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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, 2022
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 $0.001 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 13, 2022, there were approximately 11,592,000 shares of common stock of the registrant issued and outstanding.
The aggregate market value of the voting stock held on December 31, 2021, by non-affiliates of the registrant was approximately $40,756,000 based on the closing price of $3.72 per share, as reported on the NYSE American on December 31, 2021, 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).
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TABLE OF CONTENTS
PART I
Item 1. Business 3
Item 1A Risk Factors 64
Item 1B Unresolved Staff Comments 86
Item 2. Properties 86
Item 3. Legal Proceedings 86
Item 4. Mine Safety Disclosures 86
PART II
Item 6. Selected Financial Data 90
Item 7A Quantitative and Qualitative Disclosures About Market Risk 98
Item 8. Financial Statements and Supplementary Data 98
Item 9A. Controls and Procedures 98
Item 9B. Other Information 99
PART III
Item 10. Directors, Executive Officers, Promoters and Corporate Governance. 100
Item 11. Executive Compensation 102
Item 14. Principal Accountant Fees and Services 109
PART IV
Item 15. Exhibits, Financial Statement Schedules 110
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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.
ITEM 1: BUSINESS
Organization and Nature of Business
NanoViricides, Inc. (the “Company”, “NanoViricides”, “we,” or “us”) was incorporated in Nevada on April 1, 2005. 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 development stage company with several drugs 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.
We have several drugs in our pipeline. Of these, two drugs developed to combat the COVID-19 pandemics, namely NV-CoV-2 and NV-CoV-2-R, are our most advanced drug candidates. We believe that the essential preclinical work including GLP Safety/Toxicology studies has been completed for taking NV-CoV-2 into human clinical trials evaluation. We are working diligently towards the goal of filing an Investigational New Drug Application (IND) for NV-CoV-2 as soon as possible. We are also working towards the goal of starting clinical trials outside of the USA for NV-CoV-2. We believe that once Phase I clinical trials of NV-CoV-2 are successful, both NV-CoV-2 and NV-CoV-2-R can enter Phase II and further clinical studies. We have successfully made oral formulations of NV-CoV-2 as both (i) NV-CoV-2 Oral “Gummies” and (ii) NV-CoV-2 Oral Syrup. In addition, we have developed the injectable form, (iii) NV-CoV-2 for Injection, Infusion or Inhalation. The other drug, NV-CoV-2-R comprises NV-CoV-2 with remdesivir encapsulated in the belly of the polymeric micelles. The clinical program is expected to start with evaluation of the NV-CoV-2 Oral Syrup and NV-CoV-2 Gummies in adults, with extension to pediatric populations upon success. Clinical Trials of the Injectable NV-CoV-2 are expected to follow thereafter. We will report on these objectives via press releases as meaningful advancements take place.
In response to the recent Monkeypox virus (MPXV) epidemic, we have begun a limited drug development program to treat MPXV patients. At present, while it appears that this epidemic is quieting down, 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
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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, the Company has 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.
The Company intends to run both MPXV and EV68 programs by initially evaluating the Company’s existing drug candidate library for effectiveness. If effective existing drug candidates are found, the Company intends to undertake additional work as well as seek additional financing, preferably via non-dilutive funding sources.
We plan on undertaking further clinical advancement of our other lead drug candidate, NV-HHV-1 skin cream for the treatment of shingles (previously referred to as NV-HHV-101), after the COVID-19 program completes initial human clinical studies. The essential preclinical work including GLP Safety/Toxicology studies of NV-HHV-1 were completed and we began to assemble a draft IND application just when the global COVID-19 pandemic struck. We continued to work on NV-HHV-1 until we had developed viable drug candidates against COVID-19, circa May/June 2020, and thereafter focused completely on the COVID-19 drug development, putting the NV-HHV-1 program on hold.
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, which 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.
NanoViricides is one of a few biopharma companies that has its own cGMP-compliant manufacturing facility. The Company intends to produce its drugs for clinical trials in this facility. The Company has 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 first-in-human use in the current SARS-CoV-2 pandemic for our anti-coronavirus drug in development, as well as for the anticipated clinical trials of NV-HHV-1 skin cream for the treatment of shingles.
We would like to note that in response to the current global COVID pandemic, the scientific community at large and regulatory efforts to date have remained focused on (a) vaccines, (b) antibodies, and (c) re-development of pre-existing drugs. Even as alarm bells were raised by renowned scientists regarding the likelihood of escape mutations and the limitations of any vaccines and antibody therapies in combating a rapidly evolving global viral pandemic, there has been an effort to downplay these risks at all levels. This has left the world now grappling with a situation where vaccines are being rolled out even as virus variants that are highly likely to be resistant or are already resistant to current vaccines and antibody drugs have already been found to be spreading rapidly. Current vaccines are now assumed to require constant updates, as in the recent bi-valent vaccines that incorporate the original antigen and a new one from the Omicron family of variants, and re-inoculation campaigns (aka “booster shots”) to keep up with ongoing changes in the virus. Attention needs to be focused instead on broad-spectrum antiviral therapeutics that minimize the possibility of virus variants escaping the drug, thereby making the costly ongoing development of vaccine updates, their deployment and re-inoculation campaigns, practically unnecessary.
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.
Additionally, to the best of our knowledge, we are the only Company that is developing antiviral treatments that are designed to (a) directly attack the virus and disable it from infecting human cells, and (b) simultaneously block the reproduction of the virus that has already gone inside a cell. Together, we expect this strategy of a two-pronged attack against the virus, both inside the cell and outside the cell, can to result in a cure for coronaviruses and other viruses that do not become latent.
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The Company’s nanoviricides® platform technology is based on biomimetic engineering that copies the features of the human cellular receptor of the virus. No matter how much the virus mutates, all virus variants bind to the same receptor in the same fashion. It appears that the later variants of SARS-CoV-2 may have evolved to bind to the human cellular receptor ACE2 more strongly, in general, based on published datasets. Thus, if these features of the cellular receptor are appropriately copied, the resulting nanoviricide drug would remain effective against current and future variants of the virus.
Our current drug candidates to combat the COVID-19 pandemic are designed to attack not only SARS-CoV-2 and its current and future variants, but also many other coronaviruses, and therefore are expected to be valuable even after the pandemic is over, since several coronaviruses are endemic in human populations. SARS-CoV-2 with its variants and substantial penetration into human populations worldwide is on course to become an endemic virus, or may have already become endemic by now.
Our COVID-19 drug candidates successfully entered core safety pharmacology studies required prior to commissioning human clinical trials around October/November, 2020. These studies have now been completed and we have received the GLP Safety/Toxicology reports from the external CRO in August 2021. We are now engaged in the preparation of clinical trial protocols and other activities that would be necessary for filing of an IND with the US FDA or equivalent regulatory filings for entering into human clinical trials in other countries.
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. To understand this, we are providing a short review of the current state of the pandemic below:
Strong government support led to rapid emergency use approval, and later full approval, of an already known antiviral drug now called Veklury (Remdesivir, Gilead) early on. Strong fiscal support and regulatory enablements from the government also led to the emergency use approval of two different antibody drugs, one from Regeneron (REGN-CoV-2, a monoclonal antibody cocktail containing two different antibodies) and one from Eli Lilly (bamlanivimab, a single antibody for restricted use) in the fastest ever drug development timeframe. All of these antibody drugs target the viral Spike protein that binds to the human cellular receptor, ACE2.
Even stronger commitments and strong government support led to the fastest ever emergency use approval of two vaccines, both employing nanotechnology: one by Pfizer-BioNTech, and one by Moderna. Subsequently, additional vaccines have been approved in various countries and several are in development. Almost all of these vaccines target the original 2019-nCoV-Wuhan variant, and all but a few target primarily its Spike protein. Pfizer and Moderna have introduced bivalent vaccines with Wuhan antigen and an early Omicron antigen in the same vaccine as of this writing.
Yet, as the vaccines and boosters have been deployed, several new virus variants of tremendous concern have already emerged. Additional virus variants will continue to emerge at an even faster rate because of the widespread dissemination of the virus with many patient bodies serving as virus factories providing historically the greatest ever opportunities for the virus to escape existing vaccines and antibody drugs. It has already been found that as new variants emerge, the effectiveness of the antibody drugs against the new variants is diminishing rapidly. Failure of vaccines and antibody drugs is therefore certain; the only question is how long will it be before the vaccines become substantially ineffective.
Replacing current vaccines with a new vaccine, as has been suggested, would be an endless game of chasing a rapidly changing epidemic that would be costly and also would remain substantially non-responsive to the threat, since the virus will continue to remain many steps ahead of the vaccine. Giving booster doses of existing vaccines repeatedly is scientifically epidemiologically or ethically unsupportable except for specific subsets of populations that do not respond to the vaccine without multiple boosters. An additional complicating factor is that it is now generally believed that immunity from these vaccines is not enduring; in fact the protective effect of vaccines has been estimated to be as short as 3 to 6 months only, although weak protection may remain for a longer period. Since introduction of the first vaccines circa January/February 2021, there are already a total of 4 shots of vaccines given by May/June 2022, and new bi-valent vaccines (2 shots) beginning in September/October 2022, a cycle of potentially six shots in less than 2 years!
It is well known that viruses, particularly RNA viruses, mutate rapidly, and that such changes produce “variants” that can escape from vaccines as well as from antibody drugs. SARS-CoV-2 has a repair mechanism that retains some fidelity during reproduction, and therefore it changes less rapidly than Influenza A viruses or HIV. Nevertheless, given the significant penetration of the virus into human population, and the very high viral loads achieved in severe cases of the infection, the virus has a huge opportunity to change. Additional virus variants will undoubtedly continue to emerge at an even faster rate because of the widespread dissemination of the virus through many patients, their bodies effectively serving as “factories”. This important concern, voiced by several eminent scientists, has not been
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regarded with the seriousness it deserves by supporting and enabling rapid regulatory development of broad-spectrum drugs targeted at the coronaviruses.
