U.S. Markets closed

NNVC: NanoViricides: Developing Antiviral Medication Using Nanotechnology



NYSE:NNVC

Introduction
NanoViricides Inc. (NNVC) is an early stage nano-pharmaceutical company that was first listed in 2005 and became a reporting company the following year. The company is involved in discovering and developing therapeutics for treating viral infections with drug candidates in the preclinical stage . NanoViricides is focused on the development of a potential candidate for the treatment of shingles (herpes zoster), which is caused by the reactivation of varicella zoster virus (VZV). The company also intends to further develop this lead candidate for the prevention of post-herpetic neuralgia (PHN), a debilitating neuropathic pain syndrome that is the most common complication of shingles and occurs long after the blisters disappear. An IND is expected to be filed for this treatment in mid-2019. The company is developing variations of the drug for several other diseases caused by herpes viruses, including oral and genital herpes, external eye viral infections and others. NanoViricides is involved in other research programs for Influenza, HIV, Rabies, Ebola, and Marburg viruses.

Indication: Shingles rash
VZV belongs to the family of herpes viruses and causes chickenpox in children. Initial infection by VZV establishes the virus in the sensory nerve ganglia. In immunocompromised patients, the virus is reactivated and causes shingles. Since the virus has invaded the nervous system, the symptoms of shingles are more severe than those of chickenpox and its symptoms are characterized by blisters that burn, are itchy and painful. The rash develops over the course of about one week and clears in two to three weeks’ timeframe. The long-lasting pain from the rash, called PHN, is the most common complication of shingles and can last for months or years, long after the rash has cleared. Shingles and PHN occur most commonly in older adults greater than sixty years of age.

Currently available treatment options…
As in any anti-viral therapy, early intervention and treatment can reduce or prevent severe pain and help clear the blisters. Temporary relief from pain and quick drying of blisters can be achieved by placing a cool, damp washcloth on the blisters and keeping the area clean. This treatment also can help avoid a secondary bacterial infection. The goal in treating viral infections such as shingles is to reduce viremia.

Vaccination against shingles is recommended for persons who have already experienced primary VZV infection (chickenpox). The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommends zoster vaccine for all persons aged 60 years and above who have no contraindications. Currently, there are two vaccines available in the market: the Shingrix® vaccine by GlaxoSmithKline and the Zostavax® vaccine by Merck.

Shingrix was approved by the FDA in 2017 for individuals over 50 years of age and contains VZV glycoprotein E and the AS01B adjuvant system. It is recommended to administer two doses (0.5 mL each) annually with a cost of roughly $280 per 2-dose course.

The FDA based their approval on data from two pivotal placebo-controlled, observer-blinded trials published in the New England Journal of Medicine in 2015 and 2016. In the 2015 study, researchers administered Shingrix vaccine to 7,344 participants and a placebo vaccine to 7,415 subjects, with both groups having 50 years of age or older individuals. Shingrix was 97% effective in reducing shingles as compared to the placebo group. In the 2016 study, researchers administered the Shingrix vaccine to subjects aged 70 and older (6,541) and a placebo vaccine to 6,622 subjects. They found that Shingrix was 85% effective for reducing shingles. For those in their 80s, who are most at risk of developing singles related complications, the vaccine was found to be 91% effective.

The second vaccine is Merck’s Zostavax™ which was approved by the FDA in 2005. Zostavax is a single dose, lyophilized, live, attenuated VZV (Oka/Merck) vaccine indicated for individuals greater than 50 years of age for the prevention of shingles and shingles-related PHN1. It is priced at $213 for a single dose.

The Shingles Prevention Study (SPS) and ZOSTAVAX Efficacy and Safety Trial (ZEST) were the two pivotal Phase III studies that demonstrated the efficacy of Zostavax against shingles. Zostavax had been found to be just over 51% effective for people over 50, approximately 38% effective in those aged 70 and older and 18% effective in those aged 80 and older. The vaccine’s efficacy lasted up to eight years post vaccination and decreased the incidence of shingles over time. Several post-marketing observational studies were conducted that confirmed the effectiveness of the vaccine. The results were consistent with clinical trial data.

