM Sales Agreement”) with B. Riley Securities, Inc. and Kingswood Capital Markets, a division of Benchmark Investments, Inc. (now EF Hutton Securities) (each a “Sales Agent” and collectively, the “Sales Agents”), pursuant to which we may offer and sell, from time to time, through or to the Sales Agents, shares of common stock (the “Placement Shares”), having an aggregate offering price of up to $50 million (the “ATM Offering”).
On March 2, 2021 we sold 814,242 shares of common stock at an average price of $7.83 under the ATM Sales Agreement with the Sales Agents. The net proceeds from the offering were approximately $6.1 million after deducting underwriting discounts and commissions and other offering expenses.
On May 5, 2023, we filed a registration statement on Form S-3 (File No. 333-271706) with the Securities and Exchange Commission (the “SEC”), as amended on May 8, 2023, which registration statement was declared effective by the SEC on May 22, 2023. Under this shelf registration process, we may, from time to time, sell up to $150 million in the aggregate of shares of common stock, shares of preferred stock, debt securities, warrants and units.
On or about August 1st, 2023, the ATM Sales Agreement was amended to name EF Hutton, division of Benchmark Investments, LLC as the only sales agent (the “Agent”) and to remove B. Riley Securities, Inc. as a sales agent. On August 4, 2023, we filed a prospectus supplement relating to the issuance and sale of our common stock, par value $0.00001 per share, having an aggregate offering price of up to $5,713,022 from time to time through or to our Agent. These sales, if any, will be made pursuant to the terms of the amended ATM Sales Agreement between us and the Agent.
Management believes that the Company has several important milestones to be achieved in the ensuing year. Management believes that as it achieves these milestones, the Company’s ability to raise additional funds in the public markets would be enhanced and support our goals of obtaining approvals for our COVID-19 drug candidates, marketing, establishing additional commercial scale manufacturing, and re-engaging additional drug development programs that are currently on hold.
Our drug development strategies may be influenced by considerations regarding the ability to engage into licensing or co-development relationships with other pharmaceutical companies. Pharmaceutical drug development is an expensive and long duration proposition. Management’s plan is to develop each of our nanoviricides to the necessary stage(s) for potential collaborations. Such licensing or co-development relationships may entail upfront payments, milestones payments, cost sharing, and eventual revenue sharing, including royalties on sales. There is no guarantee that we will be able to negotiate agreements that are financially beneficial to us. We intend to develop our drugs on our own if a suitable collaboration does not occur. As and when needed, management plans to continue to raise additional funds for our continuing drug development efforts from public markets. However, there can be no assurance that we will be successful in obtaining sufficient financing on terms acceptable to us.
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Investor Outreach
We have retained Tradigital, Inc. as our investor relations firm. In addition, we have presented at various investor conferences.
On December 6, 2022, Dr. Anil Diwan, presented at the RHK Capital Disruptive Growth Conference in New York City, providing an update on the NV-CoV-2 Clinical Trials Program.
On January 9, 2023, Dr. Anil Diwan, presented at Biotech Showcase in San Francisco, providing an update on the NV-CoV-2 Clinical Trials Program.
On April 4, 2023, we announced that we had out-licensed NV-CoV-2 and NV-CoV-2-R for further development and commercialization in the territory of India to Karveer and that Karveer had obtained regulatory approval in India for starting Phase 1a/1b human clinical trials of NV-CoV-2 Oral Syrup and Oral Gummies for development in India.
On June 5, 2023, Dr. Anil Diwan presented the Company’s assets and current development stage at the BIO International Conference in Boston, MA.
Additionally, we have provided updates on our progress via press releases.
NanoViricides Drug Programs
Our Drug Programs for Coronavirus Infections Including COVID (Table 2.A):
We are currently developing the following drug products for the treatment of COVID-19 disease:
(i) NV-CoV-2 Oral Syrup,
(ii) NV-CoV-2 Oral Gummies, and
(iii) NV-CoV-2 Solution for Injection, Infusion and Inhalation.
We were pleasantly surprised with the strong oral bioavailability of NV-387, the API of the drug product NV-CoV-2 in our animal studies. Very rapidly we developed two oral formulations of the drug. The oral gummies are a convenient and palatable form that resembles a soft candy or gummy. This form may have an advantage in terms of acceptability, particularly with pediatric population, and possibly in terms of its absorption characteristics, as it dissolves slowly in the mouth. The oral syrup has the advantage that it can be given in amounts proportional to body weight, a requirement that arises with treatment of very young children. These oral drugs are being developed for the treatment of mild to moderate COVID-19 disease.
The injectable form of NV-CoV-2 is designed for the treatment of hospitalized patients. Initially, we plan on delivering the drug NV-CoV-2 as a 30 minute infusion for hospitalized patients with severe COVID-19.
We plan to reduce the drug administration to a simple, slow-push, I.V. injection rather than the infusion if the data suggest that such injection will be well tolerated and effective. If so, we believe the injections would be for use in non-hospitalized patients that have moderate to severe disease which may require hospitalization if not treated immediately.
The same injectable form of NV-CoV-2 can be directly introduced as a mist into lungs using a simple hand-held nebulizer device. We expect such inhalation would deliver NV-CoV-2 at high concentration directly at the site of viral injury, i.e. the respiratory tract and lungs, for the most direct protective effect on the lungs. Such inhalation, possibly in conjunction with injection or infusion, would likely result in rapid benefit to severely ill, hospitalized patients requiring oxygen assistance.
We are also developing an additional drug product for the treatment of COVID-19 disease:
(iv) NV-CoV-2-R Solution for Injection, Infusion and Inhalation.
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NV-CoV-2-R
In addition to NV-CoV-2 itself as a drug to combat COVID-19, we are also developing another SARS-CoV-2 drug candidate, NV-CoV-2-R, which encapsulates remdesivir inside NV-CoV-2 represents a drug of the Nanoviricides Platform Modality#3 type. While Remdesivir substantially blocks the replication of the virus inside cells, NV-CoV-2 is designed to block the virus outside cells by entrapping it and thereby not allowing it to infect the cells in the first place. Thus NV-CoV-2-R is designed to block both the intra-cellular life cycle of the virus and the extra-cellular life cycle of the virus. Blocking both lifecycles should enable complete control of the viral disease, promising a potential cure. Remdesivir, sponsored by Gilead, is a known antiviral drug that has received full FDA approved for treatment of COVID-19 and has received EUA in many countries. We are developing NV-CoV-2-R on our own, independently of Gilead.
NV-CoV-2-R was observed to provide significant advantages over its encapsulated component remdesivir in terms of substantially superior pharmacokinetics consistent with our expectation in designing this drug by encapsulating remdesivir within our lead drug candidate NV-CoV-2. This encapsulation results in the dual-acting drug candidate NV-CoV-2-R which we believe has the promise of a potential pan-coronavirus cure.
The NV-CoV-2-R infusion, and if needed, associated inhalation of the same into lungs, may provide true cure of the SARS-CoV-2 infection by mounting a strong, double-whammy attack on the entire lifecycle of the virus, with NV-387 attacking the Re-infection Cycle, and Remdesivir attacking the Replication Cycle, to shut down the virus potentially completely. Such attack would also make drug escape or resistant variant generation highly unlikely if not practically impossible.
Both Remdesivir and NV-CoV-2 have demonstrated broad-spectrum activity against coronaviruses. Thus NV-CoV-2-R is expected to continue to be active in spite of evolution of novel variants of SARS-CoV-2. In contrast, antibody drugs and vaccines which induce antibodies lose effectiveness against variants. The more the variant drifts from the original strain, the less protection is offered by vaccines, and effectiveness of antibodies also diminishes significantly. This is now known to be occurring for current vaccines and antibodies during the global COVID-19 pandemic.