The world has already witnessed at least five important SARS-CoV-2 variants with significant impact, as a result of the large number of persons becoming infected. The very first important variant, namely D614G, replaced the original Wuhan strain completely and rapidly during the first wave of the pandemic itself. In the second wave, we have seen emergence of the lineage B.1.1.7 variant from United Kingdom (Kent and London; now called alpha variant), the N501Y-V.2 (also called lineage B.1.351) from South Africa, and the P.1 variant (also called lineage B.1.1.248) from Brazil. California has seen lineage B.1.429 /(CAL.20C) variant become dominant in Los Angeles county recently, with over 50% of the infections. It appeared to be replacing the earlier dominant CAL.20G variant.
The delta variant from India replaced the alpha variant almost globally and caused a widely spread and severe wave of infections. It was subsequently replaced by the Omicron variant that was far more infectious and transmissible, but thankfully less pathogenic compared to delta, possibly because of residual immunity from earlier variants and vaccinations. Nevertheless, the sheer large number of infections resulting from Omicron led to higher fatalities than caused by the delta variant. The original Omicron variant was soon replaced by additional variants in the same family of mutations. At present, there are several variants that all have substantially escaped existing antibody drugs as well as existing vaccines. These include BA.4, BA.5, BA.2.75, and more recently BA2.75.2 and BQ.1. With each successive variant, the transmissibility appears to be greater than the previous one, but rates of hospitalization and fatality appear to remain the same, indicating some possible reduction in pathogenicity. However, it is quite possible that a variant can emerge that combines the near complete immune escape of these newer variants and the high pathogenicity of the delta variant. Such a possibility cannot be ignored as long as the coronavirus cases go down to negligible levels. Besides, SARS-CoV-2 can and does infect animals. This implies that it would not be possible to completely eliminate this coronavirus. It is on its path to become an endemic, as we had anticipated when we undertook our coronavirus drug development program.
At the low or lull-level of the pandemic, the current projected US fatality rates in excess of 150,000-200,000 annually directly ascribable to SARS-CoV-2 is still over five times more than the typical seasonal influenza fatalities, approximately 35,000 in a non-pandemic year.
It is generally believed that existing vaccines have provided significant reduction in hospitalizations and fatalities, while they worked. As the newer Omicron variants have almost completely escaped the original vaccines, new bi-valent vaccines have been developed. Clearly, it can be reasonably expected that these new bi-valent vaccines would lose effectiveness in face of new variants that would certainly arise within a matter of months.
Most of the previously available antibodies under EUA have had their EUA’s revoked because of loss of effectiveness as resistant variants have emerged. The new variants have exhibited significant resistance to even the Evusheld cocktail that was expected to be broadly neutralizing. It is only a matter of time that any remaining available antibodies lose utility as new escape variants emerge.
Remdesivir is the only approved drug at present and requires long infusions. It is approved for use in hospitalized patients or patients with high risk of hospitalization. Its human clinical effectiveness has not matched its strong effectiveness in cell cultures. Molnupiravir (Merck/Ridgeback), an oral nucleoside analog, was a known mutagen and its EUA was based on very limited protection. Paxlovid® (Pfizer), another oral drug, was found to be superior to molnupiravir. However, recent clinical study reports have indicated that its effectiveness is limited to patients over 65 years of age with co-morbidities. In the general patient population not matching these criteria, the effect of Paxlovid was not distinguishable from placebo. (Arbel et al., Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge. N Engl J Med 2022; 387:790-798 DOI: 10.1056/NEJMoa2204919).
Thus, the current set of tools available for combating the COVID-19 pandemic is not robust enough to allow a “Living with COVID” attitude.
Clearly, “Living with SARS-CoV-2” is not a viable option unless a strong, broad-spectrum antiviral is developed, which we believe is the promise of NV-CoV-2. We have seen extremely strong effectiveness of NV-CoV-2 in preclinical studies in comparison to the known most effective drug, remdesivir. This gives us the belief that NV-CoV-2 is likely to be one of the best oral and injectable drugs available, if not the best. The strong preclinical safety we have found for NV-CoV-2 is expected to enable increased dosages if necessary to control the infection.
A major concern is the fact that the variants that are now becoming dominant have an accumulation of multiple mutations. This is predictive of such variants being more resistant to drugs and vaccines in use. These variants are likely to have been selected against drug
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pressure or immune system pressure, and thus would likely have resistance to vaccines, antibody drugs, as well as other commonly used drugs, as suggested by eminent scientists. Further, it is now well known that some of the new variants can cause infection of a previously recovered coronavirus patient, as well as previously vaccinated persons, and sometimes may lead to more severe disease than the earlier infection. Such new variants can be logically expected to be resistant to antibodies as well as vaccines. Additionally, it has already been found or suspected that many of the new variants are or are expected to be increasingly resistant to existing antibody drugs. Given the known weak effectiveness of available antibody drugs, even a small resistance would likely allow a variant to escape the current antibody drugs.
Of note, the currently approved drugs, namely remdesivir, the Regeneron antibody cocktail, or the Eli Lilly single antibody drug, had demonstrated only moderate effectiveness in clinical trials. Remdesivir reduced the length to recovery in severe disease cases in hospitalized patients by approximately six days, from 18 days to 12 days in a clinical trial, NIAID ACIT-1, as reported in its European (CHMP) Product Information. The Regeneron drug dosing in a clinical trial was at 2.4g or 8g of total antibody, while the Eli Lilly antibody drug dose in the combination therapy clinical trial was at 5.6g, although single antibody therapy dosages from 700mg upwards are also being evaluated. These high dosage levels are indicative of relatively weak effectiveness. The U.S. Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) for the Regeneron REGEN-COV cocktail, and also to an Eli Lilly single antibody bamlanivimab (LY-CoV555) with both authorizations restricted to the treatment of mild to moderate COVID-19 only. The effectiveness of oral Paxlovid was similarly limited but it led to a significant statistical reduction in hospitalization rate. Thus, further loss of effectiveness of the existing drugs as new variants emerge would have devastating consequences.
Fiscal Year 2021 - 2022 in Review
The SARS-CoV-2 virus, despite its current and future variants, is extremely unlikely to escape a broad-spectrum anti-coronavirus drug like the drugs NV-CoV-2 and NV-CoV-2-R that we are developing. This is in complete contrast with drugs based on antibodies, antibody cocktails, small chemicals such as paxlovid or remdesivir, as well as with preventative vaccines.
In the reported year and subsequently to date, we are working diligently towards the goal of filing an Investigational New Drug Application (IND) for NV-CoV-2 as soon as possible. We have almost 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 will be able to complete the process of developing the Clinical Protocols and complete the IND for the US FDA after engaging a Clinical Research Organization to define and execute the clinical trials. We are also working towards the goal of initiating clinical trials outside of the USA for NV-CoV-2. We will report on these as meaningful advancements take place in our objectives.
We have been developing broad-spectrum anti-coronavirus drug candidates since the early reports of the new virus from China, then known as 2019-nCoV. We were able to bootstrap this development using our knowledge gained in the earlier endeavors working on SARS-CoV-1 and MERS coronaviruses.
We have been able to conduct this novel drug development at an accelerated pace because of the benefits of our platform technology. We were able to bootstrap our SARS-CoV-2 drug development efforts using the c-GMP-compatible manufacturing processes developed for our then flagship NV-HHV-1 drug candidate for shingles dermal treatment. Further, we have a tremendous advantage in that the Company has its own cGMP-capable manufacturing facility in Shelton, CT. This facility is capable of producing approximately 4kg of the COVID-19 drug (API, or active pharmaceutical ingredient) per batch. We anticipate that this scale would be sufficient for human clinical trials, and possibly for initial introduction under Compassionate Use, EUA or similar regulatory approval.
Previously, we have already completed pre-clinical IND-enabling studies on our novel SARS-CoV-2 drug candidate NV-CoV-2. 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. 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 US 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.
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We intend to develop NV-CoV-2 through Phase1/2a clinical trials first. Most other drugs for COVID-19 have received EUA only. Dexamethasone, a well-known anti-inflammatory drug, has been found to be very useful in the treatment of severe COVID-19 and is thought to act by suppressing the body’s own immune reaction that is responsible for substantial portion of the lung damage seen in COVID-19, but has severe side effects at the dosages employed. It is not expected to be reducing the viral load itself.
NV-CoV-2 and NV-CoV-2-R were found to be highly 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:
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 strong 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.
The Company 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 strong effectiveness of NV-CoV-2 and NV-CoV-2-R drug candidates in this animal model is consistent with their previously reported effectiveness in cell culture studies against infection of two human coronaviruses, hCoV-NL63, which was used in this animal efficacy study, and hCoV-229E, another circulating coronavirus that uses a distinctly different receptor, namely APN. In contrast, while remdesivir was highly effective in the cell culture studies, it was not very effective in this animal efficacy study, a result that is consistent with human clinical studies 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-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.
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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.
We have developed NV-CoV-2 and NV-CoV-2-R based on the Company’s platform nanoviricides® technology. This approach enables rapid development of new drugs against a number of different viruses. A nanoviricide is a “biomimetic” - it is designed to “look like” the cell surface to the virus. The nanoviricide technology enables direct attacks at multiple points on a virus particle. It is believed that such attacks would lead to the virus particle becoming ineffective at infecting cells. Antibodies in contrast attack a virus particle at only two attachment points per antibody.