Other antiviral prescriptions include acyclovir, valacyclovir, and famciclovir that help in reducing the severity of the attacks. Other treatments including anti-inflammatory corticosteroids such as prednisone are considered when facial nerves are affected.

Shortcomings of Current Therapy
Treatment with antiviral therapies are required to be initiated within the first 72 hours of onset of shingles rash for maximum benefits. Clinical trials have demonstrated that antiviral therapies must be taken as multiple doses per day to minimize the intensity of pain and duration of healing. While Shingrix reduced PHN by 90%, Zostavax had shown just a 67% reduction in adults aged 60 or older, according to the SPS study2. For both acyclovir and valacyclovir, dosage alterations are required for patients with significant renal dysfunction3. Further, antiviral therapies are not effective in PHN and require patients to resort to analgesics to alleviate pain temporarily.

NNVC’s platform technology
NanoViricides, Inc. is developing a drug candidate to treat shingles and also potentially minimize the related PHN. The company is developing drug candidates that are designed to identify, engulf and destroy the virus particles without harming the healthy cells. Additionally, the company has demonstrated Accurate-Drug-In-Field™ (ADIF) technology capabilities where a drug candidate can be developed in the field using stockpiled nanomicelles to specifically target a virus. Initial drug doses can be developed in timeframes as short as three weeks. NanoViricide drug candidates can be formulated for topical, parenteral or oral routes of administration.

The following sections describe the drug candidate’s mechanism of action and discuss the results from the early in vitro testing using human skin infection model that demonstrated inhibitory behavior against VZV.


View Exhibit I - A NanoViricide (source:www.nanoviricides.com)

The NanoViricide technology is being developed to render a virus completely incapable of invading the host cell. The company describes a nanoviricide as “a polymeric nano-micelle made from polyethylene glycol and alkyl pendants with virus-specific targeting ligands attached”.  Virus-specific ligands are attached covalently to the basic structure of the polymer to mimic the binding site on the cell surface receptors. The company characterizes their platform technology to attack viruses using a war-like analogy called “Bind-Encapsulate-Destroy”. A nanoviricide is designed to seek a specific virus type. The technology is designed to attack only the virus outside cells, and potentially also the virus infected cells that display viral coat proteins on their surface, thus sparing other normal cells.

NanoViricide – Mechanism of Action


View Exhibit II - Role of a NanoViricide (source:www.nanoviricides.com)

Infection commences when the virus particle binds to a receptor on the host cell, fuses with the cell membrane, is internalized, and subsequently releases its capsid/genome into the cell, where the viral genome is then copied to generate more viral proteins. The newly formed viral proteins and genome assemble and eventually exit as fully formed viral particles from the cell. These particles can then circulate and infect new cells (“reinfection”). Antiviral antibodies developed as drugs either bind to the cell surface receptor and inactivate it (anti-receptor antibodies) or bind to the virus and inactivate it (anti-virus antibodies). Additionally, currently available antiviral therapies target certain crucial steps in a virus’ life cycle to inhibit its activity. Certain molecules block the receptor on the host cell surface while others target the proteins on the capsid surface responsible for the uncoating (the genome is released from the capsid). Some even inhibit the activity of neuraminidase, an enzyme on the viral surface that is required for the influenza virus particle to exit the cell. Most drugs often only block a single enzyme or step in the virus’ replicative process, which does not yield complete control of the viral infection. More effective control (than with single agent) requires the patient to resort to combination therapies where multiple steps in the virus’ life cycle are targeted. Nevertheless, these approaches are not completely efficient in blocking the virus’ ability to attack, exhibit off-target side effects and result in toxicities from their interaction with the host.