NV-CoV-2-R combines (1) the power of the nanoviricides® platform attacking the virus particle outside cells with (2) the power of Remdesivir in attacking the virus reproduction inside cells. Additionally, we believe that (3) NV-CoV-2-R improves the effect of remdesivir by (a) enabling a higher effective concentration of remdesivir in the body and (b) sustaining this higher concentration for a substantially longer period of time, both compared to the standard formulation of remdesivir, as observed in this pharmacokinetic animal study.
Both NV-CoV-2 and Remdesivir are expected to retain their effectiveness against existing and emerging variants of SARS-CoV-2. NV-CoV-2 has shown effectiveness against multiple unrelated coronavirus types. Remdesivir has been demonstrated to possess antiviral activity in cell culture against a large number of RNA viruses.
The strong effectiveness of our drug candidates NV-CoV-2 and NV-CoV-2-R against two unrelated coronaviruses, namely hCoV-NL63 and hCoV-229E, and SARS-CoV-2 pseudovirions in cell culture studies indicates their strong potential for treatment of coronavirus diseases including COVID-19, irrespective of variants or coronavirus types. The broad-spectrum effectiveness of the Company’s drug candidates is very important as coronavirus variants that are reported to evade antibodies, potentially causing disease in spite of vaccination, are becoming widespread as the COVID-19 global pandemic is progressing into its second year.
We believe that our broad-spectrum anti-coronavirus drugs will continue to be effective even as the virus continues to mutate developing into a number of variants of concern. Antibody protection afforded by vaccines and the effectiveness of antibody drugs have continued to decline progressively as new SARS-CoV-2 variants continue to emerge. We believe that our unique anti-viral nanomachine technology overcomes these issues.
Oral administrations of NV-CoV-2 as well as NV-CoV-2-R were also found to be highly effective in a lethal coronavirus lung infection rat model. The oral delivery requires more dosing for equivalent effect compared to injectable delivery, as is normal for all drugs except a few that directly work in gastroenteric tract itself. Additionally, the extremely strong safety of our drugs, particularly NV-CoV-2, is expected to be very important for pediatric application.
Therefore we plan to include pediatric cohorts into clinical trials at the appropriate stages.
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NV-387 (NV-CoV-2) is Safe
In a NOAEL/MTD Study in rats, there were no clinical signs of immune or allergic reactions such as itching, biting, twitching, rough coat, etc. Further, there were no observable changes in any organs including large intestine or colon on post mortem in gross histology. The only reportable changes observed were, in the highest dosage groups, loosened stools associated with the non-absorption of water, in the colon. In clinical usage, the drug candidates are not anticipated to be administered in such high levels. The objective of this study was to discover the dosage level at which such an effect may occur. Loose or very loose stools at very high dosages in such a study is an expected and acceptable side effect of the polyethylene glycol (PEG) moiety, which we believe forms the backbone of the nanoviricides drug candidates. PEG is used prior to colonoscopy in humans to promote loose stools and internal cleaning of the intestines, by causing non-absorption of water, and is also used as a stool softener to counteract constipation. The NOAEL was estimated at 1,200 mg/Kg and MTD was estimated at 1,500 mg/Kg in rats, demonstrating extremely strong safety of NV-387 in animal model in this study.
Pharmacokinetics of NV-387-Encapsulated Remdesivir Is Substantially Superior to the Standard Remdesivir/SBECD Formulation
Almost double the amount of Remdesivir remained intact in plasma when given as the encapsulated NV-CoV-2-R form, in comparison to the standard remdesivir formulation made in betadex sulfobutyl ether sodium (SBECD), during the first day of dosing in a rat pharmacokinetics study in the time profile. Additionally, remdesivir accumulation was observed on repeated dosing of NV-CoV-2-R. After the fifth dose of NV-CoV-2-R (on day 7), in comparison to the standard remdesivir dosing pattern (twice on day 1 followed by daily thereafter; on day 7), the circulating level of intact remdesivir in plasma was 75% greater in the NV-Cov-2-R group as compared to the standard remdesivir group. The data were normalized to reflect the same amount of remdesivir given to the animals per kg body weight for uniform comparison. The assays were performed using the well-established isotopic internal standard method of remdesivir estimation with LCMS detection.
The increased circulating level of intact remdesivir when given as NV-CoV-2-R encapsulated formulation without any increase in toxicity is significant. It can be expected to result in improved antiviral effectiveness of the remdesivir component in human usage of NV-CoV-2-R treatment. This is important because remdesivir is a highly effective drug in cell culture and pre-clinical studies but does not show clinical effectiveness in humans at levels that would be expected based on its cell culture efficacy due to its rapid metabolism. Additionally, there is very little margin to increase remdesivir dosing in its standard formulation because of dose limiting toxicity.
Importantly, NV-CoV-2-R was found to be less toxic than the standard remdesivir formulation in this study. At day 7, when a total of 80mg/kg remdesivir was dosed in the standard formulation, the body weight loss was approximately 9.5% in male and 9.5% in female animals. In contrast, when 80mg/kg of remdesivir was delivered as NV-CoV-2-R encapsulated formulation, at day 7, the weight loss was only approximately 3% in male animals and 1% in female animals that was the same as with the vehicle treatment reflecting injection trauma itself and no drug toxicity.
These data demonstrate that the pan-coronavirus nanoviricide drug candidate NV-CoV-2-R substantially decreases the loss of remdesivir to bodily metabolism in comparison to the standard formulation, and also minimizes toxic effects of remdesivir. We anticipate that this stabilizing effect should lead to a highly effective pan-coronavirus drug that could potentially cure most cases of COVID-19 infection.
The standard Veklury® formulation of remdesivir in betadex sulfobutyl ether sodium (SBECD) helps with suspending remdesivir in solution, but does not appear to significantly improve upon the metabolic effects. In contrast, NV-CoV-2-R is an encapsulation approach wherein remdesivir would slowly leak out into the bloodstream from the polymeric nano-micelle over time, imparting protection against metabolism and sustained effective levels of the encapsulated drug component over a longer time period.
NV-CoV-2 (API NV-387) and NV-CoV-2-R (API NV-387-R) Were Statistically Effective Against Lethal Lung Coronavirus Infection in an Animal Model
NV-CoV-2 and NV-CoV-2-R were found to be statistically effective against a totally lethal lung infection caused by coronavirus NL-63 that uses the same receptor, ACE2 as SARS-CoV-2, and exhibits similar but less severe human pathology compared to SARS-CoV-2, in rats based on multiple indicators:
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Survival: While rats in the untreated infected group succumbed to the disease in 5 to 6 days, the rats in the NV-CoV-2 treatment group survived for 14 days, and the rats in the NV-CoV-2-R treatment group survived for 16 days. In contrast, rats treated with remdesivir formulated in SBECD (comparable to the FDA-approved Veklury® formulation of remdesivir) survived for only 7.5 days. The total dose of remdesivir was 90mg/kgBW for the remdesivir treated group, and it was 80mg/kgBW when encapsulated in the NV-CoV-2-R group. Thus compared to treatment with remdesivir, treatment with the Company’s drug candidate NV-CoV-2 extended the lifespan by approximately four times more days. Further, treatment with the Company’s other drug candidate NV-CoV-2-R extended the lifespan by approximately five times more days.
Body Weight: Both NV-CoV-2 and NV-CoV-2-R protected the animals from body weight (BW) loss that results from the infection and immune response, in addition to the substantially increased survival, in this lethal coronavirus infection model. NV-CoV-2 group lost only about 7% BW (12.5 g/animal) at day 13, and the NV-CoV-2-R group lost as little as ~1.8% BW (3g/animal) at day 13. In contrast, the remdesivir group had already lost ~17% BW (30g/animal) by day 7 and succumbed to the disease soon thereafter.