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 fuse with the virus lipid envelope, 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 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.
In addition, the nanoviricide technology also simultaneously enables attacking the rapid intracellular reproduction of the virus by incorporating one or more active pharmaceutical ingredients (APIs) within the core 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, thus blocking the complete lifecycle of the virus, enabling complete control of a virus infection.
We have developed NV-CoV-2-R based on this encapsulation capability that is built into its nanoviricide NV-CoV-2. The Company has chosen to encapsulate remdesivir as the participating drug for blocking the viral replication cycle. Remdesivir is approved by the US FDA for the treatment of patients hospitalized with COVID-19. Encapsulation of remdesivir in the nanoviricide envelope is believed to protect it from metabolism in the body. This protection can be expected to lead to significant enhancement in the effectiveness of remdesivir itself (in the encapsulated form), by potentially increasing both the effective remdesivir concentration and its duration of action. This could be an additional favorable effect for the Company’s anti-coronavirus drug candidate NV-CoV-2-R. Remdesivir is sponsored by Gilead. The Company is developing its drug candidates independently at present.
It should be noted that animals metabolize remdesivir relatively rapidly, and this has been cited as a reason for poor efficacy of remdesivir in animal models. We further note that the human clinical evidence of remdesivir efficacy against SARS-CoV-2 appears to reflect substantial metabolism in humans as well, albeit perhaps not as strong as in rats, because the human clinical data to date did not reflect as strong an effectiveness of remdesivir in blocking the viral infection as would be expected based on its cell culture studies. Thus, treatment with NV-CoV-2 and with NV-CoV-2-R, at both dose levels employed, markedly extended survival of rats infected intra-tracheally (directly into the lungs) with a lethal dose of human Cov-NL63 virus emulating the SARS-CoV-2 lung disease. Importantly, both treatments were also markedly superior to Remdesivir treatment alone.
Therefore, we believe that both NV-CoV-2 and NV-CoV-2-R have shown strikingly superior effectiveness in animal models of the lung disease caused by the surrogate coronavirus, as compared to the standard of care, remdesivir. The strong safety of NV-CoV-2 is expected to allow its use in circumstances where remdesivir may not be recommended or may be contra-indicates, such as pregnancy or pediatric situations.
The non-GLP safety/toxicology studies in rats have been completed for both NV-CoV-2 and NV-CoV-2-R. Rats dosed at up to 562 mg/kg body weight by tail vein intravenous injection on Days 0,1,3,5,7,and 9 for a total of 3,375mg/kg dose of NV-CoV-2 showed no side effects. No evidence of any severe adverse reactions was observed during the administration of the NV-CoV-2 or Vehicle during the study period and at postmortem examination in all dose groups of animals. All groups including the NV-CoV-2 and Vehicle groups tolerated the compounds similarly. The body fluids and fecal analysis showed no significant difference between the groups. Histopathological examination showed no changes either in the areas of small intestine or large intestine. No changes in organ weight or histology were observed in all dose groups.
The GLP Safety/toxicology studies for NV-CoV-2 have been completed with no evidence of adverse effects. In a GLP neuro-pulmonary safety pharmacology study in rats, the following conclusion was drawn: The intravenous administration of NV-CoV-2 at doses of 25, 50 and 100 mg/kg did not affect respiratory function in rats.
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In a GLP cardiovascular function study in the NHP cynomolgus monkeys, the following conclusion was drawn: Intravenous infusion of NV-CoV-2 at 25, 37.5, and 50 mg/kg did not have any toxicologic effects on cardiac rhythm or ECG morphology in cynomolgus monkeys in this study. No significant effects on blood pressure and heart rate were observed after the intravenous infusion of NV-CoV-2.
The broad-spectrum anti-coronavirus effectiveness of NV-CoV-2 and NV-CoV-2-R was established in cell culture studies. Both NV-CoV-2 and NV-CoV-2-R were found to be highly effective in comparison to remdesivir against two distinctly different coronaviruses in our new cell culture studies. Remdesivir is one of the most effective anti-coronavirus drugs in cell culture studies. Therefore our finding that NV-CoV-2 was highly effective and comparable to remdesivir in activity in these cell culture studies was pleasantly surprising. Even more striking was the finding that NV-CoV-2-R exceeded the effectiveness of remdesivir itself in these cell culture studies. These results indicate that NV-CoV-2 and NV-CoV-2-R could be some of the strongest weapons in the fight against coronaviruses and the current COVID-19 global pandemic. These results are consistent with the effectiveness of NV-CoV-2 and NV-CoV-2-R in animal studies against a coronavirus with lung pathology similar to the COVID-19 pathology.
Additionally, strong SARS-CoV-2 infection inhibition activity of NV-CoV-2 was observed in a standard pseudovirion study. Pseudovirion assay is a standard method for evaluating virus entry-inhibitors in BSL2 laboratories and is primarily used for viruses that require high security BSL3 or BSL4 laboratories otherwise. In this study, SARS-CoV-2- pseudovirions virus particles that carry a green fluorescent protein (GFP) producer mRNA inside, and use the SARS-CoV-2 S1 protein on their surface to bind to ACE2 receptor protein on cells were made. They were incubated with NV-CoV-2, or a known neutralizing antibody (positive control), or just the vehicle buffer (negative control). Then these solutions were separately used to infect ACE2 positive cells and the virus allowed to grow. The virus infectivity was determined by measuring the number of GFP positive cells (i.e. infected cells) versus the uninfected cells. In this well-known assay, NV-CoV-2 was as effective as the neutralizing antibody in reducing the virus infection. This study demonstrates that NV-CoV-2 attacks the SARS-CoV-2 virus particle and renders it incapable of binding to the ACE2 positive cells.
NV-CoV-2-R
NV-CoV-2-R was observed to provide significant advantages to 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.
Pharmacokinetics of Encapsulated Remdesivir Compared to Standard 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 because of 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.
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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.
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 would be improving 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.
NV-CoV-2-R combines two different mechanisms of attack against the virus and therefore is expected to be substantially more difficult for the virus to evade than either NV-CoV-2 or remdesivir alone. This is important because scientists believe it is only a matter of time before variants of SARS-CoV-2 that evade current vaccines and antibody drugs become commonplace.
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 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.
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 path itself. Additionally, the extremely strong safety of our drugs, particularly NV-CoV-2, is expected to be very important for pediatric application.
Thus we believe that we will be able to develop oral formulations suitable for use in pediatric patients, and we plan to include pediatric cohorts into clinical trials at the appropriate stages. As the variants evolve, pediatric infections and their severity have begun to rise, causing major worldwide concerns even as the world is trying to move towards normalcy in education and child social interactions.
Corporate Events - Intellectual Property
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
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for several drugs with specific targeting mechanisms for the treatment of a number of human viral diseases including coronaviruses, herpesviruses, VZV, HIV, Influenza, and others.
On June 9, 2020, we reported in a press release that the Company signed a Memorandum of Understanding (“CovMoU”) with respect to anti-viral treatments for coronavirus derived human infections (the “Field”) with TheraCour. The MoU specifically provides a limited, exclusive license to all research and development in the Field for further research and development purposes towards human clinical trials. Dr. Diwan recused himself in the Board’s discussions on the MoU, and recuses himself from the Company’s discussions regarding the license agreements as well. Our Board of Directors retained an independent consultant for the evaluation of the assets in order to develop the full license agreement. 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.
On September 14, 2021, we announced execution of a license agreement for the field comprising anti-viral treatments for coronavirus derived human infections with TheraCour on September 9, 2021 (the “CoV Agreement”). The licensed field includes antiviral drugs to treat SARS-CoV-2 and its variants that cause the COVID-19 disease resulting in a global pandemic that continues to rage through the world, wave after wave, as new variants develop and take hold. There was no upfront cash payment for the license and the compensation terms were generally consistent with prior licenses, and are summarized below.
Under the CoV Agreement, we have obtained a world-wide, exclusive, sub-licensable, license to use, promote, offer for sale, import, export, sell and distribute antiviral drugs that treat human Coronavirus infections using TheraCour’s proprietary as well as patented technology and intellectual property, including the new patent application cited above. The discovery of ligands and polymer materials as well as formulations, the chemistry and chemical characterization, as well as process development and related work will be performed by TheraCour under the same compensation terms as prior agreements between the parties, with no duplication of costs allowed. We will not make any upfront cash payments to TheraCour and we have agreed to the following milestone payments to TheraCour: 100,000 shares of the Company’s Series A Convertible Preferred Stock, par value $0.001 per share (the “Series A Preferred Stock”) upon the execution of the Agreement; 50,000 shares of Series A Preferred Stock after the grant of the approval of Licensee’s Investigational New Drug (IND) Application, or its equivalent; cash payments of $1,500,000 after the initiation of Phase I clinical trials or its equivalent; $2,000,000 after the completion of Phase 1 Clinical Trials or its equivalent for at least one product within twelve (12) months from the date of the acceptance of the IND; $2,500,000 no later than six (6) months after the completion of Phase 2A Clinical Trials or its equivalent for at least one product within twenty (24) months from the date of the completion of Phase 1 or its equivalent; 100,000 shares of Series A Preferred Stock after the initiation of Phase 3 clinical trials or its equivalent; and, at TheraCour’s option, $5,000,000 in cash or 500,000 shares of Series A Preferred Stock, no later than six (6) months after the completion of Phase 3 Clinical Trials or its equivalent for at least one product within thirty-six (36) months from the completion of Phase 2 Clinical Trials or its equivalent. In addition, we agreed to pay to TheraCour fifteen percent (15%) of net sales of licensed products and any income from sublicensed products, consistent with previous agreements. Under the CoV Agreement, TheraCour retains the exclusive right to develop and manufacture the Licensed Products. The Agreement contemplates that the parties will enter into a separate Manufacturing and Supply Agreement for the commercial manufacture and supply of the drug products if and when we intend to engage into commercialization of the drugs. The CoV Agreement provides that the Manufacturing and Supply agreement would be on customary and reasonable terms, on a cost-plus basis, using a market rate based on then-current industry standards, and include customary backup manufacturing rights, as with prior agreements. The Series A Convertible Preferred Shares are only convertible upon a “change of control” of the Company as defined in its full specification, are non-transferrable and have no trading market. Each Series A share carries 9 votes, and is convertible only upon a change of control into 3.5 shares of the Company’s common stock.
