NanotechnologyEnabled Specifically Targeted Viricides

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• Nanotechnology-Enabled Specifically Targeted
  Viricides

Anil R. Diwan, PhD President Cell
203-606-9180 adiwan_at_nanoviricides.com
Leo Ehrlich, Chief Financial Officer Cell
917-853-6440 leo_at_nanoviricides.com
Eugene Seymour, MD, MPH Chief Executive
Officer Cell 310-966-1941 eugene_at_nanoviricides.co
m
135 Wood Street, Ste. 205, West Haven, CT 06516.
T/F [phone].
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Prophylactics and Therapeutics
Two Wheels of a Cart
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NanoViricides Pendantized Polymeric Micelles
based, Conformationally Flexible, Specifically
Targeted Drugsgt Regulatory Implications for
(a) Normal IND-enabling Study, and (b) a Novel
"War-like" Bio-threat Response Mechanism
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NanoViricides Approach

• Build a Guided Missile
• A Homing Device (Biochemical Ligand)
• Target Specifically the Infectious Agent
• Hide API in the Belly of the Missile
• API Active Pharmaceutical Ingredient
• OPTIONAL!
• NanoMedicine Concept 1959 Polymer Chemistry!
• First Actualization 2006 by NanoViricides

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NanoViricides Nano-Machines

• Bind to Specific Receptors on Viruses
• Multiple Receptors at Once!
• Multi-Point Docking (Velcro Effect)
• Can Encapsulate or Attach Multiple APIs for -
• Viral Dis-Assembly
• Genetic Material Destruction
• Non-Viral Nano-Machines

API Active Pharmaceutical Ingredient
Patents Pending
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First Generation Simple Products - No
EncapsulationCovalently Attached Ligands
to a Single Molecular Chain
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Antiviral Spectrum is Specified by Ligand Set
ex Influenzas
Common Influenzas - All Broad Spectrum
High Path Influenzas Group-Specific
H5N1 Strain-Specific Current Threat
Emerging Pandemic Threats
33,000 deaths US, gt250k World Per Year
enables A Novel Treatment Methodology
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Several Magnitudes Efficacy Improvement over
Current Drugs with NanoViricidesEx Influenzas,
Comparative Efficacies (Putative Estimates)
NanoViricide D Broad Specificity FluCide-I
NanoViricide J H5N1 Specific AviFluCide-I

• Based on our Current Work, Literature Data and
  using similarity projections

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It is of Interest toAccelerate the Development
of Highly Efficacious Antiviral Drugssuch as
Nanoviricides

• Potentially Reduced Mutation Frequency
• Need to establish experimentally
• to what extent?
• Likely Less Resistant Strains
• guidelines

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Future of our Approach

• Can be Extended to Many Viruses
• Some other non-viral Infectious Diseases also
• Difficulties Exist

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NanoViricides Polymeric Micelles Key
Differences from Usual Drugs Biologics I.
Characteristics

• Conformationally FLEXIBLE Polymers
• Well Defined Non-Particulate Materials
• Single Molecular Chains
• Heterogeneous Molecular Sizes
• MW Avg, MW Distributions
• Ligands Attachment
• non-Quantitative Chemistries
• Average Substitution Levels
• Blocking open sites -Or Not!

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NanoViricides Polymeric Micelles Key
Differences from Usual Drugs Biologics II.
Limitations in Chemical Characterization

• Operational Definition of the Species MW
• Retained by NMWL xxx Rejected by NMWL yyy
• Membrane Manufacturer QA Dependence
• MW Distribution - Very Little Control
• Process Parameters Not very viscous materials
• Ligands Substitution Levels
• Averages Characterized over all species
• possibly via surrogate chemical characteristics

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NanoViricides Polymeric Micelles Key
Differences from Usual Drugs Biologics III.
Limitations in Physical Characterization

• Amphiphilic Materials - Complications
• self-assembly - MW, MW-Distr experiments
• mostly soluble in organic, aqueous as well as
  intermediate solvents - fractionation issues
• Non-Particulate Materials
• SEM, TEM, AFM not very useful
• optical microscopy not useful

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Polymeric Micelles PrecedenceClosest Cases are
Some Excipients

• Some Excipients in common use are polymers with
  similar average-specified characteristics
• However, there is no efficacy associated with
  them in theory

