Both the injectable FluCide drug for use in severely ill patients with influenza, and the oral FluCide drug for less sick out-patients bear a virus-binding ligand that mimics sialic acid. Moreover, this ligand is capable of substituting for both the mammalian form (sialyl-alpha2,6-gal-) or the avian form (sialyl-alpha2,3-gal-). Since the novel H7N9 (2013) virus is transitioning from avian to human host, the dual biomimetic capability of our FluCide ligand should have a favorable impact.
CDC, and scientists from China and Japan have reported, based on the genetic structure of the novel H7N9 virus, that this virus is likely to bind well with the mammalian form of sialic acid. This virus is also reported to bear other mutations that enable it to infect mammalian hosts effectively. Existing H7-vaccine viruses are not well matched to this novel H7N9 virus, and new vaccine development will take some time. This H7N9 is resistant to amantadine and rimantadine, as are most US and European Influenza A virus strains. It is suggested to be susceptible to neuraminidase inhibitors such as oseltamivir (Tamiflu®) and zanamivir (Relenza®), but certain mutations suggest resistance to these drugs. CDC authors Dr. Uyeki and Dr. Cox note that clinical research is urgently needed on new antiviral agents, including drugs with different mechanisms of action.
FluCide is based on a completely novel mechanism of action wherein the drug micelle is designed to bind to the virus particle via multi-dentate interactions, and then to spread onto the virus surface via lipid-lipid interactions with the viral lipid coat, thereby covering the entire virus particle. Some viruses can also be dismantled by such attack. This is similar to antibodies, in that antibodies bind to the virus particle and cover its cell-binding sites. However, each antibody (IgG) binds via only two points to the virus, whereas a single polymer chain in FluCide can be designed to have as many as twenty or even larger numbers of virus-binding ligands, that are uniformly spaced along the chain. In addition, an antibody itself alone is generally insufficient for viral destruction. The antibody-coated virus particle or a resulting immuno-precipitate must be further acted upon by the human immune system in various ways for the virus infection to be controlled. In contrast, a nanoviricide® agent is designed to perform its antiviral effect even if the immune system is compromised. Further, antibodies are highly specific to a virus strain, and since influenza virus can mutate rapidly it can escape the antibody. In contrast, the virus-binding ligands on FluCide are chosen to mimic the sialic acid. Binding to sialic acid is an absolutely required first step for any influenza virus to infect a human host. Thus, a proper choice of virus-binding ligand allows us to suggest that FluCide should be effective against the novel H7N9 strain of influenza.
Both the oral and the injectable FluCide drug candidates have shown extremely high effectiveness in highly lethal mouse models of two distinctly different influenza A virus infections, viz. H1N1 and H3N2, indicating that FluCide drugs indeed have a broad-spectrum effect against influenza viruses, irrespective of the subtype or strain.
In these highly lethal studies, FluCide drug candidates have achieved complete survival (22+ days), while in contrast, Tamiflu® (oseltamivir) resulted in only 8-9 days survival, and the untreated animals die within 5 days. The FluCide oral and injectable drug candidates also protected the lungs of the animals much better than did oseltamivir, indicating a clear benefit. The protection from influenza virus was clearly reflected in the strong increase in survival time in the FluCide-treated animals as compared to oseltamivir. The FluCide drugs were seen to be far superior to Tamiflu also in terms of viral load reduction. The FluCide drugs were extremely well tolerated, in contrast to oseltamivir. No dose-limiting side effects have been seen for our FluCide candidates as yet, indicating that in a severely ill patient, the dosage of FluCide can be increased even further. In these animal studies, the mouse serves only as a “test tube” and FluCide is designed to attack the virus (not the host). Thus the results are expected to correlate well with the impending human clinical studies.
Binding to sialic acid on the cell surface is a completely conserved property of all influenza viruses. The avian influenza viruses tend to prefer binding to the a-2,3- variant of sialic acid, whereas those causing disease in humans tend to prefer binding to the a-2,6- variant. Pigs and some other species serve as “mixing species” where both the avian and mammalian viruses can grow, and further, avian viruses can mutate to mammalian viruses.
The Company has previously reported that it is enabling cGMP production of the FluCide drug candidates in the near future. The Company reports further that the design phase of the cGMP clinical batch production and laboratory facilities is completed and bidding phase for subcontracts has begun.
The Company has held a pre-IND meeting with the US FDA at the end of March, 2012, for the injectable FluCide drug candidate, and has been working on the IND enabling studies for this drug. The Company has previously reported that it has successfully developed the very first orally bio-effective nanomedicine. This development has added the oral FluCide as an additional drug candidate to the Company’s pipeline. Oral anti-influenza drugs have estimated market size of $4B to $7B at present, which could expand substantially if a highly effective anti-influenza drug such as FluCide is developed.