To assist in the analysis of the terms of the CoV Agreement, we commissioned research reports on Coronavirus drug market sizes for the Coronavirus antiviral field from an independent consulting agency, Nanotech Plus, LLC. Additionally, we obtained business analysis and valuation reports for potential licensing terms for a coronavirus drug from an independent consultant. NanoViricides was represented by McCarter & English, LLP while TheraCour was represented by DuaneMorris LLP.
A new international PCT patent application regarding coronavirus drug candidates has been 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 was filed on June, 28, 2022, with a requested priority date of the 2021 application. The intellectual property covered by both of these patent applications is automatically licensed by us under the CoV Agreement for the licensed field. 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,
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manufactured products, and methods of use, among other specifics. The first of these patent application was filed on June 25, 2021, application number PCT/US21/39050, entitled “Self-Assembling Amphiphilic Polymers As Anti-Covid-19 Agents”, and the second one was filed on June 28, 2022, application number PCT/US22/35210, entitled “Self-Assembling Amphiphilic Polymers As Anti-Covid-19 Agents”. The nominal expiry date 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 we currently do not need a license for the use of remdesivir in developing the novel nanoviricide drug candidates that encapsulate remdesivir. We have undertaken encapsulation of remdesivir into the drug candidate NV-CoV-2-R for the treatment of coronavirus because we believe that this encapsulation would result in substantial patient benefits. However, we believe that our anti-coronavirus drug candidate NV-CoV-2 by itself has shown significant anti-coronavirus activity in cell culture and animal studies, and therefore is expected to be highly effective drug against human coronavirus infection, without encapsulating remdesivir.
We believe that encapsulation of remdesivir inside the polymeric micelles of NV-CoV-2, thereby resulting in the drug NV-CoV-2-R, would improve the pharmacokinetics of remdesivir and thereby improve its effectiveness when in encapsulated form in human clinical trials, in close correspondence with what was seen in animal studies. These possibilities can only be evaluated in a human clinical trial. We believe that any license for the use of remdesivir encapsulation in our novel drugs, if necessary, will be feasible in the interests of resolving the pandemic. We would also be willing to collaborate with Gilead Sciences, Inc., the developer of remdesivir, for developing the encapsulated drug. There is currently no collaboration agreement with Gilead Sciences, Inc., nor any assurance that such an agreement can be reached. The Company is currently developing its anti-coronavirus clinical drug candidates NV-CoV-2 and NV-CoV-2-R independently.
Corporate Events - Financing
We had approximately $14.1 million cash in hand as of June 30, 2022, the end of the reporting period. We spent approximately $5.9 million in cash on operating activities in the reported year, although our expenditures are expected to increase upon commissioning of human clinical trials. 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 fiscal 2023.
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. (“Kingswood”, 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 the public offering price of $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 “Sales Agreement”) with B. Riley Securities, Inc. and Kingswood Capital Markets, a division of Benchmark Investments, Inc. (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”). Sales pursuant to the Sales Agreement will be made only upon instructions by us to the Sales Agents, and we cannot provide any assurances that it will issue any shares pursuant to the Sales Agreement. Actual sales will depend on a variety of factors to be determined by us from time to time, including (among others) market conditions, the trading price of our common stock, capital needs and determinations by us of the appropriate sources of funding. We are not obligated to make any sales of common stock under the Sales Agreement and we cannot provide any assurances that it will issue any shares pursuant to the Sales Agreement. We will pay a commission rate of up to 3.5% of the gross sales price per share sold and agreed to reimburse the Sales Agents for certain specified expenses, including the fees and disbursements of its legal counsel in an amount not to exceed $50,000 and have agreed to reimburse the Sales Agents an amount not to exceed $2,500 per quarter during the term of the Sales Agreement for legal fees to be incurred by the Sales Agents. We have also agreed pursuant to the Sales Agreement to provide each Sales Agent with customary indemnification and contribution rights.
On March 2, 2021 we sold 814,242 shares of common stock at an average price of $7.83 under the “At-the-Market Issuance” 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.
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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.
Corporate Events - Board
On November 19, 2020, we announced that Mr. Brian Zucker, CPA, has joined the Company’s Board of Directors, effective November 13, 2020, as an independent director. He was also appointed as a member of the Board’s Audit Committee, Nomination Committee and Compensation Committee. Mr. Zucker is a Partner at CFO Financial Partners, LLC (https://www.cfopartners.com/), a firm that provides outsourced CFO (Chief Financial Officer), Controller and Financial Operations services as well as back office reporting and bookkeeping services for public and private companies, broker dealers, hedge funds, and family offices and high net worth individuals, among others. Mr. Zucker also serves as the CFO and Financial Operations Principal for numerous broker dealers and hedge funds. In addition to and simultaneously therewith, Mr. Zucker has served as a Partner at RRBB Accountants & Advisors, (aka Rosenberg Rich Baker Berman & Co.), a full-service accounting, advisory and consulting firm located in Central New Jersey. He has over thirty years of experience as a CPA specializing in the securities industry.. From 1983 through 1986, Mr. Zucker was a Senior Consultant at Deloitte Haskins and Sells and at Price Waterhouse from January 1987 through September 1989. He has previously served as the President and Chairman of Atlantis Business Development Corp. (ABDV), CFO of Natcore Solar Technology, Inc. (NTCXF) and as a Managing Director of American Frontier Financial Corp. (EVIS). Since May 2018, he has been serving as the CFO of EIG Energy Partners Capital Markets, LLC. Brian holds a CPA in States of New Jersey and New York, and holds several FINRA licenses. He is on the Board of Directors of National Investment Banking Association (NIBA). Mr. Zucker obtained a B.S. in Public Accounting from Pace university. We believe we have thus strengthened our Audit Committee and our Board of Directors with the addition of Mr. Brian Zucker who brings valuable multi-faceted experience with public companies, as well as financings and banking institutions to our Board.
On January 15, 2022 Mr. Stan Glick, CPA, Chair of the Audit Committee and Director of NanoViricides, passed away. Stan joined the Board as the first Independent Director circa June, 2012 and guided us in uplisting NanoViricides from the OTC Bulletin Board to NYSE American exchange, in the project of building the new world-class nanomedicines R&D and Manufacturing campus facility at 1 Controls Drive, Shelton. His hallmark traits were competence, calmness, integrity, clarity, strength, and support. We will miss him. Mr. Brian Zucker, CPA, a member of the Audit Committee has been named as Interim Chair of the Audit committee.
The Nanoviricide Platform Technology in Brief
The Company develops its class of drugs, that we call nanoviricides®, using a platform technology. This approach enables rapid development of new drugs against a number of different viruses. A nanoviricide is a “biomimetic” - it is designed to “look like” the cell surface to the virus. The nanoviricide® technology enables direct attacks at multiple points on a virus particle. It is believed that such attacks would lead to the virus particle becoming ineffective at infecting cells. Antibodies in contrast attack a virus particle at only a maximum of two attachment points per antibody. In addition, the nanoviricide technology also simultaneously enables attacking the rapid intracellular reproduction of the virus by incorporating one or more active pharmaceutical ingredients (APIs) within the core 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 Company’s 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 cognate receptor. These ligands are chemically attached to a nanomicelle, to create a nanoviricide®.
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 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 binds to the virus but also complete the task of rendering the virus particle ineffective.
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Our Drug Programs for COVID-19 (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, 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. 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.
The safety and effectiveness of NVN-CoV-2 was discussed already.
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.
As discussed earlier, 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.
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 effective control of the virus by an effective therapeutic would minimize such post-COVID after-effects 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.
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We believe NV-CoV-2 will probably be one of the best tools to address the COVID-19 spectrum, 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.
Our Drug Programs for Varicella Zoster Virus (VZV), Cause of Shingles and Chickenpox (Table 2.B):
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.
On August 5, 2019 we reported that NV-HHV-1 has been found to be safe and well tolerated at all dosage levels in the clinical observation portion of the GLP Safety/Toxicology study of NV- HHV-101 as a dermal treatment. The in-life stage of the first part of the GLP Safety/Toxicology studies was completed. Both the non-GLP and GLP Safety/Toxicology studies were conducted by Bioanalytical Systems (“BASi”), Evansville, IN, a Contract Research Organization that is specialized in IND-enabling safety/toxicology studies.
On December 9, 2019, we further reported the current status of NV-HHV-1 in a press release, as discussed at the Annual Shareholders’ Meeting held on December 7, 2019. The in-life animal studies portions of the required GLP safety/toxicology studies were already completed then and resulting blood samples were sent by the contract research organization, BASi, to other laboratories for different analyses. We had also sent the NV-HHV-1 drug product for other required testing to different laboratories. Most of the studies were already completed by the external collaborators and we were then awaiting draft reports from the completed studies to guide the IND application drafting.
