Fludase® (DAS181) is a broad-spectrum drug candidate under development for the prophylaxis and treatment of respiratory infections caused by all types of influenza virus, including the Pandemic Influenza A(H1N1) that is currently causing a worldwide influenza pandemic, as well as all types of parainfluenza virus. Fludase® is currently undergoing a Phase II clinical trial for the treatment of community acquired influenza (click here for detailed information on the trial).

MECHANISM OF ACTION: FLUDASE^® BLOCKS IFV ENTRY INTO CELLS

Fludase is delivered by a simple generic device called “Cyclohaler,” click here to see it in action

FLUDASE® EFFECTIVE AGAINST ALL TYPES OF INFLUENZA INCLUDING PANDEMIC INFLUENZA A(H1N1), H5N1, and TAMIFLU-RESISTANT STRAINS

In a study performed by the Centers for Disease Control and Prevention, DAS181 was shown to prevent death in mice infected with the highly-lethal (to humans) A/VN/1203/04 strain of H5N1 influenza virus. DAS181 was used both as a prophylactic (see figure 2) and therapeutic agent (see figure 3) and showed remarkable efficacy in both applications.

In a separate study performed at the CDC, DAS181 was recently shown to have significant activity for strains of Pandemic Influenza A(H1N1). Please see this recent publication for full information.

Studies at NexBio have shown DAS181 to be highly active against viruses resistant to Tamiflu®. Please see this recent publication for full information.

FLUDASE^® SHOWN EFFECTIVE AGAINST PARAINFLUENZA

Fludase® has shown efficacy against multiple parainfluenza (PIV) virus strains. This virus may cause serious respiratory infection similar to influenza in patients of all ages and is a known cause of community-acquired pneumonia. There is no approved vaccine or therapeutic for PIV. Other viruses may also show susceptibility to Fludase®.

FLUDASE^® PRODUCT POSITIONING

Fludase® will be positioned for the prevention, treatment and containment of pandemic influenza due to strains such as H1N1 and H5N1. For seasonal use, Fludase® will be positioned for the prevention, treatment and containment of Influenza-Like Illness (ILI), the set of symptoms that drives a patient to seek medical attention complaining of “the flu.” Extensive market research with physicians confirms the need for a broad-spectrum respiratory antiviral agent. We believe Fludase® may offer an improved treatment option for all ILI patients, including those currently not treated, those treated with other anti-viral approaches, or, those inappropriately receiving broad-spectrum antibiotics.

CURRENLTY AVAILABLE INFLUENZA ANTIVIRALS

There are four influenza antiviral drugs approved for use in the United States.  Oseltamivir (Tamiflu®) and Zanamivir (Relenza®) are Neuraminidase Inhibitors: amantadine (Symmetrel®) also generic), and rimantadine (Flumadine®, also generic) are Adamantanes. Despite these being the only approved options for seasonal variations of influenza, and despite extensive stockpiling by governments for pandemic influenza, there are growing concerns regarding effectiveness due to emergence of resistance and due to side effects.

Influenza Resistance to Adamantanes and Neuraminidases
There is increasing concern about influenza viruses' resistance to antiviral drugs. Since 2005, scientists have known that seasonal flu viruses have become widely resistant to the Adamantanes, with at least 90% of H3N2 strains and at least 15% of seasonal H1N1 strains no longer susceptible to the drugs. In view of the rapid increase of Adamantane resistance among circulating influenza A viruses worldwide, these medications are no longer recommended by the Centers for Disease Control and Prevention (CDC) for prevention or treatment. This leaves only oseltamivir and the less widely used zanamivir as treatment options, and, as a result, this has led to oseltamivir being the most commonly used influenza antiviral in the world. However, like the Adamantanes, oseltamivir resistance is now growing among seasonal influenza strains. In January of 2009, the Centers for Disease Control and Prevention reported that that 86 of the 88 seasonal H1N1 surveillance samples tested in the U.S. were resistant to oseltamivir.  Responding to the rapid emerging of resistance to oseltamivir in the U.S., Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York said: “It’s quite shocking.” “We’ve never lost an antimicrobial this fast. It blew me away.” (Jan 8, 2009, New York Times) Similar rates of resistance to oseltamivir have been found around the world. 100%, or close to 100%, of surveillance samples taken during the Southern Hemisphere 2008 flu season were found resistant to oseltamivir (South Africa, 225 of 225, New Caledonia, 7 of 7, New Zealand, 2 of 2, Senegal 10 of 10, Australia 47 of 59, and Uruguay 13 of 26). The resistance is due to a mutation called H274Y. Ultimately, seasonal H1N1 isolates during the 2008-09 flu season reached a 99%+ resistance rate to Tamiflu® worldwide. This same H274Y mutation has now been documented in approximately 96 cases of Pandemic Influenza A(H1N1) cases to date.

Targeting Host, Not Virus, May Reduce Emergence of Resistance
Both the Neuraminidase and Adamantane classes of marketed drugs target a component of the influenza virus itself. Virtually all drugs currently in development, such as peramivir (Biocryst), T-705 (Toyama/Fuji), and CS-8958 (Biota/Daiichi-Sankyo), do as well. This targeting drives selection pressure, such that as these viruses mutate, which they do rapidly as a matter of course, viruses preferentially emerge that are resistant to these anti-virals. As indicated by the emergence of influenza resistance in both of these cases, a new approach is required. Unlike current antiviral compounds and vaccines, Fludase® targets human host receptors, not virus components, and thus carries a reduced risk of drug resistance due to lack of selection pressure. Extensive, prolonged nonclinical studies have not shown the development of any meaningful resistance.

Neuropsychiatric Events Associated with Neuraminidases
Neuropsychiatric events have also been associated with the use of both oseltamivir and zanamivir. Such events may have led to the death of children in Japan. While the cause of these events has not been fully established, in 2008 the Food and Drug Administration recommended that the makers of both oseltamivir and zanamivir add a “Neuropsychiatric Event” warning to both drugs’ labels.

VACCINES

Inactivated or attenuated live human influenza vaccines are in worldwide use, especially for high-risk groups. However, these vaccines must be modified yearly to maintain efficacy due to constant viral mutation. Each year it may take several months before the updated or modified influenza vaccine is ready for use against the annual influenza epidemic. Vaccines are not 100% effective when administered, they take 2-3 weeks to become effective (so they cannot be used for acute illness), and higher risk patients, e.g. the elderly and the immunocompromised often have poor responses.