The success in treating AIDS with multiple combinations of three antiviral drugs is a model for the successful management of viral resistance. Can we expect that a deep arsenal of anti-influenza virus drugs will be developed?
So far we have Â three antiviral drugs against influenza viruses. Most H3N2 strains are resistant to rimantidine, which targets the viral M2 ion channel, although it is still effective against H1N1 strains. There are two neuraminidase (NA) inhibitors: oseltamivir (Tamiflu) and zanamavir (Relenza). The latter is effective against H1N1 and H3N2 strains, but widespread resistance of H1N1 strains to oseltamivir has emerged. Clearly a deeper anti-influenza pipeline is needed.
The news is good: there are a number of promising new NA inhibitors in development. One is CS-8958, a modified version of R-125489 produced byÂ Daiichi Sankyo Co. by adding an acyl chain to the 3-O position. The two drugs were tested in NA inhibition assays against a wide variety of H1N1, H3N2, and influenza B viruses. Importantly, CS-8958 was also found to inhibit NA activity of oseltamivirÂ resistantÂ H1N1, H3N2 and B patientÂ isolates. CS-8958 also significantly improved survival of mice infected with a mouse-adapted H1N1 strain.Â Interestingly, CS-8958 protected mice when administered up to 10 days before infection. Zanamavir was protective when given to mice no earlier than 1 day before infection. These results may not translate to humans, but in the best of circumstances, CS-8958 might have prophylactic value in treating influenza. This property is useful for controlling outbreaks in communities and institutions.
Daiichi Sankyo Co. started a Phase III trial for adults and a pediatric Phase II/III trial with CS-8958 in November 2008. The double-blind study is meant to confirm that a single inhaled dose of CS-8958 is as effective as 75 mg of oseltamivir administered orally twice daily for 5 consecutive days.
Another promising NA inhibitor is A-322278, a modified version ofÂ A315675, a pyrrolidine-based compound developed by Abbott Laboratories.Â A315675 has been shown to be as active against H1N1 and H3N2 strains as zanamavir and oseltamivir. In the study cited below, the effect of the drug on mortality rates, mean weight loss, mean days of death, and lung viral titers was assessed.Â A-322278 was shown to protect mice against challenge with both wild type H1N1 virus and theÂ oseltamivir resistantÂ NA mutant H274Y.Â
Other influenza antivirals in development include BioCryst Pharmaceutical’s NA inhibitor, Peramivir, an intravenous/intramuscularly administered drug in Phase 3 development; T-705, an oral RNA polymerase inhibitor from Toyama Chemical, in Phase 2, and DAS181, an inhaled drug from Nexbio, which is in Phase 1. DAS181, or Fludase, is unique in that it incorporates a sialidase that removes sialic acids from mucosal membranes, thereby preventing viral attachment via the HA glycoprotein.
The fact that some of the new inhibitors are not affected by the amino acid changes that lead to oseltamivir and zanamavir failure is encouraging. If the antivirals fare well in clinical trials, it will be possible to devise combinations of the drugs to better cope with emerging resistance.
Yamashita, M., Tomozawa, T., Kakuta, M., Tokumitsu, A., Nasu, H., & Kubo, S. (2008). CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity Antimicrobial Agents and Chemotherapy, 53 (1), 186-192 DOI: 10.1128/AAC.00333-08
Baz, M., Abed, Y., Nehme, B., & Boivin, G. (2008). Activity of the Oral Neuraminidase Inhibitor A-322278 against the Oseltamivir-Resistant H274Y (A/H1N1) Influenza Virus Mutant in Mice Antimicrobial Agents and Chemotherapy, 53 (2), 791-793 DOI: 10.1128/AAC.01276-08