However, the COVID-19 epidemic expanded across the US, and also globally, since March 2020, and did not show signs of abating rapidly. It became apparent that this epidemic would have a significant impact on any new clinical trials for other viruses such as for our shingles treatment development. The impact would be in terms of the ability to recruit and retain patients, as well as in the design of the clinical trial in presence of COVID-19 related contingencies, and most importantly, in the interpretation of the resulting datasets. We therefore determined that it was better to wait for resolution of the COVID-19 epidemic prior to entering into NV-HHV-1 clinical trials.
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.
Our NV-HHV-1 drug is thus in the IND-enabling stage and we intend to file the IND soon after the COVID-19 epidemic situation resolves. Assuming an IND application is approved by the US FDA, we will then be able to commence clinical trials in this program.
In addition to these highest priority and most advanced drug programs, we have several additional drug programs at various stages and different levels of priorities that are discussed further below under “The Company’s Drug Pipeline”.
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). Our other HerpeCide program candidates in progress at present are mostly based on NV-HHV-1, thereby maximizing return on investments and shareholder value.
Market Size, Shingles, Herpes HSV-1 and HSV-2:
The market size for the treatment of shingles is estimated at approximately one billion dollars by various estimates. 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.
The market size for our immediate target drugs in the HerpeCideTM program is variously estimated at billions to tens of billions of dollars. The Company believes that its dermal topical cream for the treatment of shingles rash will be its first drug heading into clinical
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trials in the HerpeCide program. The Company believes that additional topical treatment candidates in the HerpeCideTM program, namely, HSV-1 "cold sores" treatment, and HSV-2 "genital ulcers" treatment are expected to follow the shingles candidate into IND-enabling development and then into human clinical trials.
Our Coronavirus Drug Development Program Prior to Clinical Candidate Declaration – Rapid Development of Novel drug Candidates Against a Novel Disease-Causing Virus was Enabled by Our Platform Technology:
Since January 2020, the Company began working on developing a treatment for the SARS-CoV-2 virus (then known as 2019-nCoV virus) infection that causes COVID-19 spectrum of diseases. Our efforts were at that time boot-strapped upon existing work being performed for our Shingles treatment drug candidate and earlier work that we had performed on developing drug candidates for MERS-Coronavirus in 2014, and for SARS-Coronavirus in 2012. Although we had designed and made drug candidates for MERS-CoV, these candidates were not tested as the global efforts quickly shifted to the Ebola epidemic in the 2014-2015 timeframe. For the SARS-CoV-2 drug development program, we had a good head start because the structure of the first SARS-CoV and its interaction with the human receptor ACE2 had been solved. SARS-CoV-2 uses the same receptor, ACE2, as does SARS-CoV, and another coronavirus, namely h-CoV-NL63. Also it was found that SARS-CoV antibodies were cross-reacting with SARS-CoV-2.
The Company achieved several milestones in the newly instituted drug development program against SARS-CoV-2 since beginning these efforts.
Very quickly, in January 2020, we developed anti-viral ligands capable of binding to the SARS-CoV SPIKE protein (i.e. S1 antigen) at the same site where this viral spike protein binds to the human ACE2 cellular receptor protein as a doorway to enter and infect the cell. We perform design of such anti-viral ligands using molecular modeling tools. We continued to evolve these developments further as the program progressed. We already had some of the lead chemicals or their fragments for these newly designed ligands in our existing chemicals and ligands library. We used the same polymer backbone as used for NV-HHV-1 to speed up the development, and attached the different test anti-coronavirus ligands to the polymer backbone using covalent chemical linkages, resulting in new anti-coronavirus nanoviricides test compounds.
Viral mutations lead to viruses escaping drugs such as antibodies and small chemicals in the field. In spite of mutations, the virus binds to the same site on the same cellular receptor in the same fashion. We develop small chemical ligands that are designed to bind to the virus protein at the same binding area, mimicking the cellular receptor. Thus, even if the virus mutates, the nanoviricide drugs so designed would continue to work, provided they mimic the cellular receptor adequately and successfully.
We also developed anti-coronavirus assays for testing these compounds in our own BSL2 certified Virology laboratory very quickly. These cell culture assays employ known less hazardous, circulating human coronaviruses. Of these, coronavirus hCoV-NL63 uses the same ACE2 receptor, but causes a milder disease with similar pathological manifestations, as do SARS-CoV-1 and -2. HCoV-NL63 is known to cause severe lower respiratory tract infections in young children leading to hospitalization. The symptoms are generally less severe than SARS-CoV-2 but are similar. In most cases, hCoV-NL63 causes relatively mild disease, often associated with croup, bronchiolitis, and lower respiratory tract disease in children, and is considered to cause some of the common colds in adults. Thus, the clinical manifestation of hCoV-NL63 infection in pediatric patients is similar to that of SARS-CoV-2, although much less severe. SARS-CoV-2 causes clinically similar milder forms of disease in most patients, but moderate to severe disease requiring hospitalizations in about 15-20% of infected persons. These similarities imply that hCoV-NL63 should be a reasonable model virus for antiviral cell culture and animal studies in BSL2 environment in the course of antiviral drug development for SARS-CoV-2. Thus NL63 serves as a good surrogate for SARS-CoV-2 drug development. Another coronavirus we are testing against, namely hCoV-229E, uses a different but somewhat related receptor (in terms of biophysics). Investigating against both of these strains would allow us to examine which of the test candidates have more broad-spectrum effectiveness against coronaviruses. However, there can be no assurance that successful results against these forms of coronaviruses will lead to similar results against SARS-CoV-2. There can be no assurance that even successful results against SARS-CoV-2 itself will lead to successful clinical trials or a successful pharmaceutical product. This is true of every drug development effort against SARS-CoV-2. The effectiveness of a drug against SARS-CoV-2 will need to be evaluated in human clinical trials.
We confirmed in a press release on January 30, 2020, that we had begun working on developing a broad-spectrum anti-coronavirus drug for the treatment of SARS-CoV-2 and other coronaviruses.
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On March 16, 2020, we reported in a press release that we had completed synthesis of certain test candidates that we had designed, and that we had completed development of anti-Coronavirus assays for testing such novel candidates, in our own laboratories.
On May 12, 2020, in a press release, we reported that we had successfully developed drug candidates that demonstrated very high anti-viral effectiveness in cell culture studies against multiple human coronaviruses. Two of the tested nanoviricides drug candidates were highly effective in cell culture assays against multiple coronaviruses that infect humans. In particular, they were several-fold more effective than favipiravir (aka T-705), against the tested viruses. favipiravir is a broad-spectrum nucleoside-like analog drug that is in clinical testing against SARS-CoV-2, originally developed by Fujifilm. We tested these drug candidates for anti-viral effectiveness against two distinctly different, unrelated coronaviruses that cause human disease, namely hCoV-NL63, and hCoV-229E. The assays evaluated the reduction caused by the drug candidate in cell death upon viral infection, formally known as cytopathic effects (CPE) assays.
We found that the same two nanoviricides drug candidates were highly effective against hCoV-NL63, the coronavirus that uses the same cellular receptor as SARS-CoV-2, as well as another coronavirus, namely hCoV-229E, that causes seasonal common colds in humans. HCoV-229E uses the APN (Aminopeptidase-N) membrane protein on human cells as its receptor to enter cells, different from the ACE2 receptor used by hCoV-NL63 and SARS-CoV-2. ACE2 and APN may be considered to belong to a common super family of enzyme membrane proteins in terms of biophysics. The various receptors used by different coronaviruses all appear to fall in the broad family of membrane-associated serine proteases. As a family, they share several structural features. Their substrate specificities are dictated by specific amino acid residues and their positions.
We believe the fact that these nanoviricides anti-coronavirus drug candidates are highly effective against two distinctly different coronaviruses that use different cellular receptors is very significant. Specifically, we believe this provides substantial confidence and scientific rationale that even as the SARS-CoV-2 coronavirus mutates resulting in variants, these nanoviricides can be expected to continue to remain effective. In contrast, it is now well known that SARS-CoV-2 escapes antibodies as drugs as well as immune protection from vaccines as new variants are generated. Antibodies are known to become ineffective upon viral mutations.
We believe that broad-spectrum anti-coronavirus drugs such as our nanoviricides drug candidates would be expected to provide the ideal solution for combating COVID-19, provided that the candidates show effectiveness in human clinical trials.
On May 20, 2020, we reported in a press release that strong effectiveness against infection by an ACE2-utilizing coronavirus in an animal model was observed for our test drug candidates in development against SARS-CoV-2 to treat COVID-19 spectrum of diseases. In this lethal, direct-lung-infection model, animals in all groups infected with hCoV-NL63 developed lung disease which later led to multi-organ failures, a clinical pathology resembling that of the SARS-CoV-2. Reduction in loss of body weight at day 7 was used as the primary indicator of drug effectiveness. Rats were infected directly into lungs with lethal amounts of hCoV-NL63 virus particles and then different groups were treated separately with five different nanoviricides test drug candidates, remdesivir as a positive control, and the vehicle as a negative control. The treatment was intravenous by tail-vein injection.
