NanoViricides Inc. (NNVC)

[changes_iv]

Dr. Eugene Seymour, CEO of NanoViricides, Inc., never said Phase 1 in one week or two weeks. Here is what Dr. Eugene Seymour, CEO of NanoViricides Inc., said:

"by the way, I'm sure that when you think human trials for drugs you think of hundreds of millions of dollars and years of time, well in this case because the disease only lasts a week, two weeks,...that it is possible to complete human trials in the space of a few short months...four parts to the human trials" ~ Dr. Eugene Seymour, CEO Nanoviricides, Inc.

On the CEO letter to shareholders (2014) he went to explain how would this be possible:

...The number of patients that need to be enrolled in a clinical trial depends upon how good the drug is. If the drug effect is very easily separated from the placebo, and more so, from the standard of care, then the trial would require fewer patients to reach the clinical end point of determining that the drug is indeed effective or superior, as the case may be. Therefore we believe, based on the very strong efficacy observed in our animal studies, that our influenza clinical trials will be short, and will be relatively inexpensive.

http://www.nanoviricides.com/2014-ceo-letter.pdf

What do we know about PEG, the backbone for every NanoViricides, Inc. therapeutic drug?

PEG has a toxicological profile of very low concern and is well tolerated at high doses after chronic and acute administration. The PEG associated with a biological molecule itself should provide no extra concern because the toxicity versus exposure relationship in animals and humand has been thoroughly investigated and metabolism/excretion is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposures of PEG associated with toxicity, the therapeutic index is large (=600-fold). The metabolism of PEG is limited to metabolic modification of the hydroxyl group, and the data available suggest that the metabolites seen in humans are seen in animals. Also, for PEGs typically used on biologicals, metabolism will not play a major role in PEG elimination. In light of these data, PEG metabolites do not represent a significant issue, especially when combined with the low overall exposure to PEG discussed above.

Studying the metabolism of PEGylated biologics will represent a significant challenge. First, radiolabeling of PEG associated with a biological molecule is not a viable option. Second, the doses of these PEGylated biologicals are usually very low. Third, PEG is present in a range of products that humans are routinely exposed to. The detection of trace exposures of PEG metabolites produced from PEGylated biologicals will be impossible against the background of PEG and its metabolites present as a result of routine exposure. Moreover, because the products of metabolism are the same regardless of the route of administration, because metabolism represents a minor route of clearance, and because data demonstrate that PEG exposures considerably higher than those possible from PEGylated biologicals are required for toxicity, any additional experiments seem unjustified and of very limited value.

The data presented in this article indicate that, assuming toxicological evaluation of a biological molecule of interest is completed in an appropriate species and satisfactory therapeutic windows are achieved, the PEG associated with a protein or other biological molecule does not represent a significant additional unquantified risk to humans, because of 1) the low exposures involved, 2) the low toxicity profile of PEG, and 3) the similarity of the metabolites that are formed in all species.

Further studies to elucidate the metabolism of the PEG associated with a biological molecule in humans will not provide any more information to place into context the safety of PEG, and such studies may not even be possible. http://dmd.aspetjournals.org/content/35/1/9.full

Of course, Phase 1 and 2 of the toxicology study were completed last year, and the results...?

WEST HAVEN, Conn., Jan. 23, 2015 /PRNewswire/ -- NanoViricides, Inc. (NYSE MKT: NNVC) (the "Company"), a nanomedicine company developing anti-viral drugs, reported a good safety profile of an optimized FluCide® drug candidate in a GLP-like toxicology study in rats. These results are extremely important since they indicate that FluCide continues to look very promising as one of the most advanced candidates in the Company's drug development pipeline.
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The next phase of the toxicology package studies will involve larger animals, and will require much larger quantities of the drug candidate. The Company is in the process of commissioning operations at the new 1 Controls Drive, Shelton, CT facility in order to perform the scale up studies needed for making the large quantities of materials in a controlled manner. These upcoming studies will be performed in cGLP compliant manner to provide safety and toxicology data that are required for an IND submission to regulatory agencies.

http://www.prnewswire.com/news-releases/nanoviricides-reports-that-the-flucide-candidate-was-found-to-be-very-safe-in-cglp-like-safety-and-toxicology-study-in-rats-performed-by-basi-300024776.html

What can we expect to read on results of the third and final Phase of the toxicology study, once the 2Kg of FluCide(TM) ships to BASi? Very likely, something along these lines...