These results clearly indicate statistically effectiveness of NV-CoV-2 as well as NV-CoV-2-R in fighting the coronavirus lung infection and its ill effects, as compared to the FDA-approved drug Remdesivir.
The (1) significant improvement in lifespan by a factor of four to five, and (2) the significant prevention of body weight loss, upon treatment with NV-CoV-2 as well as NV-CoV-2-R as compared to treatment with the FDA-approved Remdesivir are important indicators for potential human clinical success of the Company’s drug candidates.
We studied the effectiveness of these drugs against the human coronaviruses h-CoV-NL63 (NL63) that uses the same ACE2 human cellular protein as receptor to gain entry into cells, as do all variants of SARS-CoV-2 and SARS-CoV-1. Additionally, the human pathology of NL63 infection closely mimics that of SARS-CoV-2, albeit with limited disease severity. NL63 is a circulating human coronavirus that can be used in BSL2 labs. NL-63 is therefore being used as a model for anti-SARS-CoV-2 drug development in various labs including ours (see Chakraborty and Diwan for a review: A. Chakraborty and A. Diwan (2020). “NL63: A Better Surrogate Virus for studying SARS- CoV-2”. Integr Mol Med, 2020, vol.7, pp 1-9, doi: 10.15761/IMM.1000408).
Remdesivir (Veklury®, Gilead) has shown relatively weak effectiveness in animal and clinical studies in contrast to its strong effectiveness in cell culture studies. This has been related by scientists to the metabolism of remdesivir in the blood stream that causes loss of effectiveness. The Company has developed the drug candidate NV-CoV-2-R by encapsulating (“hiding inside”) remdesivir into NV-CoV-2. The Company believes that this encapsulation should protect remdesivir from bodily metabolism and thereby significantly increase its clinical effectiveness (see below about pharmacokinetics of NV-CoV-2-R and protection of remdesivir).
The effectiveness of NV-CoV-2-R observed in this study can be understood as a combination of (a) the improvement in the effectiveness of remdesivir due to encapsulation, and (b) the effectiveness of NV-CoV-2 by itself. NV-387-R is a representative of the Nanoviricides Platform Modality 3, whereas NV-387 is representative of the Nanoviricides Platform Modality 1.
NV-CoV-2-R, we believe, is an excellent demonstration of the power of the Nanoviricides Platform technology that enables combining multiple modalities seamlessly into a single drug.
We believe that these in vivo study results support a potential synergistic improvement in the drug effect as a result of combining the two different mechanisms of attacking (i) the virus reinfection cycle and (ii) the virus replication cycle simultaneously.
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“Long COVID” or Post-Acute Sequelae of COVID (PASC)
The COVID-19 pandemic is rapidly evolving into an endemic wherein regular waves of variants are expected to occur a foreseeable future, with peaks of between one to three times a year. Each wave of variant makes obsolete the previously developed antibody drugs and reduces the effectiveness of vaccines and prior immunity. However, the residual immunity, which in the COVID-19 scenario has not been enduring, still has helped draw down the fatality rates per wave, although infection rates per wave have actually increased wave-over-wave so far. Additionally, catching COVID as well as in some cases the COVID vaccines have been linked to increased incidences of future heart diseases, Type I diabetes, ischemia and stroke, among other life-threatening events, even if the COVID infection itself was mild, (https://fortune.com/2022/10/06/strokes-heart-attacks-sudden-death-america-long-term-risks-catching-covid-carolyn-barber/?showAdminBar=true). A significant percentage of COVID infections result in long drawn out syndromes of pathology collectively referred to as “Long COVID” or Post-Acute Sequelae of COVID (PASC) which, according to one highly publicized recent CDC study, afflicts some 20% of COVID-19 survivors ages 18 to 64 (https://www.theatlantic.com/ideas/archive/2022/10/long-post-covid-symptoms-mild-cases/670469/?utm_source=apple_news).
We believe that control of the virus infection by an effective therapeutic would minimize such post-COVID after-effects (“Long COVID”) that experts suggest may be linked to a new pro-thrombotic and pro-inflammatory physiological state that is raised in the patient. Thus there is an urgent need for a highly effective therapy for coronavirus variants infection.
We believe NV-CoV-2 will probably be one of the best tools to address the COVID-19 spectrum of diseases, based on the pre-clinical safety and strong pre-clinical efficacy data that we have accumulated of NV-CoV-2 and NV-CoV-2-R, and based on our studies of similar pre-clinical datasets and their correlation to the clinical findings of the currently approved drugs.
Expansion of Indications for NV-387 and NV-387-based Modality #3 Drug Candidates
As previously noted, NV-387 is based on the S-PG class of attachment receptor(s) to which over 90% of human pathogenic viruses are known to bind.
We have also developed NV-387-Rp (as an improvement over NV-387-R), and NV-387-Ribvp as drug candidates that could be potential cures for a large number of viruses based on the activities of NV-387, Remdesivir, and Ribavirin, respectively.
We have therefore engaged in exploring other virus candidates for which NV-387 or its encapsulation-derivatives based on Modality #3 could be effective therapeutics and potential cures.
Our Drug Programs for RSV (Table 2.B):
Our very first exploratory studies towards expanding indications of the API NV-387 have led to successful demonstration of strong effectiveness in an animal model of lethal lung infection by RSV. We believe that we will be able to declare NV-387 as a clinical drug candidate in the near future. We plan to pursue NV-387 as a treatment for RSV infection towards the goal of Phase II/III clinical trials once the Phase 1a/1b trial of NV-CoV-2 (API NV-387) are completed and the report becomes available.
Treatment of RSV Infection Remains an Unmet Medical Need
Two protective antibodies are approved for administering to infants, namely palivizumab (Synagis) and the recently approved nirsevimab (Beyfortus), but not for treatment of RSV infection. Two vaccines have recently been approved for RSV prophylaxis. Arexvy (GSK), and Abrysvo (Pfizer) were approved in May, 2023 for use in adults over 60 years of age and both reduced severity of RSV infection. There are no vaccines currently approved for infants and children.
Nevertheless, there is no drug approved for the treatment of RSV infection, other than the highly toxic Ribavirin that is indicated only as a last resort. Thus there is a significant unmet medical need for a safe and effective RSV therapeutic.
GrowthPlus Reports, in June 2023, said the market size for RSV therapeutics was worth $1.8 billion in 2022, and is expected to grow at a CAGR of 18.9%, reaching $8.73 billion by 2031.
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Injectable NV-387 was found to be statistically effective in a lethal direct-lung RSV infection in a mouse model study
In July, 2023, we reported that NV-387 was found to be statistically effective against RSV in a lethal RSV infection animal model study.
Orally administered NV-387 Injection was found to be statistically effective in the same lethal direct-lung RSV infection study
Animals treated with injection vehicle solution alone survived 7 days. Ribavirin, a toxic drug, was used as a positive control. Animals treated with injections of ribavirin survived 16 days, whereas animals treated with injectable NV-387 survived 15 days, almost matching the efficacy of ribavirin treatment.
NV-387 administered by oral gavage was also found to be statistically effective in the same lethal direct-lung RSV infection study.
Animals treated with oral drug vehicle alone survived 7 days. Orally administered Ribavirin, a toxic drug, was used only as a positive control. Animals treated with oral ribavirin survived 16 days, whereas animals treated with oral NV-387 survived 15 days, again almost matching the efficacy of Ribavirin treatment.