Animals treated with the five different nanoviricides showed significantly reduced body weight loss. The body weight loss was only 3.9% for the best nanoviricide candidate, ranging to 11.2% for the potentially least effective one, as compared to 20% in the vehicle-treated control group, in female animals (n=5 in each group). Male animals treated with the same nanoviricides also showed significantly reduced body weight loss. The body weight loss in male animals was 8.0% for the best nanoviricide candidate and ranged up to 10.9% for the potentially least effective one, as compared to 25% in the vehicle-treated control group (n=5 in each group). In comparison, remdesivir treatment led to a body weight loss of 15.2% in females and 18.6% in males in this study. Remdesivir is known to be rapidly metabolized in native animal models, and its effectiveness was evaluated in specially constructed serum esterase negative mice in published literature. Importantly, this study demonstrated that our drug candidates were highly effective in a native animal model of lethal coronavirus lung infection, which may be considered more stringent than the clinical condition in human patients. Smaller numbers mean less loss in body weight compared to starting body weight in the group, and indicate greater drug effectiveness.
The striking difference in weight loss between the two sexes in this animal model was remarkable. It has been widely reported that men are more likely to suffer severe infection and fatalities from SARS-CoV-2 than women in the current pandemic. This feature was replicated in our animal model study indicating that biological sex differences are the driver of the differences in the severity of infection by the coronaviruses that utilize the ACE2 receptor.
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The strong effectiveness of nanoviricide test drug candidates in this model is consistent with the effectiveness observed in cell culture studies against infection of both hCoV-NL63, which was used in this study, and hCoV-229E, another circulating coronavirus that uses a distinctly different receptor, namely APN.
Thus this study corroborated the cell-culture effectiveness and provided confidence that these nanoviricides drug candidates may be expected to result in a clinical candidate to be pursued in human clinical trials.
On July 8, 2020, we reported in a press release that excellent safety and tolerability of the drug candidates in development against SARS-CoV-2 to treat COVID-19 spectrum of diseases was observed in an animal model. Three different drug candidates at three different dosage levels (low, medium, and high) and vehicle control were administered to separate groups of mice intravenously in this non-GLP Safety-Tolerability study. Sixteen mice in each group (8 males, 8 females), were administered one of the three drug candidates at one of the three dose levels, and additionally, one group was administered vehicle control, for seven days by daily tail-vein intravenous infusion in this blinded study with additional evaluations on 8th day. This non-GLP safety/tolerability study was conducted under GLP-like conditions by AR BioSystems, Inc., Tampa, FL.
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 high dosage groups of two of the three drug candidates tested, associated with the non-absorption of water, in the colon. This is consistent with the clinical observation of loosened stools in the same groups. 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.
Clinical observations and gross post-mortem studies showed that the tested drug candidates were safe and well tolerated, thereby clearing the path for further development towards a treatment for SARS-CoV-2 infection that has caused the current COVID-19 pandemic.
On the basis of these studies, we have developed a strategy for drug development with the goal of creating the most effective medicine to obtain regulatory approval for emergency use in the COVID-19 pandemic in the shortest timeline feasible, after having achieved proof of concept of broad-spectrum anti-coronavirus effectiveness of test candidates. To this end, we have worked to harness the full power of the nanoviricide platform, which (1) enables attacking the virus particle blocking infection by itself as described above, as well as (2) enables protection and delivery of other payload drug(s) that can interfere with the replication of the virus inside cells.
A curative treatment for a virus such as SARS-CoV-2 coronavirus would require a multi-faceted attack that shuts down (i) the ability of the virus to infect host cells, and simultaneously, (ii) the ability of the virus to multiply inside the host cells. The nanoviricide® platform enables direct multi-point attack on the virus that is designed to disable the virus and its ability to infect new cells. At the same time, a nanoviricide is also capable of carrying payload in its “belly” (inside the micelle) that can be chosen to affect the ability of the virus to replicate. The nanoviricide is designed to protect the payload from metabolism in circulation. Thus, the nanoviricide platform provides an important opportunity to develop a curative treatment against SARS-CoV-2, the cause of COVID-19 spectrum of pathologies.
We accelerated the development of a second generation nanoviricide against COVID-19 given that a well known drug that affects the replication cycle is already, namely Remdeservir, available and is the only direct-acting antiviral currently authorized in the U.S.A. While highly effective in cell cultures, the human clinical effectiveness of remdesivir is known to be limited by the rapid metabolism it undergoes in the bloodstream upon infusion. We had hypothesized that by encapsulating remdesivir into our nanoviricide, it may undergo limited metabolism thereby improving its effectiveness. This hypothesis has borne true as discussed above under the heading “Pharmacokinetics of NV-CoV-2-R”.
On September 16, 2020, we announced that we had nominated a clinical drug candidate, identified as NV-CoV-1-R for further development. We also continued to work on additional variants of various potential anti-coronavirus drug candidates. We thus guard against the risk of unknown effects in the drug development process.
One of these newer drug candidates, namely, NV-CoV-2 was found to have several advantages over NV-CoV-1 in terms of manufacturability and dose formulation. Therefore we determined that it was best to advance NV-CoV-2 and NV-CoV-2-R as the top-level clinical drug candidates against COVID-19.
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Remdesivir is a well-known antiviral drug (developed by Gilead) that has been approved for emergency use treatment of SARS-CoV-2 infection or COVID-19 in several countries. NV-CoV-2 is a novel agent that is being used as an adjuvant to remdesivir in creating NV-CoV-2-R, to improve the overall effectiveness. It is well known that remdesivir suffers from rapid metabolism in circulation that breaks down the pro-drug to its nucleoside form which is not readily phosphorylated and therefore has poor effectiveness. We anticipate that encapsulation in NV-CoV-2 may protect remdesivir from this rapid metabolism. If this happens, the effective level and stability of remdesivir in the body would increase. This increase may lead to increased effectiveness if there are no adverse effects. Such increased effectiveness, if found, may also allow reduction in the required dosage of remdesivir in the encapsulated form, i.e. as NV-CoV-2-R. In this sense, NV-CoV-2 can be viewed to act as an adjuvant that enhances the effect of remdesivir, a known antiviral against SARS-CoV-2. We have already found that in animal studies indeed the remdesivir effective levels are increased in the encapsulated form of NV-CoV-2-R, and the effectiveness is also increased as an anti-coronavirus agent, as compared to the standard remdesivir/SBECD formulation Veklury (Gilead).
Investor Outreach
During the reporting period and thereafter, we continue to make significant efforts in our investor outreach programs. We have retained Tradigital, Inc. as its investor relations firm. In addition, we have presented at various investor conferences. We have also been interviewed on national and investor-oriented channels, unsolicited, due to our engagement in COVID-19 drug development efforts.
On February 4, 2020, the Company reported in a press release that Dr. Diwan was interviewed on the Kennedy show on Fox Business News (FBN), on January 23, 2020. The Company has licensed a copy of the video excerpt from FBN and it is available on the Company’s website (www.nanoviricides.com) under the heading “NanoViricides In the News”, by clicking on “Dr. Anil Diwan on Fox Business - 01/23/2020 - By - Kennedy”.
On February 10, 2020, the Company reported in a press release that Dr. Diwan was interviewed on the Stuart Varney show on Fox Business News (FBN), on January 28, 2020. The Company has licensed a copy of the video excerpt from FBN and it is available on the Company’s website (www.nanoviricides.com), home page, under the heading “Dr. Anil Diwan on Fox Business - 01/28/2020”.
Dr. Diwan participated as a panelist on a virtual panel discussion entitled, “COVID-19: Current Pipeline and Innovations for Therapeutics and Vaccine”, organized by BioCT, an association of biotechnology and pharmaceutical businesses in Connecticut, on April 8, 2020. The panel was moderated by Dr. Mostafa Analoui, Executive Director, Venture Development & Technology Incubation Program (TIP), Office of the Vice President for Research, University of Connecticut, Storrs, CT. A transcript of the panel discussion is available at https://www.youtube.com/watch?v=WpTP_wnEZKw&feature=youtu.be.
On April 13, 2020, the Company reported that Dr. Diwan and key staff members at the Company’s Shelton, CT headquarters were interviewed by broadcast journalist Christine Corrado of Proactive Investors on March 27, 2020, remotely, from their New York office.
On April 22, 2020, Dr. Diwan presented a corporate update focused on the COVID-19 and shingles programs at the Planet Microcap Virtual Showcase 2020.
On June 30, 2020, we reported in a press release that Nanoviricides, Inc. had been added to the Russell Microcap® Index effective after the U.S. markets opened on Monday, June 29, 2020. Membership in the Russell Microcap® Index, which remains in place for one year, means automatic inclusion in the appropriate growth and value style indexes. FTSE Russell determines membership for its Russell indexes primarily by objective, market-capitalization rankings and style attributes. Russell indexes are widely used by investment managers and institutional investors for index funds and as benchmarks for active investment strategies. Approximately $9 trillion in assets are benchmarked against Russell’s US indexes. Russell indexes are part of FTSE Russell, a leading global index provider. Inclusion of NanoViricides in the Russell Microcap Index may be expected to increased participation in the NNVC stock positions of investment managers and institutional investors that purchase, follow or employ this index.
On July 21, 2020, Dr. Diwan, was invited to participate in the “B. Riley FBR Virtual Infectious Disease Summit – Therapeutics Day”. The Conference was organized by B. Riley FBR, Inc. (https://brileyfbr.com/). Dr. Diwan participated in Panel #3 at 2020 at 2:10 p.m. ET, entitled “Taming the Severe Disease Presentations”.
On September 3, 2020, Dr. Diwan provided a further update on our programs at the LD500 Virtual Conference, as reported by the Company in a press release issued on September 4, 2020.
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On September 30, 2021, Dr. Diwan presented an update at the Benzinga Healthcare Small Cap Conference-2021 on our programs entitled “Pan-coronavirus Broad-spectrum Nanomedicines NV-CoV-2 and NV-CoV-2-R to Attack the SARS-CoV-2 Virus and its Variants in the Global Pandemic”.