NanoViricides Inc. a nanomedicine company developing anti-viral drugs, reported a good safety profile of an optimized FluCide® drug candidate in a GLP-like toxicology study in large animals.

Why are Clinical Trials for FluCide(TM) not in the U.S.???

How much does it cost to develop a new drug? According to Joseph Dimasi of the Tufts Center for the Study of Drug Development, on average, the capitalized cost comes out to about $1.3 billion (adjusted to 2009 dollars). And a not-insignificant portion of these costs comes from regulatory burdens – specifically, the FDA’s standard Phase I/II/III trial design. Indeed, as my Manhattan Institute colleague, Avik Roy, has documented, pretty much everything involved in a clinical trial has become more expensive.
http://www.forbes.com/sites/theapothecary/2014/01/24/shocking-secrets-of-fda-clinical-trials-revealed/

At NanoViricides, Inc. we know something about "FDA expensive". The FDA asked our small company to find the toxic dose on PEG based FluCide(TM) even though we already knew "PEG has a toxicological profile of very low concern and is well tolerated at high doses after chronic and acute administration"

On the other hand...

Australian research centres have made significant contributions to global clinical trial programs within Novartis. A good example has been the development of an improved method of tracking response to therapy in CML. This new method looks at the clearance of the disease at the molecular level. This methodology was developed and validated at a hospital research centre in Adelaide alongside the Novartis global development program. This methodology has now become the global gold standard for tracking response to therapies for this disease and is a significant advancement over the previous approach.
https://www.australianclinicaltrials.gov.au/industry-and-sponsors/success-stories

Why clinical trials for FluCide(TM) in Australia?

1) Australia has a fast and pragmatic regulatory pathway for clinical trials. Under the Clinical Trials Notification (CTN) scheme administered by the Therapeutic Goods Administration (link is external) (TGA), research proposals are submitted directly to Australian human research ethics committees (HRECs) which assume the primary review responsibility for ethical and scientific review. The usual review cycle takes only 4 to 8 weeks and is based on the submission of a protocol, investigator brochure and if required, an independent toxicology report. This effective and efficient process avoids costly preparation of extensive regulatory applications and means that research can start much sooner.

The TGA also administers the Clinical Trials Exemption (CTX) scheme, under which proposals are submitted to the TGA for scientific review followed by ethical review conducted by the HREC.

2) The Australian Government’s generous Research & Development (R&D) Tax Incentive encourages more industry investment in R&D.
The Incentive provides businesses investing in eligible R&D with generous tax offsets:

- a 45 per cent refundable R&D tax offset (equivalent to 45c per $1 of eligible R&D) for companies with aggregated annual turnover of less than A$20 million; and
- a 40 per cent non-refundable R&D tax offset (equivalent to 40c per $1 of eligible R&D) for all other eligible companies.

Other benefits under the new R&D Tax Incentive include:

-Clinical trials can be eligible R&D activities under the program and are considered for eligibility under the same rules as any other activity;
-The Incentive provides for increased access by international companies. In particular, there is no requirement to hold the intellectual property in Australia;
-Certainty and stability of the rate of support to companies as the rates are no longer linked to the company tax rate;
-Increased level of expenditure that can be claimed on R&D activities undertaken overseas in support of Australian R&D projects, under certain conditions.

Above all, the new system provides a globally competitive tax incentive for conducting R&D activities in Australia. More information about the R&D Tax Incentive can be found at www.business.gov.au (link is external).

3) The seasonal differences between the Northern and Southern hemispheres allows trials dependent on seasonal factors (e.g. flu vaccine, allergy or respiratory ailments trials) to be conducted or continued in Australia, extending the appropriate period for patient recruitment...
read more: https://www.australianclinicaltrials.gov.au/industry-and-sponsors/why-conduct-clinical-trial-australia#F

Australia has developed ethics review processes for multi-centre research (link is external)that help to reduce unnecessary duplication of review of research.

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About Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study(2014)

Abstract

Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.

FROM THE CLINICAL EDITOR:

Applications of nanoparticle synthesis with microfluidic methods are typically limited to in vitro studies due to low production rates. The team of authors of this proof-of-principle study reports on the successful parallelization of NP synthesis by 3D hydrodynamic flow focusing using a multilayer microfluidic system to enhance production rate without losing the advantages of reproducibility, controllability, and robustness.
http://www.ncbi.nlm.nih.gov/pubmed/23969105