Unlike Ribavirin, NV-387 has been found to be safe in preclinical studies. Therefore, it would be possible to increase the dose level or frequency of NV-387 to increase its effectiveness. Thus this study demonstrated that NV-387 is an effective drug candidate for the treatment of RSV infection with significant patient benefits.
NV-387 demonstrated very high oral bioavailability in this study
The dosing of NV-387 orally given was twice as much as that given by I.V. injection to compensate for oral bioavailability. The apparent oral bioavailability of NV-387 based on efficacy parameters appears to be of the order of almost 50% in this study, a very high value.
NV-387 can advance directly into Phase II Human clinical trials for RSV treatment
It is expected that NV-387 can be advanced into Phase II studies against RSV once the current Phase I studies of NV-CoV-2 (which contains the same API, NV-387) are completed. This will significantly speed up the development of the RSV drug, save costs, and improve return on investments (ROI).
Our Drug Programs for Varicella Zoster Virus (VZV), Cause of Shingles and Chickenpox (Table 2.C):
NV-HHV-1 skin cream for the treatment of shingles rash
NV-HHV-1 is our lead drug candidate in the HerpeCideTM program. It has advanced as a skin cream through pre-clinical development stages and at present it is at the IND application stage, with the design of clinical protocols, clinical site selection, and preparing for clinical trials, in process. Shingles is caused by reactivation of VZV (Varicella-Zoster Virus), which causes chickenpox in children.
Several additional indications in the HerpeCideTM program, including skin creams for the treatment of “genital ulcers” (HSV-2), and for the treatment of “cold sores” (HSV-1”) are expected to follow the shingles candidate into clinical development
NV-HHV-1 is a Virus-Family-Specific drug candidate based on the Nanoviricides Platform Modality #2. The ligand used therein copies features of the HerpesVirus Entry Mediator (HVEM), which is the receptor used for cell entry by HSV-1 and HSV-2. It was not known whether VZV uses HVEM.
As part of the IND-enabling development of our topical skin cream for treatment of shingles rash, we have performed a substantial amount of safety and toxicology studies. We performed non-GLP safety toxicology studies in a rat model with two of the development stage candidates first. Both candidates were extremely well tolerated and no adverse events occurred. These safety/toxicology studies along with efficacy studies in the Human Skin Organ Culture model of Dr. Moffat, led us to identify a clinical candidate, namely, NV-HHV-1. We have performed IND-enabling non-GLP Safety Toxicology studies of this clinical candidate in multiple animal species. NV-HHV-1 was well tolerated at all dosages tested and none of the parameters tested were affected. A GLP Safety/Toxicology study of dermal treatment in mini-pigs also found that NV-HHV-1 was well tolerated as a skin cream. These safety results are in agreement with histopathological observations in the human skin organ culture model studies.
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We manufactured NV-HHV-1 in a cGMP-compliant manner at our own facility for its IND-enabling GLP Safety/Toxicology study. The drug substance, or active pharmaceutical ingredient (API) was produced at approximately 1Kg-scale. Drug products, i.e. different dose levels of the skin cream, were made at scales of 3-5kg batches.
We have conducted a Pre-IND Meeting with the FDA regarding NV-HHV-1 as treatment for Shingles rash, and received a response from the FDA in May, 2019. In particular, the Agency agreed that the Company’s strategy for drug substance and drug product acceptance criteria is adequate. The Agency further agreed that the IND-enabling non-clinical studies proposed by the Company are generally adequate. The FDA also stated that the proposed design of the IND-opening human clinical studies appears reasonable at this time. The FDA made valuable suggestions in the pre-IND response. The additional non-clinical studies recommended by the Agency were generally consistent with our then-planned IND-enabling non-clinical studies. These studies have been completed subsequent to the Pre-IND Meeting.
Shingles and associated pain, post-herpetic neuralgia (PHN)
Shingles is caused by re-activation of the chickenpox virus that most humans acquire in childhood. The chickenpox vaccine for children is a live, attenuated virus (LAV). The LAV is not as pathogenic as the wild-type virus. However, this means the virus is present in the vaccinated individual, but remains suppressed by the immune system. In both vaccinated and unvaccinated persons, re-activation occurs when the immune system is suppressed which may be simply because of stress, advanced age, or some other immune modifying circumstances including immune-compromise due to organ transplants or other diseases. Generally, humans in the age range of 50-60 are more prone to shingles, with next reactivation occurring about 10~15 years later. There is a shingles vaccine approved for adults age 60 and above which is also available for adults younger than that.
Acyclovir-based oral drugs, such as valacyclovir (Valtrex®), are available as systemic therapy for shingles. Intravenous acyclovir is also employed for treatment of various VZV indications. However, VZV is substantially less sensitive to (val)acyclovir than is HSV-1. Thus the oral drug generally does not result in optimal level of the active drug at the site of VZV viral production, and does not result in significant control of the pathology. The antiviral drugs may be given for a period of 14 days or longer, with as much as 5g of dose per day, due to poor efficacy. In some indications, the treatment has been continued for a year or so. Thus, there is an unmet need for developing anti-VZV antivirals with high efficacy and safety.
Most adults with shingles recover in about 15~30 days from the shingles rash. While the rash is unsightly, its stinging pain is often the debilitating pathology that leads to lost workdays and other effects. Further, 65~70% of patients develop Postherpetic neuralgia, or PHN, a stinging, debilitating pain that lasts more than 30 days, and, in some patients, may last for years.
It is generally believed that PHN results from damage to the local nerve endings and nerve cells caused by the uncontrolled production of the shingles virus. However, VZV has been found to be present in at least 75% of PHN cases in a study, indicating a role for antivirals in controlling PHN. We believe that an effective therapy, such as our nanoviricide against VZV, which blocks progression of the virus to infect new cells and thereby limits further production of virus, would minimize the damage to nerve endings and nerve cells caused by the virus. We believe that this would minimize the occurrence, severity, and time period of PHN, in addition to having significant effects on the severity of shingles rash, lesions, and healing time.
In light of this we have conducted an animal study regarding the effect of our nanoviricide drug candidates against shingles on neuropathic pain in a classical animal model of pain (without VZV infection). On August 7, 2018, we reported that our anti-Shingles drug candidates were effective in ameliorating pain sensations in an animal model of abnormal pain. In this animal study, topical treatment with the nanoviricides® anti-VZV compounds significantly reduced the measures of abnormal pain sensations in a rat model of neuropathic pain. The study was conducted at AR BioSystems in Tampa FL. A characteristic excruciating pain is a debilitating pathology of shingles presentation. Thus a direct pain-reducing effect of the Company’s anti-shingles drug candidates would be very important in ameliorating the pathology of shingles, in addition to the already demonstrated significant antiviral effect.
We believe that a skin cream would be the best form of treatment to provide rapid control of the virus and shingles lesions patch expansion, since the shingles outbreak remains highly localized. A skin cream would afford much greater local exposure of drug to virus compared to a systemic oral or injectable treatment.
An effective therapy for patients with severe shingles continues to be an unmet need.
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NV-HHV-1 Skin Cream is intended for topical (dermal) application directly onto the shingles rash. It is expected to be useful in mild to moderate cases with limited body coverage of the rash in non-hospitalized patients.
Importantly, NV-HHV-1 has shown broad-spectrum activity against HSV-1 (cause of “cold sores”), HSV-2 (cause of “genital ulcers”), and VZV (the varicella-zoster virus, that causes chickenpox in children and immune-compromised humans, and shingles in adults). We therefore believe that NV-HHV-1 Skin Cream may be useful as a topical treatment of HSV-1 “cold sores” and HSV-2 “genital ulcers” in addition to treatment of Shingles skin rash.
