We were in DC last week on Wednesday, June 22nd for the 2011 Nano Caucus http://www.vincentcaprio.org/senate-convenes-nano-caucus-briefing-wednesday-june-22nd.
We had the honor of Senator Ron Wyden, D-OR kicking off the Nano Caucus. Then, we had presentations from:
Sally Tinkle, Ph.D., Acting Director, National Nanotechnology Coordination Office, Nanoscale Science, Engineering, and Technology Subcommittee, Committee on Technology National Science and Technology Council
Jim Hussey, Chief Executive Officer, Nanoink, Inc.
Travis Earles, Ph.D., Advanced Materials and Nanotechnology Initiatives, Lockheed Martin Corporation, and former Assistant Director of Nanotechnology, White House Office of Science and Technology Policy
Frank A. Ignazzitto, Vice President, Government Business, QD Vision, Inc.
I would like to thank Lynn Bergeson, Partner, Bergeson & Campbell and Chair of the NanoBusiness Commercialization Association EHS Committee for helping to organize the event.
In this month’s interview, we talk to Anil R. Diwan, Ph.D., President and Chairman of NanoViricides. Dr. Diwan has extensive product discovery and development experience while raising financing from collaborations, SBIR grants, and other revenues. He has extensive experience in a number of bio-pharmaceutical, biosciences, and biomedical fields and technologies that leads to his novel, integrative approach in solving problems with low costs, high innovation, and world-leading feature sets. Dr. Diwan is the inventor, developer, and principal investor of TheraCour® and NanoViricides® technologies. The nanomaterials based on these technologies form the basis of Nanoviricides® drugs.
Anil holds a US patent on his older polymeric micelle technologies, with his colleagues at University of Massachusetts. He has continued to work further in the field, to develop nanomaterials that are capable of multi-specific multi-targeting of viruses, and at the same time capable of encapsulating active pharmaceutical ingredients (API) in industry-leading payload capacities. This new work has resulted in nanomaterials called “TheraCour”® (therapeutic courier), and the underlying technology is the subject of several new patent applications. Multi-targeting means the binding of nanoviricide polymer chain to the virus particle like a Velcro tape with multiple points of contact, and Multi-specificity enables highly selective binding to a specific type of virus. The encapsulated API can get injected into the virus particle. Anil holds a Ph.D. from Rice University, TX, a B.Tech. from Indian Institute of Technology, Bombay (IIT-B), India, and has consistently held high scholastic ranks and honors. Anil has over 18 years of Bio-Pharmaceuticals R&D experience with 12 years as an entrepreneur.
In our interview, we discuss NanoViricides technology and its applications in medicine. We hope you enjoy the interview with Anil Diwan.
– Steve Waite
Director of Research and Strategy, The NanoBusiness Commercialization Association
DISCLAIMER
All of the information and opinions contained in this document, including the potential and future of NanoViricides technologies and Products, are the personal views of Anil R. Diwan, Ph.D., and are not official statements by NanoViricides, Inc. Information presented herein contains “forward looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21B of the Securities Exchange Act of 1934. Any statements that express or involve discussions with respect to predictions, expectations, beliefs, plans, projections, objectives, goals, assumptions or future events or performance are not statements of historical fact and may be “forward looking statements.” Forward looking statements are based on expectations, estimates and projections at the time the statements are made that involve a number of risks and uncertainties which could cause actual results or events to differ materially from those presently anticipated. Forward looking statements in this action may be identified through the use of words such as “projects,” “foresee,” “expects,” “will,” “anticipates,” “estimates,” “believes,” “understands,” or that by statements indicating certain actions “may,” “could,” or “might” occur.
SW: Thanks for taking the time to speak with us, Anil. We enjoyed your presentation at the NanoBusiness conference in New York City in April. Give us a little history about NanoViricides and why you launched the company.
AD: I became interested in the field of gene therapy and drug delivery in the late 80’s. The delivery problems in gene therapy, oligonucleotide and antisense therapy were quite complex. So I set my goals to less difficult issues. It was very clear to me that the then existing anticancer therapies were just cell killing chemicals, and that they kill any cell that they can, not cancer cells specifically. This is like strafing with a machine gun onto a crowd when you only want to kill one terrorist. That is unacceptable! So I set out to develop novel technologies which would be able to take such drugs, keep them away from normal cells, and put them into cancer cells, where they would destroy the cancer cell.