A nanoviricide micelle contains multiple polymer chains. Each polymer chain can carry tens of virus binding ligands. The micelle itself may display hundreds of virus binding ligands on its tiny surface. Although its mechanism of action is similar to that of an antibody in that they both identify the virus, a nanoviricide has the ability to grasp and encapsulate the virus particle with a multi-dentate attack. This ability makes it self-sufficient in its capabilities to thwart the mechanism of virus infection and reinfection without the support of the immune system. Not only does it block the binding sites, but has “molecular chisels” that can dismantle the virus particle and completely disintegrate it. The nanoviricide technology has the ability to hold within the micelle active pharmaceutical ingredients (APIs) that can kill or disrupt virus production inside infected cells, allowing for complete control of the viral lifecycle. Nanovircides are biodegradable and are excreted through the body’s natural mechanisms of elimination. A nanoviricide can be developed as a topical gel/eye drops, or an oral formulation or administered as an injection or infusion to treat VZV, HSV-1, HSV-2, influenza, HIV, Ebola, Rabies and other viruses.

NNVC’s pipeline
NanoViricides has identified drug candidates for other indications such as cold sores, genital ulcers, herpes keratitis and acute retinal necrosis in the HerpeCide program. In addition, NanoViricides has drug candidates in development against different kinds of flu including bird flu, HIV, Dengue, Ebola and Marburg viruses. The company has performed preliminary safety studies of injectable FluCide™ drug candidate in both mouse and rat models.


View Exhibit III - NanoViricides’ Pipeline (source:www.nanoviricides.com)

Clinical development plan for VZV:
The company’s lead clinical drug candidates for VZV were further evaluated in the following studies.

Study 1: In late 2016, NanoViricides entered into an agreement with SUNY Upstate Medical University to test its novel drug candidates against VZV. The research conducted by Dr. Jennifer Moffat included in vitro and ex vivo studies. Dr. Moffat has extensive experience in VZV infection and antiviral agent discovery.

Evaluation in cell cultures:


View Exhibit IV - NV-118 versus VZV Yield (source:www.nanoviricides.com)

The study was conducted using retinal cell lines (ARPE-19). VZV was pre-incubated with the compounds or vehicle for an hour, then added to ARPE-19 cells and cultured for six days. VZV-infected cells were detected by immunocytochemistry and measured by ELISA. The graph above shows NV-118 demonstrated close to five times superiority in inhibiting VZV at the highest drug dose as compared to acyclovir. Additional studies with another cell line, namely BS-C-1 produced comparable results. No cytotoxicity was observed at any of the doses tested.

Evaluation in human skin organ culture:

Tiny pieces of human skin are infected with VZV and then treated with a drug to determine if the drug is effective in reducing viral yield.

The human skin organ culture (SOC) is composed of all the major cell types including dermis, epidermis, hair follicles and sebaceous glands that are correctly positioned and differentiated. There is growing evidence that hair follicles are the site of VZV transfer to the skin from infected T cells. An ex vivo human skin patch model involving VZV infection is considered to be a close representation of natural course of shingles4. The panel of the drug candidates evaluated in cell cultures previously were evaluated in human skin organ culture compared to cidofovir as a positive control.


View Exhibit V - Human skin patch (ex vivo study): Left -VZV lesion in the epidermis with multinucleated giant cells and breach of the basal cell layer. Right - Normal Dermis and Epidermis. No viral infiltration or lesions seen (source:www.nanoviricides.com)

The drug candidate was applied to the skin five minutes after VZV inoculation.  The tissue was stained with hematoxylin and eosin (HE) for contrast. In Exhibit V, the infected skin shows VZV lesion in the epidermis (circled), multinucleated giant cells (orange arrow), breach of the basal cell layer (black arrow) and the vesicle forming in lesion in between the arrows (*). In the patch treated with NV-118, no VZV lesions were observed. The skin appeared to have normal skin layers and hair follicles were abundant. The black arrow shows needle track where VZV was inoculated.


