Cracking antifungals

For decades, the mainstays for treating fungal infections have come from two compound classes: azoles, which were introduced in the late 1960s, and polyenes, which were introduced in the 1950s. Today, there are two additional drug classes plus a few miscellaneous drugs approved to treat fungal infections. However, none of them are without shortcomings, such as a narrow spectrum of activity, toxicity, poor pharmacokinetics, or fungistatic activity.

In the past, the antifungal space did not provide a major market opportunity, limiting efforts to overcome these shortcomings. Now, with an increasing number of immunocom-promised transplant, cancer and HIV patients, interest in potent antifungals has increased. A growing number of companies are looking at either improving existing treatments or developing fungicidal compounds based on novel mechanisms.

However, the hurdles for developing antifungals are higher than for drugs against bacterial infections. There, the challenges of pathogen diversity, pathogen resistance, efflux pumps that rapidly pump drugs out of cells and the emergence of new strains also exist. But the most important challenge is posed by the cellular and metabolic similarities between fungi and mammals. As a result, many effective antifungals cause serious toxicity, while there is a shortage of fungi-specific targets.

Moreover, many fungi can exist in multiple forms - many have both bud-like and filamentous states - and are able to change form to alter their pathogenic features and escape the immune system. On the other side of the coin, the special nature of fungi also provides opportunities, and may make it possible to prevent the change to an invasive form.

To get to better drugs, companies are following two different paths.

While the current compound classes have known limitations, they do address validated targets. Thus, several companies still think it is worth improving their safety, potency and/or increasing spectrum of activity. These companies are focusing on azoles and a new class called echinocandins. Yet as witnessed by last week's FDA approvable letter for anidulafungin from Vicuron Pharmaceuticals Inc., going after approved drug classes provides no guarantees (see "Anidulafungin Relapse," A8).

A handful of more adventuresome companies are going for novel targets. Interestingly, these targets are not necessarily specific for fungi, and the search for novel antifungals illustrates that genomics must go hand in hand with biology.

"If you look at the space,

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