SW: NanoViricides’ products are based on TheraCour technology that has been in development since the early 1990s. What is special about the TheraCour® technology and Nanoviricides?
AD: Imagine a truck that you can load up with bombs, and then program it to find a particular enemy target and let it roam for thousands of miles until it hits and explodes onto the target. That is what the TheraCour technology enables. Very few other technologies have such capability. When it comes to the nitty-gritty of drug development, there are a number of additional features that are built into the platform technology – you get them for free – such as biocompatibility and biodegradability. If a foreign substance is put into the human body, especially a substance in the nano- or micro-scale size range, the immune system recognizes it as foreign and mounts an attack on it to clear it out of the system. Nanoviricides are highly biocompatible materials, which means that they are designed so that the immune system should not mount an attack against them. So the possibility of adverse events becomes very limited. In addition, a potent drug such as this should eliminate itself after it has done its job. We accomplish this by making nanoviricides biodegradable in the body itself. In other words, they are designed to work for a length of time and then become food to the body, or get excreted otherwise.
SW: What are some of the viruses you are targeting with your NanoViricides® technology?
AD: Influenza binds to human cells through a relatively simple receptor called sialic acid. So we started working on influenza first. This program is now developed to the point that we have clinical-quality candidates and we are developing additional datatsets for US FDA pre-IND application filing. You may recall the great bird flu scare in 2005-2006. We could not get access to the bird flu H5N1 virus so we went to VietNam and conducted studies there to develop nanoviricide drug candidates that were highly effective against different H5N1 types in cell-based assays. In the process, we also began working on anti-Rabies nanoviricides, and achieved preliminary successes in animal studies. We then started working with USAMRIID to develop nanoviricides against the killer viruses of the Ebola and Marburg families. We received tremendous success in our very first animal studies with nanoviricides against HIV-I. We also developed nanoviricides against adenoviral EKC (epidemic keratoconunctivitis’ a severe red eye disease), Dengue, and recently against oral and genital Herpes viruses (HSV-1, and HSV-2). Nanoviricides is a broad technology platform and once we develop a ligand for a virus family, we can construct nanoviricides to attack that virus family.
In summary, we now have several commercially important drug programs that include Influenza, HIV, HSV, and viral diseases of the external eye. We also have some neglected tropical diseases (NTD) programs that include Dengue and Rabies. In addition, we have a BioDefense program that includes Ebola/Marburg, and a novel technology that we call “ADIF™” – for “accurate drug in field”.
The number of targets is only limited by availability of resources. There are a large number of viral diseases that do not have good medicines or vaccines available against them. And Nature keeps throwing new challenges at us constantly. Like the SARS outbreak, and the recent H1N1/2009 “swine flu” pandemic.
SW: Tell us more about NanoViricides’ flu product. Why do you think it will be more effective than the other products available on the market today?
AD: When we conducted our very first anti-Influenza animal study, we found that the nanoviricide candidates were substantially superior to oseltamivir (Tamiflu®, Roche). By some metrics, the best was 8X more effective. Of course, the efficacy of Tamiflu itself is very limited. In particular, it is not strong enough to be useful against severe killer influenzas like the H5N1 bird flu or other highly pathogenic (avian) influenzas (HPAI). We had some successes against H5N1 already. So we began improving our drug candidates with classical methods called “SAR” or “structure-activity-relationship” optimizations. We call this anti-influenza drug program “FluCide.™” The best FluCide drug candidate last year caused about 30-fold reduction in lung viral load, which was about 15-fold greater than Tamiflu, in mice. We took one more run at SAR this year, when we were getting the processes ready for manufacture. Three of these newly optimized FluCide drug candidates achieved 1,000-fold or greater reduction in lung viral load, as opposed to less than 2-fold on Tamiflu. Two of the nanoviricide-treated groups survived the full 21 day study, but died a day later. Another one survived 20 days. In contrast, Tamiflu-treated animals survived only 8 days while untreated animals died in just 5 days. If we look at the viral load, these optimized FluCide candidates are about 500X (50,000%) superior to Tamiflu. That is truly astounding.