Our other HerpeCide program candidates in progress at present are mostly based on NV-HHV-1, thereby maximizing return on investments and shareholder value.
HerpeCideTM Drug Candidates Based on HVEM, the Potential Common Cognate Entry Receptor for the Nine Human Viruses in the Orthoherpesviridae Family Enable Additional Indications (Modality #2, #3) :
As previously noted, NV-HHV-1 is based on copying the herpesvirus binding site on the human cellular receptor HVEM. Therefore, NV-HHV-1 is likely to be a potential pan-herpesviridae nature of our anti-HSV drug candidates is expected to enable several anti-herpesviral indications. HSV-1 primarily affects skin and mucous membranes causing “cold sores”. HSV-2 primarily affects skin and mucous membranes leading to genital herpes. HSV-1 infection of the eye causes herpes keratitis that can lead to blindness in some cases. In addition, human herpesvirus-3 (HHV-3), aka varicella-zoster virus (VZV) causes chickenpox in children and, when reactivated in adults, causes shingles. Shingles breakouts are amenable to topical treatment, as are the HSV cold sores, genital lesions, and herpes keratitis of the eye.
Topical treatment is expected to result in extremely high antiviral efficacy. This is because such treatment would provide higher concentrations of the antiviral at the site where the virus is manifesting at its highest levels. Highly effective topical treatments in most of these scenarios remain unmet medical needs. Most of these indications do not have satisfactory treatments at present, if any.
Many of the herpesvirus family infections may also warrant systemic therapeutics (oral or injectable) in addition to topical therapeutics, for greater effectiveness. As demonstrated with NV-387 oral bioavailability, we believe we have potentially orally available drug candidates in the herpesvirus drugs pipeline.
We are also developing possibly even more effective pan-herpes drugs compared to NV-HHV-1 based on Modality #3, i.e. by encapsulating replication inhibitors inside the polymeric micelle “belly” of NV-HHV-1. We have developed derivatives of the well-known anti-herpes drug acyclovir for efficient encapsulation within NV-387 for this purpose. Further, the treatment of herpes virus infections caused by acyclovir- and famciclovir- resistant mutants is currently an unmet medical need. We are developing replication-inhibitors addressing this resistance issue as well, that we plan on encapsulating within NV-HHV-1.
It is known that many of the human herpesvirus infections produce lifelong latent infections. The Modality #3 drugs we are making are expected to reduce the breakout frequency of such latent infections and may eventually cure the infection completely after repeated treatment. This is likely because it is well known that even repeated application of acyclovir-class of drugs in some patients leads to reduction in the breakout frequency or recurrence of herpe labilis (“cold sores”) caused by HSV-1. We do not expect that HHV-6A or HHV-6B infection could be cured by the Modality #3 approach because these two viruses are known to integrate their genome into human cells.
With additional indications in the diseases caused by viruses in the herpes virus family, it is likely that our HerpeCide program could expand into a much broader product pipeline than previously anticipated. We anticipate that many of these new drugs would be variations on our current drug candidate for VZV, namely, NV-HHV-1. This should simplify drug development pathway and also maximize the Return on Investments (ROI).
We are developing drugs against three indications in the HerpeCide program in parallel at present, namely, HSV-1 “cold sores” (orolabial herpes and recurrent herpes labialis or RHL), HSV-2 “genital ulcers”, and VZV shingles. We are developing topical treatments (skin creams or lotions) for these three indications. All of the drug candidates in these three leading indications comprise common chemistry features and are based on the same family of ligands and polymers, enabling efficient parallel development. Our parallel development of these indications maximizes return on investment and shareholder value.
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Of these, the shingles indication program has resulted in the clinical drug candidate NV-HHV-1, for which we are in the process of clinical trial design and clinical site selection, which will be a part of the IND application.
Our HerpeCideTM program has matured towards multiple drug indications. Besides the three indications listed above, modifications of the same drug candidates are anticipated to be developed into (iv) Eye Drops to treat ocular (i.e. external eye) Herpes Keratitis (HK) caused by HSV-1 or HSV-2, and possibly (v) Intra-Ocular injections to treat viral Acute Retinal Necrosis (vARN) caused by herpes viruses, primarily VZV, shingles (varicella zoster virus) and HSV-2, a cause of blindness.
In addition, we believe that the shingles drug candidate may be eligible for the PHN indication as well. PHN clinical studies are long and expensive, and we plan to advance the candidate for this indication only after its shingles indication clinical trials are completed. Further, the same drug candidate is expected to work against chickenpox in children. Chickenpox remains a sporadic epidemic disease despite vaccines.
Expansion to additional indications is likely, as we perform further studies. It is likely that some of these drug candidates with variations may be able to address diseases caused by the remaining human herpes viruses, namely EBV, HCMV, HHV-6A, HHV-6B, and HHV-7. Such expansions would enable maximization of return on investment (ROI) and maximization of shareholder value.
Including the HerpeCide program explained above, we currently have about eleven different drug development programs, attesting to the strength of our platform technology.
We have chosen to focus strategically on the applications of NV-387 which was developed as a pan-coronavirus drug initially, and which appears to have a much broader spectrum of activity.
HSV-1, HSV-2, Ocular Herpes Keratitis
We believe that a skin cream for the control of HSV-1 “cold sores” (herpes labialis, and recurrent herpes labialis or RHL) is another drug candidate that may be close to entering human clinical trials. We have already achieved strong success in animal studies against HSV-1, as discussed above.
We believe that we will be able to successfully develop a drug candidate for Ocular Herpes Keratitis (HK) as well. HK is caused by HSV-1 or HSV-2 infection of the external eye. We are developing this drug as topical eye drops or eye lotion, in order to achieve maximum local drug effect while minimizing systemic exposure. We plan on testing these drug candidates against adenoviruses as well, to determine if the same drug would also be effective against epidemic keratoconjunctivitis (EKC, the severe “pink eye” disease). If the same drug works against herpes virus and adenovirus infections of the eye, we expect this drug may cover almost 99% of all external eye viral pathologies.
We also believe that we will be able to develop a drug against HSV-2 genital herpes. We plan on developing a skin cream for this indication, to maximize local effectiveness.
Viral Acute Retinal Necrosis (v-ARN)
We are also exploring additional indications of its anti-herpes drug candidates that are expected to broaden the pipeline and require limited development work. In particular, certain eye diseases of the retina have been causatively linked to herpes viruses. For example, most cases of viral Acute Retinal Necrosis (ARN), a disease that leads to severe loss of vision and can lead to blindness, have been linked to VZV and HSV-2, with some also associated with HSV-1 or CMV infection of the eye. It is believed that, HSV-2 ARN in children and adolescents may result from undiagnosed and asymptomatic neonatal HSV-2 infection, which has reactivated several years later from latency in a cranial nerve and entered the retina. Currently, intravenous treatment followed with oral acyclovir derivatives daily for several months to years and sometimes intravitreal (into the eye) foscarnet injections are therapeutically employed with limited effectiveness, establishing the potential of effective antiviral therapy to avoid blindness as well as multiple surgeries related to retinal detachment. A highly effective antiviral that can be injected into the eye infrequently and provides sustained antiviral therapeutic effect over a long period of time for ARN is an unmet medical need.
Neonatally acquired herpes virus infections, even when asymptomatic, are thought to have led to ARN as late as age 22. There are approximately 2,500 cases per year of diagnosed neonatal herpes virus infections in the USA.