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SAFETY, EFFICACY, CMCData and StudiesA
Balanced Approach is Needed to Speed up
Development of Extremely High Efficacy
Drugssuch asNanoViricides
As Much as Possible!!!
FDA
Minimum, Expedient, Informative, Critical
Industry
Industry
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Part II War-Like Scenario- Unknown Agent -
Bioterrorism or Natural -NanoViricides Enable
Novel Public Health Approach

• Food for Thought
• Minimize Stockpiling
• Minimize Response Time Lag
• Contain Epidemic before it Grows past small
  cluster
• Avoid Pandemics Altogether
• Minimize Drugs Against Scarce Pathogens
• Respond to Unknown (incl. Engineered) Pathogens
• Minimize Casualties and Morbidities
• How?... next slide

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Part II War-Like Scenario- Unknown Agent -
Bioterrorism or Natural -NanoViricides Enable
Novel Public Health Approach

• Small Initial Clusters 5 to 100 patients
• Immediately on Presentation - No Pathogen Id.
  Need
• Use Patient Infectious Fluids
• Raise Animal Antibodies - Polyclonal
• Attach epitope to core nanoviricide material
• Treat with resulting NaonoViricide drug agent
• Within 3 Weeks - Eradicate Threat
• Respond Before Epidemic is Created!
• Only Core Nanoviricide Material is Stockpiled

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Part II War-Like Scenario- Unknown Agent -
Bioterrorism or Natural -NanoViricides Enable
Novel Public Health Approach

• Beyond Emergency Use Authorizations
• FDA and Industry Must Start Thinking
• Possibly Legislative Initiatives May be Necessary

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Title NanoViricides, Polymeric Micelle-based
flexible Specifically Targeted Drugs, Regulatory
Implications for (a) IND-enabling Study, and (b)
a Novel "War-like" Bio-threat Response
Mechanism Brief Description 1. A nanoviricide
is a polymeric single chemical chain with
covalently attached ligands that specify the
virus target. The antiviral spectrum of the drug
is determined by the specificity of the set of
ligands attached to the chain, in addition to
other functionally important aspects inherent in
the chemistries.  2. The following aspects
distinguish these materials from usual drugs and
biological materials seen by the FDA  2a. As a
polymer, it is not possible to manufacture a
single molecular weight species. It is possible
to operationally define a molecular weight
distribution, such as "retained by membrane with
NMWL xxx and passing through membrane with NMWL
yyyy". The actual MW distribution can be
characterized, but the result values are strongly
dependent on the technique of measurement.  2b. T
hese are not hard particle species. Therefore,
SEM/TEM/AFM characterization is not
possible. 2c. These are amphiphilic materials,
limiting the use of many standard
procedures.  2d. The polymer chemistries only
enable "substantially complete" attachment of
ligands, and this is essentially true for most of
the chemistries used in the process.  2e. The
material product can be defined operationally
(i.e. in terms of processes used to make it), and
further can be characterized in terms of average
result values of chemistries (e.g. average MW,
and MWD, average number of ligands per chain,
etc.).   3. The biological efficacy of
nanoviricides drugs may be several orders of
magnitude better than that of usual chemical
drugs (test case- influenza - preliminary
studies). This in itself may limit the potential
for mutant generation. There are also other key
aspects of the design of nanoviricides that are
expected to lead to minimizing mutant
generation.  The above discussion relates to
normal drug development of nanoviricides drugs.
In addition 4. "War-like" Bio-threat
Response  4a. In case of an unknown threat, it
is possible to generate antibodies in the field,
fragment them, and use well-specified fragments
as ligands, attach them, and build a specific
nanoviricide drug against the unknown,
uncharacterized threat agent. Such scenario can
occur in bioterrorism as well as in natural
outbreaks (e.g. SARS).  4b.  This is a different
level of "Emergency Response", relating to
scenarios where stockpiling is not possible
because pathogen itself is unknown.  4c. This
new scenario enabled by the naoviricides systems
solution to biothreats may require additional
regulatory perspectives. Such as (a) standard or
EUA approval for the core nanomaterial, enabling
its stockpiling, and (b) very limited,
life-threatening-use approval for the
nanoviricide generated in-field using the
approach outlined in  (4a) or a variant thereof
such as using some small chemicals or peptides
instead of antibody fragments.  4d. The purpose
of such regulatory perspective would be to enable
treatment within 2-3 weeks of threat event
notification - or shorter if feasible - in  order
to limit casualties and morbidity and contain the
threat at its source thus limiting the potential
that it can convert into an epidemic or a
pandemic.