View Exhibit VI - Bioluminescence of cell treated with NanoViricide and Cidofovir (source:www.nanoviricides.com)


View Exhibit VII - NanoViricide versus VZV yield (source:www.nanoviricides.com)

The infected skin tissue was analyzed using bioluminescence imaging to observe the kinetics of VZV replication. Overall, results revealed that NV-118 inhibited VZV infection, replication and spread in human skin cultures. This was shown by direct assay of viral infection of human skin. In addition, normal skin architecture was found to be preserved in microscopic tissue analysis of VZV-infected, nanoviricide-treated human skin, indicating excellent preliminary tolerability and safety.

The data suggest that select NanoViricides’ drug candidates may have direct viricidal activity based on their antiviral effects within the first 24 hours after viral infection. These findings corroborate the previously reported findings of inhibition of VZV infection of human cells in culture.

A topical skin cream containing 2% cidofovir is clinically used in very severe cases of shingles. The antiviral effect of the drug candidates was found to be equivalent to the effect of a topical formulation of 1% cidofovir applied directly onto the skin patch. The cytotoxicity of cidofovir is known to cause ulceration/scarring of the skin.

Study 2 (non-GLP safety and toxicology): AR Biosystems of Beverly, MA conducted this study in April 2018 to evaluate the effect of drug candidates on skin and organs as well as to assess its potential effect on organs in uninfected animals. Nanoviricide drug candidates were applied as skin cream, and were also injected subcutaneously and intravenously in different groups of animals. Full blood pathology analysis, gross histology of various organs, and microscopic histology were performed. No deleterious effects were found. There were no adverse effects on the skin at the treatment sites, and no overall observable systemic effects or direct effects on liver and kidney function. The results were consistent with the strong safety observed in the human skin patch model.

Study 3 (Direct Pain Effect Study): Following reactivation of VZV, PHN develops and persists after the disappearance of skin lesions. This pain is often prolonged, increases in incidence with age and responds poorly to classical analgesics. AR Biosystems of Beverly, MA conducted a study in 2018 using a standard rat model of neuropathic pain. The rats were not infected with VZV. The results from the investigation demonstrated that the anti-VZV compounds significantly reduced abnormal pain sensations in the animals. The results suggest that the nanoviricide compound could be instrumental in resolving PHN without resorting to aggressive pain medications such as gabapentin or morphine derivatives.

How do NanoViricides’ candidates compare to currently available therapies?
As compared to current standard of care, NanoViricides’ drug candidate for shingles is being developed as a topical treatment. A localized treatment at the site of infection is expected to be more efficient than systemic drug that is administered either orally or intravenously. The effective concentration of a systemically delivered drug at the site of rash would generally be suboptimal. Initial studies have shown that NanoViricides’ two active candidates inhibited VZV activity up to five fold better than the current standard of care (acyclovir) in cell cultures. In human skin organ culture studies, the NanoViricide drug candidates were equivalent to a topical formulation of 1% cidofovir applied directly onto the skin patch. Clinically, 2% cidofovir is prescribed for patients with severe symptoms. However, cidofovir is cytotoxic, causes ulceration at site, and has dose-limiting renal toxicity. Although the wound heals naturally it results in scarring of the skin. NanoViricides’ drug candidates did not cause ulcerations in the skin patch model. The components of a nanoviricide are biodegradable which contributes towards its safety profile. In contrast, acyclovir is not readily biodegradable which warrants a lower dosage in elderly patients or those with impaired renal function.

Antiviral Market:
Anyone who has had chickenpox, is a potential candidate for shingles. As per CDC statistics, one-third of Americans will get shingles in their lifetime and 15% of those will experience PHN and there are about 1 million new cases annually. VZV complications can cause hospitalization in about 1-4% of patients5. A study was conducted in 20096 to assess the healthcare cost associated with shingles. The annual cost of treating shingles in patients 50 years and older immunocompetent adults was estimated at roughly $1 billion. Prescription antivirals for shingles include generic version of acyclovir, valacyclovir and flamciclovir. A course of antiviral medications is usually prescribed for 7 to 10 days.