SW: How is NanoViricides approaching combating the HIV/AIDS virus and what role can nanotechnology play in treating HIV/AIDS patients?
AD: Two questions. Let me tell you what we are doing first. The HIV-AIDS virus enters human cells using two different receptor pairs, either CD4 and CCR5, or CD4 and CXCR4, or both pairs. It also uses some other features. The CD4 binding site is conserved and well studied. The CCR5 and CXCR4 binding of HIV has also been studied in some detail. So we have plenty of information to develop HIV-binding ligands to construct anti-HIV nanoviricides. We are focusing on mimicking the CD4 site where HIV binds. If we are successful, we believe we will be able to create nanoviricides which do not lose much effectiveness when the virus mutates. That is the holy grail of HIV therapy. We already have significant initial success in animal studies. We found that some of the nanoviricide drug candidates gave equal effectiveness against HIV-1 infection as the three-drug standard therapy called HAART (highly active antiretroviral therapy). HAART is highly effective, but quite noxious. It causes vomiting, lack of appetite, cachexia (weight loss), and lipid redistribution (hunchback effect). We did not see any signs of potential adverse effects in animals treated with HIVCide candidates, unlike in the HAART-treated mice. HIV animal studies are extremely expensive. This program has been moving very slowly. But we believe we will continue to build on our success, as we have done with Influenza.
Now about the role of nanotechnology in HIV-AIDS. Nanotechnology can provide research tools like more sensitive tests and parallel testing which can speed up progress. We believe that the nanoviricides technology may already have enabled “Functional Cure” of HIV/AIDS, if our animal study results hold in humans. The next challenge is a true or complete cure. This would require eliminating the reservoirs of HIV, in addition to the functional cure. I think nanotechnology holds a great promise here. Personally, I don’t believe there is a solution to this problem without using nanotechnology.
SW: NanoViricides is working on treatment for Rabies. What is novel about your approach to treating Rabies?
AD: Rabies is a uniformly fatal infection. There are very few patients who have survived, and they are all severely disabled. A single rabies virus particle is sufficient to cause death in humans. The available antibody-based treatments have shown protection in animal studies. It is not known if these treatments are therapeutic in humans.
As I said earlier, nanoviricides are far beyond antibody therapies in terms of their design. If an antibody therapy exists, then we can develop a nanoviricide therapy. Animal studies for rabies are a contrived model at best. However, the very first anti-rabies nanoviricides we developed demonstrated a therapeutic effect (i.e. treatment after infection) in mice. In one experiment, 30% of the animals infected with lethal dose of rabies virus survived due to nanoviricide treatment.
Rabies therapy development has many challenges. It is not an important disease in the developed world, so there is very limited funding, if any. There are also many scientific challenges. Rabies virus, which is usually introduced by an animal bite, such as an infected bat, dog, raccoon etc., quickly travels to the brain through nerves. There it colonizes inside the brain cells. The time from a bite to rabies disease symptoms in humans can vary from a few days to decades. When the patient presents with symptoms it may already be too late. There is a limited commercial market for this treatment. That, combined with the scientific challenges, has made us put it on the back burner. Nevertheless, we keep working on it in the background.
SW: You are also developing treatments for Dengue. Tell us about those and what makes them unique.
AD: Dengue virus challenges are very unique. It has developed a unique mechanism to defeat the human immune system. The most severe manifestation of it is called ADE (for “Antibody-Dependent-Enhancement”). There are four types of dengue viruses (I to IV), with many subtypes and strains. When a person gets infected with any one of these four types, say type X, the person will usually recover. It feels like a flu that lasts as much as three weeks and causes such pain it is called “breakbone fever.” When the same person gets infected a few years later with a different dengue virus type, say Y, this is called a secondary infection. The immune system produces antibodies against type X. However, these antibodies are not good at stopping Y. The type Y virus binds to the antibodies, the virus-bearing antibodies then bind to the Fc-receptor positive cells of the immune system, and the virus thus hitches a ride into these cells and causes an even more dramatic infection than if there were no antibodies. This leads to severe dengue disease, hemorrhagic fever, and eventually death. WHO estimates that the fatality rates from the severe dengue cases may be as high as 20%.
