The influenza virus is a tricky infection to develop drugs for because it can easily mutate and recombine, creating new strains.

The flu vaccine has to be redesigned each year to protect against the strains that are currently most prevalent. And it isn’t difficult for the viruses to develop resistance to current options for post-infection treatments, including neuraminidase inhibitor drugs such as Roche AG’s Tamiflu (oseltamivir), Glaxosmithkline plc’s Relenza (zanamivir) and Biocryst Pharmaceuticals Inc.’s Rapiacta (peramivir).

The resistance occurs through natural selection. The variants that are “not being hurt by whatever stresses – the drugs you have put in – will win,” Anil Diwan, president and chairman at Nanoviricides Inc. told BioWorld Insight.

Nanoviricides, of West Haven, Conn., has developed a nanoparticle technology that mimics the surface of a cell, including the cell surface receptors the viruses use to enter the cell. After the virus binds to the nanoparticle, the virus’ lipid coat fuses with the fatty acid interior of the nanoparticle and dissolves.

The nanoparticles are particularly amenable to ever-changing virus like influenza because natural selection works in the drug’s favor: viruses that are resistant to the nanoparticles aren’t problematic because if they can’t bind to the receptors on the nanoparticle, they won’t be able to replicate.

“No matter how many mutations there are in the progeny, if the progeny does not bind to that particular receptor, it is not infectious,” Diwan said.

Nanoviricides’ flu drug, Flucide, was highly effective in animal models, which should translate well to human studies since Flucide attacks the virus, which will be the same regardless of the host. The company is currently focused on scaling up production of Flucide so it can begin human studies.

Theraclone Sciences Inc. also is targeting the conserved region of the virus, an epitope on the N-terminus of the M2e protein conserved in over 98 percent of known influenza A strains. Rather than nanoparticles, Seattle-based Theraclone’s TCN-032 is a fully human monoclonal antibody. In a Phase IIa trial, healthy patients challenged with an influenza A infection followed by TCN-032 24 hours later, showed significant reductions in clinical symptom scores and viral load compared to placebo.

Visterra Inc., of Cambridge, Mass., also has a human antibody drug candidate, VIS410, in development, designed to inhibit the fusion of the virus’ hemagglutinin (HA) protein with the cell membrane. Like M2e, the HA protein is conserved across influenza A strains and mutations are unlikely since the protein is involved with binding of the virus to the cell membrane. Visterra expects to have VIS410 in the clinic next year.

Johnson & Johnson, of New Brunswick, N.J., likewise has an antibody program designed to target HA that it inherited through its acquisition of Crucell NV. (See BioWorld Today, September 20, 2010.)

Gemmus Pharma Inc., of San Francisco, is taking a different approach to treating the infection, focusing on reducing the severity of symptoms by modulating the inflammatory response. GP1001 activates the G-protein coupled receptor, reducing the pro-inflammatory cytokines and chemokines from activated white blood cells.

Hemispherx Biopharma Inc. also thinks it can harness the patient’s immune system to help fight infection of the influenza virus. In September, the Philadelphia-based company reported in vitro studies showing that its HPV genital warts treatment, Alferon N Injection (interferon alfa-n3), had a significant inhibitory effect against Tamiflu-resistant H7N9 influenza virus when tested in cell culture. Against wild-type H7N9 virus, Alferon produced a similar reduction in virus levels as Tamiflu.

The obvious advantage to using the patient’s immune system is that the drugs could be used in combination with direct-acting antivirals, such as Tamiflu or perhaps even the next-generation drugs targeting the conserved regions of the virus.