Financial Position and Capital Structure
As of June 30, 2018, the company maintained cash and cash equivalents of about $7 million and an accumulated deficit of more than $80 million. The company does not have any long term debt. The current cash burn rate is approximately $8 million annually. Clinical trials for NanoViricides, if and when they commence, will require substantial capital. However, this is not a near-term concern as the trials are expected to begin sometime in the second half of 2019. Management has guided that the current cash position will be sufficient to fund operations until this time. Nevertheless, management will need to raise additional financing prior to the start of Phase I trial.

Company strategy
The company has commissioned their first large-scale batch synthesis program for manufacturing sufficient quantities (~750g) of a drug candidate for the ensuing IND-enabling safety and toxicology studies. NanoViricides is planning a pre-IND Meeting with the FDA which, upon approval, will allow the company to begin manufacturing clinical trial batches for Phase I and Phase II clinical trials. The company will be able to manufacture the required estimated quantity in just a few production batches in their cGMP-capable production facility in Shelton, CT.

NanoViricides intends to advance the same drug candidates or closely related variants for the treatment of "cold sores" (orolabial herpes, primarily caused by HSV-1); genital ulcers caused by HSV-2, external eye infections caused primarily by HSV-1 (herpes keratitis), and internal ocular herpesvirus infections that are the probable cause for acute retinal necrosis. The studies are expected to be conducted by Professor Curtis Brandt, Collaborative Ophthalmic Research Laboratories (CORL), at the University of Wisconsin. Dr. Brandt is Professor in the Departments of Ophthalmology and Visual Sciences, Medical Microbiology and Immunology, and Director of the Vision Research Core at the University of Wisconsin. 

NanoViricides is open for partnership opportunities as the drug candidates mature to late-stage clinical candidates. The company is currently at an inflection point, moving from a preclinical to a clinical stage company.

Summary
The incidence of shingles is about one million new cases every year and it continues to rise. The number of cases is driven by an aging population and immunocompromised adults. The increase in incidence of viral infections highlights an unmet need for novel therapies such as NanoViricides’ that could potentially offer advantages to traditional therapies. NanoViricides has candidates for shingles treatment, which addresses a market of over one billion dollars annually.

The company has demonstrated activity in two drug candidates (NV-118 and NV-173), and has continued to further optimize them. The optimized candidate will be advanced into IND-enabling activities. The candidates have demonstrated significant therapeutic potential in preclinical models for the treatment of shingles and additional studies are being planned to determine therapeutic potential for the treatment of PHN. The firm has a number of potential product candidates in the pipeline targeting antiviral therapies for a variety of influenza and HIV viruses that may address a very large market. Currently, the company is developing a clinical plan for their candidate and anticipates initiating a Phase I clinical trial in shingles patients within the next year.

NanoViricides’ pipeline is focused on developing treatments for viral infections. The company has built a formidable IP portfolio which covers the basic technology into late 2020s. Additional drug-specific patents are expected to be filed as the company enters clinical studies, and these would be expected to provide protection beyond 2038. The company has a lean and agile management team with significant expertise in the early development of antiviral therapies which can create material value for investors if sold or commercialized.

SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR. 

DISCLOSURE: Zacks SCR has received compensation from the issuer directly or from an investor relations consulting firm, engaged by the issuer, for providing research coverage for a period of no less than one year. Research articles, as seen here, are part of the service Zacks provides and Zacks receives quarterly payments totaling a maximum fee of $30,000 annually for these services. Full Disclaimer HERE.

________________________________________________________

1 FDA, Proposed Prescribing Information
2 Sanford, M. & Keating, G.M. Drugs Aging (2010) 27: 159.
3 Gnann Jr. JW. Antiviral therapy of varicella-zoster virus infections. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 65.
4 Taylor SL, Moffat JF. Replication of varicella-zoster virus in human skin organ culture. J Virol. 2005;79(17):11501-6.
5 Shingles (Herpes Zoster), Clinical Overview
6 Yawn BP, Itzler RF, Wollan PC, Pellissier JM, Sy LS, Saddier P. Health care utilization and cost burden of herpes zoster in a community population. Mayo Clin Proc. 2009;84(9):787-94.