People in most of the tropical world have already been exposed to primary dengue. WHO estimates that several billion humans, or almost 40% of the world’s population, are at risk of secondary dengue. There can be a high fatality rate epidemic if a dengue virus mutates to become more vicious.
Thus it is necessary to develop a drug against dengue that attacks all four major types and all the subtypes and strains and possible mutants. Vaccines have been developed but did not show promising results in their earlier incarnations. This may be because of the ADE effect. Currently a tetravalent vaccine is in clinical trials and appears to show protection. Nevertheless such vaccines are not expected to protect 100% of the people that take them, but possibly only about 30-50%. Besides, vaccines usually fail with the emergence of mutated viruses. And when a person develops a disease, we still need to have a treatment.
We started working on Dengue ca 2007-2008. The first cell culture and animal studies were conducted in Professor Eva Harris’ lab at UC Berkeley just about a year ago. We found that one of the anti-dengue nanoviricide candidates demonstrated as much as 50% survival in mice. This model was an ADE-emulating model. To date, we are not aware of any other therapeutics developments that are so successful in the ADE mouse model of dengue. We presented these results at the International Dengue conference in Puerto Rico that was organized by the CDC and NIH among others, in February, 2011. It appears that at present we may be the only company with a viable drug candidate against dengue. So we are very excited about this. We are now working on improvements to make the drugs even more effective.
SW: You are also developing treatments for Herpes. Tell us about those and what makes them unique.
AD: Herpes viruses cause lifelong infections in humans. Oral herpes ulcers are caused mostly by HSV-1, and genital herpes is caused mostly by HSV-2. These viruses share similar features by which they bind to human cells. We developed our first anti-HSV-1 candidates about two years ago, for herpes infections of the eye. These infections lead to herpes keratitis. We tested the same candidates against a different HSV-1 recently. This work was done in Professor Ken Rosenthal’s lab at NEOUCOM, now called NEOMED (NorthEast Ohio Medical University). In all of these studies we have found substantial activity in cell cultures. We are now working on an anti-herpes nanoviricide skin cream. This will be tested in an animal study at NEOMED.
The best known drugs against herpes are acyclovir and its modifications. These are specific to HSV because a viral gene product called thymidylate kinase (“TK”) converts the drug to an active form. So these drugs are ineffective or weakly effective against strains of HSV lacking TK (i.e. TK- strains), which are growing in prevalence. The nanoviricides that we are developing interfere in a very different fashion than acyclovir. They are expected to attack the virus by posing as decoys of a human cell. Thus all HSV, whether TK- or TK+, are expected to be susceptible to the nanoviricides.
We are also developing an ophthalmic solution (eye drops) to combat viral infections of the eye. About 50% of eye infections are viral. Most of these are caused by adenoviruses. The rest are caused mostly by herpes viruses. We had already obtained successful results in animal model of adenoviral EKC (epidemic kerato-conjunctivitis – a very severe red eye disease). Then we ventured to develop anti-HSV nanoviricides. Now we are in the process of developing a unique nanoviricide that will attack the adenoviruses as well as herpesviruses that cause eye diseases. Of course this is not an easy task. If we succeed, we would have an antiviral that can be used against eye viral diseases without testing for the type of infecting virus, thus simplifying treatment.
As you can see, the technology is quite versatile. We can develop injectables, skin creams, eye drops, as well as oral dosage forms very readily. We can simply choose the dosage form that is most appropriate to deliver the most effectiveness against a particular disease.
SW: We’ve read stories in the past about the Ebola virus and how vicious and deadly it is. Do you think you’ll be able to come up with a treatment for Ebola in the future using your nanotechnology?
AD: Ebola virus is quite deadly. A single infectious particle can cause severe hemorrhagic disease in humans and about 50-80% of patients die. A related virus, called Marburg, is less infectious. These viruses are so deadly that they require BSL4+ facilities. Ebola is also a Category A pathogen on the CDC biodefense/terrorism category list.