We have provided updates on our progress via press releases.
Thus we have made strong progress in drug development, despite engaging into a novel drug program against coronaviruses in response to the current pandemic, as well as financing and leadership building in the reported year.
The Company’s primary focus is on bringing its broad-spectrum anti-coronavirus drug into human clinical trials as soon as possible, in response to the current pandemic, as detailed above.
Our other lead program, namely NV-HHV-1 skin cream for treatment of shingles rash, is now in IND-ready stage, with clinical trial design and clinical trial selection as the remaining steps prior to filing an IND. 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. In addition, we have drug candidates in development against severe influenzas (including bird flu), HIV, Dengue, Ebola/Marburg and other viruses at different preclinical stages. According to a 2014 market report prepared by Jain PharmaBiotech (“Jain”), entitled “Antiviral Therapeutics, Technologies, Markets & Companies,” the overall market size for our potential drugs is estimated to be between $40~65 Billion by 2023. This broad pipeline is enabled by our unique post-immunotherapeutic “bind-encapsulate-destroy” technology platform.
We are a development-stage company with the goal of commercializing special purpose nanomedicine for anti-viral drugs based on a novel, first-in-class mechanism. 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.
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 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. The Company has exclusive licenses from TheraCour for drug candidates derived from and based on TheraCour’s technologies for several viruses. In 2005, the Company 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, the Company 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, the Company completed the process of licensing the VZV (shingles, chicken pox virus) field from TheraCour in November 2019.
The Company further completed the process of licensing antivirals for the field of human coronavirus indications in September 2021. 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.
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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.
Our objectives are to create the best possible anti-viral nanoviricides and then subject these compounds to rigorous laboratory and animal testing towards US FDA and international regulatory approvals. Our long-term research efforts are aimed at augmenting the nanoviricides that we currently have in development with additional therapeutic agents to produce further improved anti-viral agents in the future. We believe that many viral infections that are at present untreatable or incurable would be curable using such an advanced approach.
The Nanoviricide® Platform Technology
NanoViricides, Inc. is engaged in the application of nanomedicine technologies to the complex issues of viral diseases. The nanoviricide® technology enables direct attacks at multiple points on a virus particle. It is believed that such attacks would lead to the virus particle becoming ineffective at infecting cells. Antibodies in contrast attack a virus particle at only a maximum of two attachment points per antibody. In addition, the nanoviricide technology also simultaneously enables attacking the rapid intracellular reproduction of the virus by incorporating one or more active pharmaceutical ingredients (APIs) within the core 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.
Our anti-viral therapeutics, that we call “nanoviricides®” are designed to look to the virus like the native host cell surface to which it binds. Since these binding sites for a given virus do not change despite mutations and other changes in the virus, we believe that our drug candidates will be broad-spectrum, i.e. effective against most if not all strains, types, or subtypes, of a given virus, provided the virus-binding portion of the nanoviricide is engineered appropriately.
This powerful 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.
It is important to realize that the flexible nanoviricides nanomedicines show substantial advantages over hard sphere nanoparticles in this antiviral drug application. 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.
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.
A nanoviricide is constructed by chemically attaching a ligand designed to bind to a virus particle, to a polymeric material that forms a flexible nanomicelle by self-assembly. If antibodies are known to affect a viral disease, it is possible to construct a nanoviricide against it, and there can be a general expectation of some success, depending upon the ligand chosen. We can choose a ligand from any of a number of chemical classes, including small chemicals, peptides, or antibody fragments or even whole antibodies.
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.
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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 mimic the cognate cellular receptor of the virus, using rational design and molecular modeling strategies and our internal, accumulated expertise. This is the receptor to which a virus binds to gain entry into the human cell. Some viruses use more than one, different, receptors. 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’ 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.
Beyond Antibodies or “Post-Immunotherapeutic” Approach: A Nanoviricide in Its Design is a Nanomachine Built to Destroy Viruses
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. 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.
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. Such viral escape from antibodies has been witnessed in almost every viral epidemic, be it HIV/AIDS, Influenza pandemic of 2009, or the Ebola epidemic of 2014-15. In contrast, a nanoviricide would complete the job of making the virus particle non-infectious, without any help from the human immune system.
Broad-Spectrum Nanoviricide Drug Candidates
A nanoviricide is generally “broad-spectrum” in the sense that it would be effective against all viruses that use the same cellular receptor, binding to the same site on that cellular receptor.
Formulation is Inherent in the Design Aspect of a Nanoviricide
Since declaring our clinical candidate, namely NV-HHV-1formulated as a skin cream for topical treatment of shingles rash, further development of this drug towards scale-up, formulation, and cGMP-like manufacture has already been accomplished in a relatively rapid manner. 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.
We were able to rapidly develop the injectable/infusion formulation, an inhalable formulation for delivery directly into lungs, as well as an oral formulation of NV-CoV-2 and NV-CoV-2-R in a very short time because of the features of our nanomedicines technology.
We have previously manufactured multi-kilogram quantities of the final drug product for shingles cGLP Safety/Toxicology studies that are required for filing an IND.
We were able to rapidly develop the injectable/infusion formulation, an inhalable formulation for delivery directly into lungs, as well as an oral formulation of NV-CoV-2 and NV-CoV-2-R in a very short time because of the features of our nanomedicines technology.
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Uniform Polymer Nature Enables 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, and the very nature of polymer and particle making processes.
The nanoviricide technology has been designed from the ground up to enable consistent manufacture and control. Thus, the nanoviricide backbone is a homopolymer of a single repeating unit or monomer, and not a block copolymer. 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. The final nanoviricide solutions can be 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.
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.
Our BSL-2 Certified Virology Lab
We have a BSL-2 (Biological Safety Level 2) certification from the State of Connecticut for our Virology suite at the Shelton campus. This suite comprises three individual virology workrooms, enabling us to work on several different viruses and strains at the same time. This facility is designed only for cell culture studies on viruses, and no animal studies can be conducted at any of our own facilities.
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 have developed in-house cell culture screening capability for developing drug candidates against human Coronaviruses(h-CoV), VZV, HSV-1 and HSV-2, as well as influenzas and HIV, among others. This capability has substantially strengthened our drug development programs. 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.
cGMP Manufacturing Facility
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 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 believe we are in a position to advance our drug candidates into clinical trials, produce the pre-clinical “tox package” batches, and the clinical drug substance batches.
We believe that this facility will be capable of scaling to the quantity of product needed for initial market introduction and revenue generation from our first drug when approved. We have already performed production of kilogram-scale batches of drug substance and multi-kg scale batches of drug product at this facility successfully. We believe this scale is sufficient for clinical trials, and, depending upon final dosage level, this scale may be sufficient for initial market entry.
Our HerpicideTM Drug Development Programs
In addition to the rapid advancement in drug development against human coronaviruses in response to the current pandemic undertaken since January 2020, as described earlier, in previous years, we had focused our efforts primarily on the HerpeCide program. We are developing drugs against three indications in this 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
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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. Of these, the shingles indication program is in the process of clinical trial design and clinical site selection, which will be a part of the IND application. The IND filing has been delayed due to the potential impact of COVID-19 on upcoming human clinical trials, and we will complete this task to engage into clinical trials as soon as the pandemic wears down to the point that these clinical trials can be conducted without excessive impact on design, execution, and cost of the trials. We believe that the other two indications will advance to an IND stage in the very near future.
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 nine different drug development programs, attesting to the strength of our platform technology. We have chosen to focus strategically on the anti-coronavirus program at present, and we believe that we have candidates that are worthy of human clinical trials. We are in the process of moving them into IND-enabling safety/toxicology studies at this time. We believe that these IND-enabling studies should be conducted rapidly due to the expedited nature of the anti-coronavirus programs at both the CROs and at the US FDA. After this, we plan on taking the NV-HHV-1 skin cream clinical drug candidate for treatment of shingles rash into human clinical trials, and further develop additional HerpeCideTM program indications and drug candidates that are expected to result in a robust franchise with drug approvals against a number of different herpes virus indications.
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. Our drug development strategies may be influenced by considerations regarding the ability to engage into collaborations with other pharmaceutical companies. 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 the Company. The Company intends to develop its drugs on its 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 the Company will be successful in obtaining sufficient financing on terms acceptable to the Company.
We believe we are one of the very few small pharmaceutical drug innovators that possess their own cGMP or cGMP-capable manufacturing facility. With our Shelton, Connecticut campus and pilot-scale cGMP-capable manufacturing facility, we are in a position to advance our drug candidates into clinical trials, produce the pre-clinical “tox package” batches, and the clinical drug substance batches.
The Company’s cGMP-capable pilot-scale manufacturing facility in Connecticut may enable initial market entry for some of our products upon approval, allowing the Company to grow into a stand-alone Pharma company, in addition to a potential licensing strategy for success. The Company thus continues to minimize risk to investors by improving the potential for success.
We have continued to make significant progress in advancing our newly engaged anti-coronavirus drug program, and our HerpeCide program drug pipeline. Our drug development capabilities are substantially enhanced by the recent financings discussed earlier.
All of these studies are dependent on external collaborators providing available time slots for us. Thus, there can be delays in achieving the milestones that are beyond the Company’s control.
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The Human Coronavirus Treatment Drug Program
In a very short time, we have been able to develop drug candidates worthy of human clinical trials to treat SARS-CoV-2 infection that causes COVID-19 spectrum of diseases. We are currently advancing NV-CoV-2 and NV-CoV-2-R as the clinical drug candidates towards human clinical studies.
