Therapy Analysis - Influenza
The fight against avian and porcine strains
In recent years, the development of therapies to treat new strains of influenza, particularly avian and porcine strains, has become increasingly important. As the recent outbreak of swine 'flu has shown, antiviral drugs have a big part to play in the treatment of these infections. Leading the way are Gilead Sciences'/Roche's oseltamivir (Tamiflu) and Biota's zanamivir (Relenza). Oseltamivir is an orally-available neuraminidase inhibitor, active against neuraminidase from all strains of influenza A and B. In a Phase III trial in 615 patients, oseltamivir at an oral dose of 75 or 150mg over five days reduced the severity of 'flu symptoms by 40% compared to placebo. Duration of illness was reduced by 33%, with a 50% reduction in secondary symptoms such as bronchitis and sinusitis. Zanamivir is also a neuraminidase inhibitor. Unlike oseltamivir, it is not orally bioavailable, and must be administered by inhalation. In a previous Phase III trial in 375 nursing home patients, 2.9% of patients receiving zanamivir 10mg/day contracted influenza, compared with 7.4% receiving standard care. In a double-blind, placebocontrolled Phase III trial in 337 families to assess influenza prevention, 4% of patients on zanamivir had more than 1 family member with laboratory-confirmed influenza, compared to 19% on placebo. With both oseltamivir and zanamivir showing efficacy in treating the latest outbreak of swine 'flu, the importance of these drugs cannot be underestimated.
Moving away from the marketed antivirals, treatment options for swine 'flu remain limited. VaxInnate is one company developing a swine 'flu vaccine using its TLR technology platform, while Vical is developing DNA vaccines against pandemic H5N1 using its Vaxfectin adjuvant. Both these projects are in preclinical development, and therefore cannot be expected to reach the market for some considerable time.
A clinical candidate showing early promise is favipiravir, a DNA-directed RNA polymerase inhibitor under development by Toyama. In murine models of avian influenza, favipiravir showed a potent therapeutic effect. In vitro, it inhibited influenza A, B and C, with high replication inhibition, including in oseltamivirresistant strains. Favipiravir is currently in Phase II trials in Japan, with Phase I trials in the US also underway. With Toyama seeking to out-license this project, this compound may well have global potential in the fight against avian influenza.
Another novel therapy currently in early stage development for the treatment of human and avian influenza is Alnylam's ALN-FLU01, a direct RNA interference therapeutic. ALN-FLU01 contains two short interfering RNAs (siRNAs), targeting highly-conserved genes required for virus replication. In preclinical studies, siRNAs showed strong antiviral activity against multiple strains of influenza, including a human clinical isolate of H5N1. ALN-FLU01 has been selected as the lead candidate, with intranasal and inhaled formulations undergoing optimization for use in Phase I trials. Alnylam is collaborating with Novartis on the project.
In the continued search for treatments for avian influenza, NanoViricides is developing a nanoviricide, AviFluCide-I. Currently in preclinical development, AviFluCide-I was shown to be 4 times superior to FluCide-I, and 40 times superior to oseltamivir. Approval for emergency use is expected in 2009, with Phase III trials and full approval expected in 2010.
Two companies following a novel approach to avian influenza treatment are Omrix and iBioPharma, both of which are developing early-stage antibody-based therapies. iBioPharma is developing monoclonal antibodies against multiple strains of pandemic avian influenza, using a vector system in non-genetically modified plants. It is currently in in vitro characterisation studies. Omrix is collaborating with the National Institute of Allergy and Infectious Diseases (NIAID) to develop an antibody-based therapeutic, which is also currently in early preclinical development.