We have been working with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) to test nanoviricides against Ebola. In the first cell culture testing experiments we have obtained very good success. In the follow-on animal study, we obtained an excellent indication of safety. In the animal efficacy study, we have obtained indications that the test materials look promising but need improvements in efficacy. USAMRIID scientists have published these studies in international conferences.
Given the improvements we have been able to achieve in other projects, we believe that it is quite feasible to develop a nanoviricide drug against Ebola. A grant application to the US Department of Defense that we had sent in collaboration with USAMRIID passed the scientific review and went into “reserve” status”. However, it did not receive funding. So at present, we are working on this project as a back burner project.
SW: What has been your experience working with the FDA thus far. Do they understand the work you are doing at NanoViricides?
AD: The FDA has been extremely interested in nanotechnology-based drugs and devices, i.e. nanomedicine and nanodiagnostics, as well as combinations of these. I was invited to speak and provide input at the “2006 Public Meeting on Nanotechnology Materials in FDA Regulated Products” held by the USFDA Nanotechnology Task Force. FDA has very good scientists. They understand a number of aspects of nanotechnology. They are committed to helping the Industry bring highly effective drugs to the market, while ascertaining highest levels of safety and of drug quality. We meet with FDA scientists at various scientific meetings. In such informal meetings, we have been able to have a candid dialog, which is of course unofficial. Such dialog is very useful.
The FDA has a process for official engagement which is the “pre-IND” application. When we submit our first pre-IND application, we will be able to engage with the FDA in a more meaningful manner towards the goal of preparing for an IND (“Investigational New Drug”) application.
SW: Last question for you today. In your view, what role will nanotechnology play in the decade ahead in developing new drugs targeting life-threatening diseases?
AD: You are already aware that nanotechnology is all around us. Plants, bacteria, and animals use nanotechnology every day. The chloroplasts that harvest light, the mitochondria that harvest chemical energy from food for use by the cell, and all of the structures in our bodies are engineered at the molecular and nano-scale levels. In Pharmaceuticals, vaccines can be considered the very first nanotech drugs, followed by “convalescent serum” therapies, and later antibodies, enzymes, proteins and peptides. As scientific knowledge advances, scientists learn more about how to engineer new “nanomachines” that are designed for a specific task.
The beauty of nanotechnology is that it enables you to engineer solutions designed for specific problems. Attacking infectious agents or rogue, rapidly growing cells as in cancer, is one thing. Killing or destruction is always easy. We are also faced with intractable diseases caused by degeneration or destruction of cells, tissues and organs. Burns and wounds cause local destruction. Nanotechnology-based approaches have been developed and some are already in use for wound healing, and also for burn patches derived from the patient’s own cells. Parkinson’s spectrum disorders are caused by destruction of DOPA-producing cells. Multiple Sclerosis and related diseases are caused by the loss of brain cells that produce myelin which coats and shield the axons as an insulator and protective. Alzheimer’s disease is caused by loss of brain cells. We do not even know the specific mechanism that causes different forms of arthritis. Some of these diseases are being linked to infectious factors, in addition to genetic factors. Attacking these diseases will require helping the cells and tissues grow, and differentiate into the specific type of cells that were depleted. Nanotechnology will become almost the first thought when thinking of approaches for attacking such difficult problems.
Think of it this way: Long ago, humans learned to roll tree trunks. That was the first “vehicle.” Now that we have learned how to make carts, then smart carts, and cars and airplanes, are we going to go back to just the tree trunks? The nanomedicine evolution is very similar. Long ago we learned about herbal extracts. Then we isolated active ingredients. Now we are learning how to engineer these systems into cars and trucks and airplanes and drones, if you will. So I think, nanomedicine is going to be pervasive. That does not mean we need to replace aspirin with a nanomedicine form, although if the nanomedicine form gives us some better properties, we will see that as well.
SW: Thanks again for your time, Anil. Great speaking with you! We wish you and your colleagues at NanoViricides all the best in the future.
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