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The FluCideTM Program
We intend to re-engage the FluCide program once the HerpeCide drug candidates enter human clinical trials, resource permitting. Previously, we had achieved industry-leading effectiveness levels demonstrating as high as 1,000-fold viral load reduction in a lethal animal model of influenza infection with multiple strains of influenza. We were developing an injectable drug candidate for treatment of severely ill patients, and an oral drug candidate for the treatment of outpatients.
Our DengueCideTM Program
We intend to reengage the DengueCide program if and when non-dilutive funding such as research grants become available to us. At present we have not applied for any grants for this program.
Our HIVCideTM Program
We intend to re-engage the HIVCide program once the HerpeCide drug candidates enter human clinical trials, resource permitting. Previously, the drug candidates in the HIVCideTM program were found to have effectiveness equal to that of a triple drug HAART cocktail therapy in the standard humanized SCID-hu Thy/Liv mouse model. Moreover, the nanoviricides were long acting. Viral load suppression continued to hold for more than four weeks after stopping HIVCide treatment. We believe that this strong effect and sustained effect together indicate that HIVCide can be developed as a single agent that would provide “Functional Cure” from HIV/AIDS. We believe that substantially all HIV viruses can be cleared upon HIVCide treatment, except the integrated viral genome in latent cells. This would enable discontinuation of treatment until HIV reemerges from the latent reservoir, which may be several months without any drugs. Moreover, we believe that this therapy would also minimize the chances of HIV transmission. These drug candidates are effective against both the R5 and X4 subtypes of HIV-1 in cell cultures. We believe that these drug candidates are “broad-spectrum”, i.e. they are expected to be effective against most strains and mutants of HIV, and therefore escape of mutants from our drugs is expected to be minimal. Certain anti-HIV nanoviricides have already been demonstrated that appear to provide extended viral load suppression for as long as 30 days or more even after stopping the drug, in animal studies. Given the chronic nature of HIV/AIDS, such a drug that has long sustained effect is expected to provide significant benefits to the patient. We believe once a week dosing is possible for our anti-HIV drugs. Anti-HIV drug development is both expensive and slow because of the nature of the animal studies that require SCID mice whose immune system is destroyed and then replaced by surgically implanting and growing human immune system tissues in the mouse body. Due to our limited resources, HIVCide development is further hampered.
Adenoviral EKC
The Company is developing broad-spectrum eye drops that are expected to be effective against a majority of the viral infections of the external eye. Most of these viral infections are from adenoviruses or from herpes viruses. The Company has shown excellent efficacy of its drug candidates against EKC (adenoviral epidemic keratoconjunctivitis) in an animal model. If feasible, we are planning to merge the anti-EKC drug development program and the ocular Herpes Keratitis drug development program, to develop a single drug that is effective against both diseases, i.e. effective against both adenoviruses and herpes viruses. This work is in research stage.
Other Drug Programs: “Disease X”, MPox, Smallpox, Acute Flaccid Myelitis (AFM, EV68), Polio, Pediatric Acute Adenoviral Hepatitis, Ebola/Marburg, Rabies and Others (Table 2.G)
In addition, the Company also has research programs against Rabies virus, Ebola and Marburg viruses, and others. We will not be undertaking socially important programs such as the development of an anti-Zika virus drug candidate, or continuation of our efforts in developing anti-Ebola drug candidate, unless non-dilutive funding for such efforts becomes available. At present we have not applied for any grants for these programs.
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NV-387-Ribvp, Potential Cure, Pandemic Preparedness, Viral “Disease X” Scenario
In addition to NV-387, we have developed NV-387-Ribvp, a Nanoviricide Platform Modality#3 type drug candidate for treatment of RSV and potentially many other viral infections. NV-387-Ribvp is made up of NV-387 that encapsulates within the belly of the polymeric micelle, a pro-drug of Ribavirin which is a known active drug against many viruses. The clinical use of ribavirin is limited by its toxicity, specifically to red blood cells, that can lead to failure of kidneys, liver and spleen at high dosages. We believe that encapsulation within NV-387 may limit these toxicity concerns, as well as make Ribavirin available for a significantly longer period of time (PK improvement), enabling better effectiveness.
Ribavirin is the standard drug of choice in unknown “Viral Disease X” (i.e. unknown or novel virus) scenarios, as well as against viruses that do not have any known therapeutic, including RSV. Thus we believe that NV-387-Ribvp could qualify as a Pandemic Preparedness and Response drug and would be an ideal candidate for National Stockpiling in the USA and possibly other countries, should its development progress successfully.
Our Smallpox/MPox/Poxviruses; “Acute Flaccid Myelitis” (AFM) (EV68); Polio; and AD-71 Pediatric Hepatitis Programs
In response to the last year’s MPox virus (MPXV) epidemic, we began a limited drug development program to treat MPXV patients. While this epidemic quieted down relatively rapidly with societal/behavioral changes and rapid mobilization of a smallpox vaccine as well as a smallpox drug from the US National Stockpile, experts expect that this virus will become endemic in the Western world, as it is in the African subcontinent (https://www.cdc.gov/poxvirus/monkeypox/cases-data/technical-report/report-3.html#dynamics).A vaccine against smallpox appears to have substantial effectiveness in protecting vaccinated persons from MPXV infection. The only currently available drug, tecovirimat (TPOXX®, SIGA), approved for smallpox, has a low resistance barrier for virus mutations, i.e., the virus can readily escape it by simple mutations, and has other limitations on its use.
Thus there remains an urgent need for broad-spectrum drugs that can treat MPXV, smallpox, and other poxviruses.
Additionally, in response to the ongoing pediatric “acute flaccid myelitis” (AFM, a disease that can lead to paralysis) cases that appear to be on an uptick, we initiated a limited broad-spectrum drug development program for the treatment of Enterovirus D68 (EV68), the cause of AFM, and potentially other enteroviruses including the poliovirus. Cases of polio have begun to emerge in the United States. Apparently due to loss of “herd immunity” as the poliovirus immunizations in childhood have dropped, the cases are caused by what is believed to a be a revertant of the attenuated strain of poliovirus that is used for vaccination in certain underdeveloped countries.
Another important pediatric disease is severe hepatitis that is caused by Adenovirus 71.
We intend to run the MPXV, EV68, and AD71 programs by initially evaluating the Company’s existing drug candidate library for effectiveness. If effective existing drug candidates are found, we intend to undertake additional work as well as seek additional financing, preferably via non-dilutive funding sources.
To date, the Company does not have any commercialized products. The Company continues to add to our existing portfolio of products through our internal discovery and clinical development programs and also seeks to do so through an in-licensing strategy.
This year, we have further focused our programs and prioritized them with the result that our first drug candidate NV-387 is now in human clinical trials.
Large Market Sizes – The Company Targets an Overall Anti-Viral Drug Market Size that Exceeds $40B
We have not attempted to evaluate the market size of coronavirus drug candidates. During the pandemic, it is clear that hundreds of billions of dollars were spent on vaccines and therapeutics for COVID-19 treatment worldwide. However, as we had expected, the overall number of cases and their severity appears to be going down with newer waves of COVID variants. Yet, novel SARS-CoV-2 variants continue to evolve and continue to improve in their transmissibility, infectiousness, as well as vaccine and antibody avoidance. SARS-CoV-2 can be considered a globally endemic coronavirus now, similar to Influenza. Additionally, our drug, NV-CoV-2 (API NV-387) is pan-coronavirus and would work against the existing seasonal coronaviruses, novel variants of SARS-CoV-2, as well as the lethal sporadic coronaviruses MERS and SARS-CoV-1, Based on these considerations, it can be expected that the market size for anti-coronavirus drugs will continue to be in several billions of dollars.
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The current market size for RSV drugs is estimated to be about $2 Billion, and expected to grow to about $8 Billion by 2030.
