T-705 - Antiviral Drug for Influenza

Under development by Toyama Chemical of Japan, T-705 is a novel oral agent indicated for the treatment of influenza.

Following promising preclinical studies undertaken in Japan and at Utah State University in the US, T-705 has now entered clinical development to determine its efficacy and safety in humans. Phase I studies were initiated in Japan in January 2007 under a Japanese IND. In the same month, the company submitted an IND application to the US Food and Drug Administration to begin clinical trials in North America.

Development of T-705 is being simultaneously carried out in Japan and the US.

Phase I clinical trials of T-705 began in March 2007 in the US, while Phase III clinical trials are scheduled to begin in Japan by the end of 2009. Phase II clinical trials have been completed in Japan.

Phase I clinical trials assessed the safety (pharmacovigilance), tolerability, pharmacokinetics and pharmacodynamics of T-705 while Phase II clinical trials performed on a large group of people assessed the effectiveness of the drug.

Randomised controlled clinical trials will be conducted in Phase III at more than one medical centre or clinic. The patient groups in the range of 300 to 3,000 will be involved in these trials.

T-705 targets viral RNA polymerase

Infection with influenza A or B viruses is the cause of influenza in humans. These single-stranded RNA enveloped viruses consist of an outer protein coat made up of the surface glycoproteins, haemagglutinin and neuraminidase.

Neuraminidase inhibitors, such as oseltamivir and zanamivir, are the main antiviral drugs currently approved to treat influenza. They work by selectively inhibiting viral neuramindase, an enzyme critical for viral replication in cells of the host’s respiratory tract. These drugs are effective in reducing the duration of illness and risk of complications.

However, their efficacy diminishes significantly if they are not taken within 48 hours of the onset of symptoms. Importantly, strains of influenza virus can develop resistance to these drugs, thereby limiting their clinical effectiveness.

Toyama’s T-705 differs from currently approved anti-influenza drugs, in that it targets influenza viral polymerase. It has been suggested that host cell enzymes (cellular kinases) convert T-705 into T-705 ribofuranosyl phosphate (T-705RTP), a form that inhibits virus polymerase without affecting host cellular RNA or DNA synthesis.

Toyama confirmed that T-705 has effective anti-influenza attributes that differ from those of Tamiflu and other existing anti-influenza drugs.

Risks from avian influenza

Influenza is a highly infectious disease that is characterised by recurrent annual epidemics and, more rarely, major global pandemics. Pandemics are caused by the emergence of a new and highly virulent strain, to which the population has no immunity. Research work carried out in the 1960s suggests that pandemics usually arise when strains of avian and human influenza combine. The so-called Spanish flu pandemic that occurred at the end of the First World War killed an estimated 40 million people.

The emergence in the late 1990s of a new avian strain of influenza A, designated H5NI, has caused particular concerns about the possibility of another global pandemic. This highly virulent avian strain has been responsible for widespread infection in poultry flocks in the Far East and sporadic outbreaks in other parts of the world. Wild birds have also been infected. There have been more than 200 documented cases of H5NI infection in humans, about half of which have proved fatal.

T-705 exhibits activity against the H5N1 strain

Preclinical in vitro and in vivo studies have shown that orally administered T-705 is a potent anti-influenza agent with activity against a range of influenza strains including avian influenza strain H5N1.

Studies in mice lethally infected with an H5N1 strain have shown that treatment with T-705 is highly effective. While all mice given the vehicle control died and only two of ten given oseltamivir survived, all ten T-705-treated mice survived.

Treatment with T-705 not only prevented death in these animals but also lessened the decline in arterial oxygen saturation and inhibited lung virus titres and lung consolidation. Subsequent challenge experiments showed that orally administered T-705, given up to 60 hours after virus exposure, also prevented death and the decline in arterial oxygen saturation.

These preliminary data suggest that T-705 may be useful for the treatment of infections caused by avian influenza virus.

Marketing commentary

Given the huge direct and indirect socioeconomic impact of influenza, finding new ways to combat this potentially life-threatening disease is a clinical priority. Vaccination is an established means of disease prevention while antiviral agents are primarily indicated for treatment.

T-705 differs from currently licensed antiviral drugs, such as the neuramindase inhibitors, in that it targets influenza viral polymerase. Thus, it offers a new approach to combating influenza, with potential to treat infections due to H5N1.

The existing market for antiviral drugs for influenza already exceeds $2bn a year. Analysts believe that this will more than double if patient needs for effective influenza prophylaxis and treatment could be met in full.