Our coronavirus drug treatment candidates were shown to be highly active against multiple coronaviruses in cell culture studies, and also highly active against a coronavirus that uses the same ACE2 cellular receptor as the SARS-CoV-2 (and SARS-CoV-1), namely, h-CoV-NL63, in animal studies. We are therefore confident that these candidates may result in a drug that can be used not only during the pandemic but also normally for the various circulating human coronavirus diseases.
Due to the severe nature of the pandemic, several companies are developing treatments and vaccines for COVID-19. Of these, only two at present are directly acting on the virus itself, namely remdesivir (Gilead), and paxlovid (Pfizer). Remdesivir is currently fully approved for use in hospitalized patients in the USA and other countries, and oral Paxlovid is approved for emergency use in USA and other countries, for COVID-19. Both of these have limited effects. They both act inside the cell by blocking the replication cycle of the virus. Several known antivirals (developed against other viruses) have been tested clinically both alone and in combinations, with limited effect if any. Several of such clinical trials are on-going.
Our nanoviricide that is designed to destroy the external virus so it does not go inside cells should be complimentary to the approach of blocking viral replication inside cells. Blocking both the external virus and the internal replication cycle at the same time could potentially result in a cure, if effective agents to do so can be developed.
Additionally, several antibodies are in development to neutralize the external virus. Antibodies are generally highly specific and the viruses are known to escape antibody treatments readily. Convalescent plasma (plasma from recovered patients that contains neutralizing antibodies) is being attempted as a treatment. The new Omicron lineage variants of SARS-CoV-2 are resistant to almost all available antibodies, and the corresponding EUA’s have been revoked. Further, several repurposed drugs that do not attack the virus but effect the host have entered clinical trials, and many of them have shown limited or little benefit. Dexamethasone, a corticosteroid, has been shown to help hospitalized patients with severe disease and reduce lethality, due to its effect on calming the human immune system attacking the lungs.
Several companies are advancing drug candidates for the management of COVID-19, and many have received EUA. Most of the drug candidates are designed to provide benefits that are not directly associated with attacking and controlling the virus. Merck and Ridgeback are developing an antiviral called molnupiravir, which may have oral use applicable to infected persons in very early stages of disease. Pfizer is developing several antivirals against coronaviruses. None of these 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-CoV-2-R is designed to do, to the best of our knowledge.
There continues to remain a need for an effective, broad-spectrum anti-coronavirus drug, in spite of all of these efforts. We believe the Company is uniquely positioned to respond to this need with its novel technology.
The Shingles Topical Treatment Drug Program
Our most advanced drug candidate is a nanoviricide against VZV (varicella-zoster virus), the virus that causes debilitating shingles rash in adults and chickenpox in children. Its first indication is expected to be as topical treatment of shingles rash. About 500,000 to 1 million episodes of herpes zoster (shingles) occur annually in the United States alone. In spite of the new ShingrixTM vaccine, the market size for a therapeutic for shingles is estimated to be in excess of $1 billion dollars according to two consulting firms, namely BioEnsemble, LLC and NanoTech Plus LLC, in reports prepared for the Company. There is currently no approved drug against shingles, PHN or chickenpox, indicating an unmet medical need.
Broad-Spectrum HerpeCideTM Drug Candidates Enable Additional Indications
The potential broad-spectrum nature of our anti-HSV drug candidates is expected to enable several anti-herpesviral indications. Thus, HSV-1 primarily affects skin and mucous membranes causing “cold sores”. HSV-2 primarily affects skin and mucous membranes
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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. Further, the treatment of herpes virus infections caused by acyclovir- and famciclovir- resistant mutants is currently an unmet medical need.
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 currently anticipated. We anticipate that many of these new drugs would be variations on our current drug candidates. It is therefore expected that the incremental cost of drug development for such additional indications could be substantially smaller than the cost of developing drugs against other viruses in our portfolio.
Progress in Identifying Clinical Lead Drug Candidates against the Four HerpeCide Program Indications
Previously, in August 2015, we obtained confirmatory animal studies data on our then current lead anti-herpes virus drug candidate from TransPharm, LLC. The data confirmed the results earlier obtained in Professor Ken Rosenthal’s Lab at the NorthEast Ohio Medical Center (NEOMED). In both studies, dermal topical treatment with our anti-HSV drug candidate led to 85~100% survival in mice lethally infected with the zosteriform, neurotropic, clinically derived and relevant strain, namely HSV-1 H129. In contrast, all of the untreated mice had severe clinical morbidity and none of the untreated mice survived. These studies established this drug candidate as a viable, effective potential drug. Professor Rosenthal has since retired from NEOMED and is now Professor of Biomedical Sciences at the College of Medicine, Roseman University of Health Sciences, Summerlin, NV.
We have developed additional variations of the ligand used in this older herpecide drug candidate using molecular modeling and rational design strategies. The new ligands appear to have substantially improved effectiveness and with a similar level of safety as did the prior tested ligand. We are now performing studies on chemical covalent conjugates of these ligands with different “nanomicelle” polymer backbones. We are performing a set of studies to identify the lead clinical candidates for the different herpes virus indications based on these new nanoviricides.
We have found in preclinical studies that the nanoviricides drug candidates developed against herpes HSV-1 and HSV-2 are also effective against the shingles virus, namely VZV, also called HHV-3 (human herpesvirus-3) in cell culture studies in house. These data were presented at the American Society of Virology 2017 annual meeting held in June 2017 at Madison, WI. Additional studies have continued to demonstrate strong effectiveness as the development progresses.
These results have enabled the identification and declaration of a clinical drug candidate in the HerpeCide program. We have taken this candidate, namely NV-HHV-101, into IND-enabling studies, towards human clinical trials. The first indication we intend for treatment with this drug is the topical treatment of shingles rash.
The Company’s drug candidates in HerpeCideTM program are being developed for direct topical application on the affected areas to control the infections. Direct topical application enables delivery of the highest possible concentrations of the active substance directly at the site of infection. This allows for maximal clinical effectiveness, while at the same time minimizing side effects that are seen with systemic therapy (such as oral drugs or injectables).
This dermal drug development workload is expected to be significantly shorter than the studies for ocular, injectable, or oral drugs. We anticipate filing an IND once the report of these IND-enabling studies is available.
Topical treatment of herpes virus infections is important because herpes viruses become latent in neuronal cells or in ganglia and cause periodic localized breakouts that appear as skin rashes and lesions. Systemic drug treatment results in side effects because of the high systemic drug concentrations that need to be achieved and the large drug quantities that must be administered. Since the virus remains mostly localized in the area of the rash and connected nerve apparatus, using high concentrations of drugs delivered in small quantities topically would allow maximizing the effectiveness while minimizing side effects.
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Since these nanoviricides are designed to attack the virus directly, we believe that human clinical studies should reflect the success of the preclinical studies.
HerpeCide Program Collaborations and Program Update
We have engaged in several collaborations to help us finalize clinical candidates and develop IND-enabling pre-clinical data in our various programs this year. Notably, we have continued collaborations with the CORL at the University of Wisconsin for HSV-1 and HSV-2, with focus on small animal models for ocular and dermal diseases.
In addition, we have a continuing relationship with BASi, a CRO for GLP and non-GLP safety/toxicology (“Tox Package”) studies. We have also engaged regulatory affairs consultants from time to time.
We also have a collaboration with the Campbell Lab at the University of Pittsburgh for in vitro cell culture models of various ocular viruses including many adenovirus and herpes virus strains, as well as animal models for ocular herpes keratitis (HK) and adenoviral epidemic keratoconjunctivitis (EKC).
In addition, we have continued our agreement with SUNY Upstate Medical University for the testing of the Company’s nanoviricides® drug candidates against VZV, i.e. the shingles virus. This research is being performed in the laboratory of Dr. Jennifer Moffat.
Initially, Dr. Moffat conducted cell culture studies i.e. in vitro studies. Upon finding that the nanoviricides drug candidates were effective against VZV in cell cultures, Dr. Moffat advanced the studies to the ex vivo human skin-patch organ culture (SOC) model studies stage, wherein our drug candidates are being evaluated against VZV infection of human skin patches.
Dr. Moffat has extensive experience in VZV infection and antiviral agent discovery. The goal of these studies is to help select a clinical drug development candidate for toxicology and safety evaluation intended for clinical trials for the treatment of shingles in humans.
VZV is restricted to human tissue and only infects and replicates in human tissue. The ex vivo studies are continuing to evaluate the efficacy of the Company’s nanoviricides to inhibit VZV in human skin organ cultures. 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 Institute 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.
The Company has established a direct relationship with the Moffat lab, without NIH as an intermediary.
In addition, the Company continues to perform extensive antiviral cell culture studies against VZV, HSV-1 and HSV-2 using multiple cell lines and multiple strains of the viruses, in our BSL-2+ anti-viral cell culture laboratory in Shelton, CT.
Shingles and Associated Pain, Postherpetic 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.
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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.
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. It 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)
The Company is 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 followed by oral acyclovir derivatives
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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.
cGMP Manufacture
We have already manufactured our drug candidate, NV-HHV-101, in a cGMP-compliant manner at this facility for the 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 also manufactured our developmental drug candidates for the treatment of human coronaviruses at approximately 0.5kg scale already in our scale-up manufacturing facility and in our cGMP-compliant manufacturing facility.
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.
DengueCideTM
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.
HIVCideTM
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. The Company believes 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. The Company believes 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, the Company believes that this therapy would also minimize the chances of HIV transmission. The Company is currently optimizing the anti-HIV drug candidates. These drug candidates are effective against both the R5 and X4 subtypes of HIV-1 in cell cultures. The Company believes 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. 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.
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
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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: Ebola, Rabies and others
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.
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.