The current market size for drugs for the treatment of different herpes simplex infections is estimated to be approximately $2-4 billion. We believe that when an effective topical treatment is introduced, the market size is likely to expand substantially, as it has for several drugs in the antivirals, oncology, and other areas.
If a highly effective drug against HSV-1 and HSV-2 recurrences is developed, we believe the Herpesvirus Drugs market size would explode, as was seen with Hepatitis C virus.
Severe cases of shingles may lead to hospitalization in several thousand cases in the USA every year. In addition, shingles appearing on the face may reach the eye and may cause significant vision issues. In addition to the older inactivated chickenpox virus vaccine, Shingrix®, a two-dose vaccine has recently been introduced. However, due to the severe side effects in a significant percentage of persons taking this vaccine at its first dose, compliance as well as market penetration may be limited.
The outpatient treatment market size for shingles at present is limited, because of the limited effectiveness of existing drugs. An effective drug could expand this market into billions of dollars globally.
The market size for severe cases of shingles may be approximately one billion dollars. These estimates take into account the Shingrix® vaccine as well as existing vaccines. About 500,000 to 1 million cases of shingles occur every year in the USA alone.
In addition, the estimated market size for an effective anti-Influenza drug is expected to be in tens of billions of dollars. The current estimate of anti-influenza drug market size is approximately $4 billion. The current market size for anti-HIV treatments is in excess of $20 billion. Other drugs in our pipeline, taken together, are estimated to be several billion dollars in market sizes.
Our focus at present is on the coronavirus program and additional indications of the same drug, NV-387 for other viruses such as RSV. Our next priority is the topical treatments for different herpes virus infections in the HerpeCide program, as listed elsewhere in this report. We plan on re-engaging our Influenza and HIV programs when sufficient resources become available.
About the Priority Levels for Our Drug Development Programs:
The priority levels for our drug development programs are set forth in the tables below. The priority levels of A and B are our current focus, with priority level C to be taken up next for advanced preclinical and clinical development. Priority levels D, E, F, and G are longer term than priority levels A, B, C, and we work on those projects as we have resources available.
NanoViricides Drug Pipeline in the CoronaVirus Program: Drugs Against SARS-CoV-2 and Variants (COVID-19) (Table 2.A)
NV-CoV-2 Oral Syrup and NV-CoV-2 Oral Gummies Drug Products are in Phase 1a/1b Clinical Trial with COVID indication. We plan on adding PhaseI/II clinical trials of the NV-CoV-2 Injectable Solution for moderate to severe COVID-19 disease indication as the clinical trials of the oral forms provide safety data. With the decrease in hospitalizations for COVID-19, the clinical trials for hospitalized COVID-19 patients are expected to become more complex and difficult to run, primarily due to the difficulty of recruiting patients. It is likely, given the strong effectiveness of the API NV-387 against RSV, that we would be able to pursue Treatment of RSV Infection in Phase II for Oral as well as Injectable formulations of NV-387 (currently the drug products are called NV-CoV-2) (Table 2.B).
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No. Drug Indications Development Stage Priority
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Broad-Spectrum Antiviral NV-387 - Additional Indications : RSV (Modality #1) (Table 2.B)
No. Drug Indications Development Stage Priority
VZV Program; NanoViricides Drug Products in Development (Modality #2) (Table 2.C)
VZV (HHV-3) Nanoviricides Efficacy Evaluation at the Moffat Lab at the SUNY Upstate Medical Center, Syracuse, NY.
In October 2016, we entered into an agreement with SUNY Upstate Medical University for the testing of its nanoviricides® drug candidates against varicella zoster virus, i.e. the shingles virus. The research was performed in the laboratory of Dr. Jennifer Moffat and included in vitro human cell culture and ex vivo human-skin model studies to explore inhibition of VZV replication by our nanoviricides drug candidates towards selection of a clinical lead drug.
VZV is restricted to human tissue and only infects and replicates in human tissue. Dr. Moffat has extensive experience in VZV infection and antiviral agent discovery. Dr. Moffat has developed the human skin organ culture VZV infection model for the evaluation of therapeutics. This model is a good representative model of natural VZV infection in humans as well as an important model for evaluating antiviral activity, because it demonstrates behavior similar to the skin lesions caused by VZV in human patients.
Dr. Moffat is an internationally recognized expert on varicella zoster virus, and her research has focused on the pathogenesis and treatment of infection by this virus. The National Institutes of Health has recognized this VZV model via a contract with Dr. Moffat’s lab for evaluating antiviral compounds against VZV. Dr. Moffat is the director of two research core facilities at SUNY Upstate: the Center for Humanized Mouse Models and In vivo Imaging.
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On July 10, 2017, the Company announced the results of successful initial testing of our anti-herpes drug candidates in the ex vivo human skin patch organ culture (“SOC”) model performed by Dr. Moffat. The anti-shingles nanoviricides drug candidates achieved dramatic reduction in infection of human skin by the VZV, the shingles virus in this study. These findings corroborate the previously reported findings of inhibition of VZV infection of human cells in culture. The antiviral effect of certain nanoviricide drug candidates was substantially greater than the effect of the standard positive control of cidofovir added into media. Even more remarkably, the effect of these nanoviricides drug candidates was equivalent to a topical formulation of 1% cidofovir applied directly onto the skin patch. A topical skin cream containing 2% cidofovir is clinically used in very severe cases of shingles. However, the cytotoxicity of cidofovir is known to cause ulceration of the skin to which it is applied, followed by natural wound healing.
Based on these studies, we selected NV-HHV-1 as the clinical drug candidate.
Further IND-Enabling Development of NV-HHV-1
Since then we completed manufacturing development and scale-up of the skin cream for Shingles treatment, NV-HHV-1. We have also completed certain IND-enabling Safety/Toxicology studies of NV-HHV-1 at BASi, Indiana. We held a pre-IND meeting for NV-HHV-1 with FDA whereby we received a written response in May, 2019. Thereafter we were in the process of completing our IND package including additional required studies and establishing relationship with a CRO. In January, 2020 we began to devote our attention to developing a drug against COVID-19, and focused on the COVID-19 program after finding leads around April-May 2020.
We worked with the Moffat Lab, initially for optimization of the drug candidates and chemistries, and thereafter towards clinical drug candidate selection. We plan on re-engaging this collaboration as we advance the Shingles drug NV-HHV-1 into an IND.
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VZV Program; NanoViricides Drug Products in Development (Modality #2) (Table 2.C)
Table 2.C. VZV Program; NanoViricides Drug Products in Development (Modality #2)
No. Virus Drug Indications Development Stage Priority
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HSV-1 Program; NanoViricides Drug Products in Development (Modalities #2, #3) (Table 2.D)
No. Virus Drug Indications Development Stage Priority
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HSV-2 Program; NanoViricides Drug Products in Development (Modalities #2, #3) (Table 2.E)
No. Virus Drug Indications Development Stage Priority
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Eye Diseases Caused by Herpesviruses (HSV-1, HSV-2, VZV); (Modalities #2, #3) (Table 2.F)
No. Disease Drug Indications Development Stage Priority
4 Injectable Solution ●Moderate to Severe Herpes Keratitis Pre-Clinical F
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All Other Programs; “Disease X” (Novel Pandemic Preparedness); MPox, Smallpox; AFM, Polio (Enteroviruses); Adenoviral Pediatric Hepatitis; Herpesviruses Expansion; HIV; Influenza; Dengue; Ebola/Marburg; Rabies; and R&D for Cures of Persistent Viruses (Table 2.G)
Table 2.G. All Other Programs; NanoViricides Drug Products in Development
Program Virus Indications Development Stage Priority
All Influenza A Oral FlucideTM for outpatients Preclinical(Modality #2) F
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Broad and Expanding Drug Pipeline Enabled by the NanoViricides Platform Technology
As can be seen from these extensive lists of drug development programs and targets, we have been making tremendous progress year-over-year in bringing highly effective anti-viral drugs based on our novel technology platform into human clinical studies.
We believe that with the human clinical trials in our coronavirus program, we will be able to accumulate the evidence of human safety and effectiveness that would help us achieve meaningful partnerships with Big Pharma. We are also working on obtaining non-dilutive funding for various programs and projects in our pipeline. At present, we have sufficient funding to take us through the ongoing Phase 1a/1b clinical trials for our COVID-19 drug candidate, NV-CoV-2. We believe that as we achieve proof of principle in human studies, we will be able to attract substantially greater market valuation and investor funding for further progress of these drugs towards approval and commercialization. We believe that once we have revenues from commercialization of our first drug or from partnership, we will be able to engage in further speeding up the development of programs in Tables 2.C through 2.G.
Management’s beliefs are based on results of pre-clinical cell culture studies, ex vivo tissue-based studies (e.g. human skin patch or a culture model), and in vivo animal studies using small animals.
Drug Development Plan
We intend to perform the regulatory filings and own all the regulatory licenses for the drugs we are currently developing. We will develop these drugs in part via subcontracts to TheraCour, the exclusive source for these nanomaterials. With sourcing of materials from TheraCour, we prefer to manufacture these drugs in our own facility. However, we may manufacture these drugs under subcontract arrangements with external manufacturers that carry the appropriate regulatory licenses and have appropriate capabilities. We intend to distribute these drugs via subcontracts with distributor companies or in partnership arrangements. We plan to market these drugs either on its own or in conjunction with marketing partners. We also plan to actively pursue co-development, as well as other licensing agreements with other pharmaceutical companies, both in the USA as well as internationally. Such agreements may entail up-front payments, milestone payments, royalties, and/or cost sharing, profit sharing and many other instruments that may bring early revenues to us. Such licensing and/or co-development agreements may shape the manufacturing and development options that we may pursue.
Competition
Our products in development target a number of diseases and conditions that include several different kinds of viral infections. There are many commercially available products for some of these diseases and a large number of companies and institutions are spending considerable amounts of money and other resources to develop additional products to treat some of these diseases. Most of these companies have substantially greater financial and other resources, larger research and development staffs, and extensive marketing and manufacturing organizations. When and if we are able to successfully develop products, they would compete with existing products based primarily on:
● efficacy;
● safety;
● tolerability;
● acceptance by doctors;
● patient compliance;
● patent protection;
● ease of use;
● price;
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● insurance and other reimbursement coverage;
● distribution;
● marketing; and
● adaptability to various modes of dosing.
Several companies have advanced drug candidates for the management of COVID-19. Remdesivir, an antiviral drug, has received full approval, but requires repeated infusions and has limited clinical effectiveness. Oral Molnupiravir (Merck and Ridgeback) has received EUA but it has very poor effectiveness and well-known risks of mutagenicity, and is not widely used. Oral Paxlovid (a combination of nirmatrelvir and ritonavir tablets taken together, Pfizer) has received full approval but was only effective in the population at high risk of hospitalizations such as persons with co-morbidities and over age 65. Its use in persons not listed is considered off-label, and recent clinical report has shown that it has no benefits relative to placebo treatment in these groups. Also in a certain percentage of cases Paxlovid has been shown to cause viral resurgence after achieving COVID-negative status upon treatment. Several antibodies had received EUAs, but all of these have been revoked due to loss of efficacy as new variants emerged. None of the available drugs attack the external circulating virus particles or block the re-infection cycle as NV-CoV-2 is designed to do. Thus, their mode is complementary to NV-CoV-2 and combination therapy with one of these drugs and NV-CoV-2 may yield substantial benefits. We also note that none of these drugs in development attack the complete lifecycle of the virus as NV-387-Rp is designed to do, to the best of our knowledge.
There are several drugs in the market that effectively control HSV cold sores and genital herpes lesions in most patients. These include the nucleoside analogues idoxuridine, vidarabine, acyclovir, famciclovir, ganciclovir, and derivatives. However, their efficacy is limited or toxicities are high. Brincidofovir, based on the toxic drug cidofovir, is in development by Chimerix, but certain clinical trials involving brincidofovir have failed to meet the desired end points. Foscarnet is also used for VZV and ARN, but its toxicity is high. FV-100 was in clinical development against VZV, but these clinical developments appear to have been abandoned. In addition, pritelivir, antibodies, and some other drugs are in advanced stages of development against HSV-1 or HSV-2. A gamma globulin was recently approved.
The prevalence of herpes simplex virus type 1 (HSV-1) and HSV-2 is 47.8% and 11.9%, respectively, for individuals aged 14 to 49 years, and increases with age, in the USA, according to CDC. HSV-2 causes a more severe disease that also has significant social costs to the patient. In spite of the existing drugs, both HSV-1 and HSV-2 cause lifelong infection that continues to reactivate at different rates in different patients. Thus, in spite of several existing drugs that are already generic, the market size for a highly effective drug is estimated to be in tens of billions of dollars for each of HSV-1 and HSV-2 treatments.
There are currently no approved drugs for the treatment of diseases caused by VZV, namely, Shingles, PHN, and Chickenpox. Valcyclovir or other acyclovir-class drugs are often prescribed orally but have little effect on shingles because VZV has an ineffective vTK enzyme, as opposed to HSV-1 and HSV-2, that is required for activating these drugs. Cidofovir is used in extreme cases of Shingles, but it is highly toxic, limiting benefit of the drug, limiting drug dosage and causing significant side effects. Several pain relievers are being developed to treat shingles pain and also the PHN pain.
Thus, a safe and effective treatment against VZV is an unmet medical need.
We are aware of no approved drugs for the treatment of viral diseases of the external eye.
The current approved drugs for influenza include the neuraminidase inhibitors Tamiflu, Relenza, and Peramivir, anti-influenza drugs that are sold by Roche, Glaxo SmithKline (GSK), and BioCryst partners, respectively. In addition, M2 channel inhibitors, generic drugs include amantadine and rimantadine, both oral tablets that only inhibit the replication of the influenza a virus have generally become ineffective because of significant viral resistance to the approved M2 channel inhibitors especially in the US. Several companies are developing anti-influenza drugs at present. Small chemical classes include neuraminidase inhibitors, M2-channel inhibitors, and RDRP inhibitors, among others. There are also monoclonal, polyclonal, and mixed antibodies, as well as enzymes as drugs in development. Xofluza (baloxivir), developed by Shionogi Pharma (Japan) is approved in Japan and in the USA, licensed by Roche/Genentech. It is an influenza endonuclease inhibitor. It appears to be substantially more effective than existing drugs in reducing viral load and viral shedding, but did not have any effect on the length of the influenza disease course. Importantly, the resistance barrier for all of these drugs is rather low, and resistant mutants have arisen in the field. Thus there is an unmet medical need for an effective and safe pan-Influenza drug that the virus is unlikely to escape.
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There are a growing number of anti-HIV drugs being sold or in advanced stages of clinical development. Companies with HCV and HIV products include Gilead, Bristol-Myers Squibb Company (BMS), Roche, Boehringer Ingelheim, Merck & Co., Inc. (Merck), in addition to several other pharmaceutical and biotechnology firms.
Some antibody drugs have become available for Ebola/Marburg viruses, but are generally expensive, require infusion, and have poor acceptance. There are no drugs available for the treatment of Dengue viruses, Hendra/Nipah Viruses, and many others that are considered potential pandemic threats.