Deadly Molds May Have Met Their Match

An ocean sponge joins the tiny list of possible weapons against a scourge

Some 25 feet below the brilliant blue surface of the Indian Ocean lives a coral-encrusted black sponge called Plakinastrella. This unassuming invertebrate, which is about the size of a breadbox, was discovered in 1990 by a team of marine biologists from Harbor Branch Oceanographic Institute (HBOI) in Fort Pierce, Fla. Now, Peter J. McCarthy, the group's leader, is promoting the lowly sponge for its elixir-like properties.

It turns out that Plakinastrella produces at least three potent--and completely novel--antifungal compounds called cyclic peroxides that chew up Candida, a nasty mold. McCarthy's group has since teamed up with MycoLogics Inc., a Denver (Colo.) biotech, to bring the compounds through the early stages of drug development. "Then we'll be jumping up and down saying: `We have these for sale,"' says McCarthy.

It's a sure bet that drug companies will be buying. While a number of potent antibiotics exist for the treatment of bacterial infections, there are few safe and effective drugs to stave off fungal infections. Large pharmaceutical companies such as Merck (MRK) and Fujisawa Pharmaceutical and small biotechs such as MycoLogics and Versicor are now racing to be the first to fill the antifungal pipeline. Such concerted research efforts have yielded positive results: The first new class of antifungals in 40 years, the so-called echinocandins, was highlighted at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Toronto in mid-September.

Human fungal infections, like bacterial infections, have become a scourge of frightening proportions. Hospitalized patients on chronic antibiotics are particularly at risk. Experts estimate that in this population, a fungus called Candida kills 38% of the victims it infects. Another soil-dwelling fungus, Aspergillus, kills 95% of the time.

Such infections were once considered rare. But with the rise in AIDS cases and other conditions that decimate the immune system, they are becoming more and more common. In 1999, for example, approximately 25% of the 2.5 million patients hospitalized for chemotherapy, organ transplantation, or AIDS developed serious fungal infections.

Candida is a particularly hardy variety that invades the mucous membranes of the vagina, esophagus, skin, and other organs. In the mouth, it forms a milky-white film that makes it difficult for patients to swallow. Analysts believe the current market for antifungals to treat Candida and its ilk is worth $2.5 billion and growing. "There's a serious need for new drugs that aren't `me, too' products," says analyst James Kelly of Credit Suisse First Boston.

Today, the antifungal arsenal is limited to amphotericin B, an extremely toxic intravenous medicine, and compounds such as Pfizer Inc.'s (PFE) Diflucan. Diflucan belongs to a class of drugs called azoles that inhibit cell growth but don't actually kill the fungus. The idea is that by slowing fungal spread, the body's immune system has more time to get the infection under control. But with prolonged use, fungi often become resistant to azoles. Moreover, for unknown reasons, dozens of fungus types simply don't respond to azoles.

In an effort to develop new antifungals, scientists are boning up on previous research on antibacterials. Some of the most potent antibacterial drugs in existence target a process called cell-wall biosynthesis. These so-called cell-wall inhibitors, which include penicillin, meropenem, and vancomycin, block a critical pathway in the germ's life cycle: how it grows and divides. What if researchers targeted the same steps in the fungal life cycle? Could they stop these terrible infections simply by designing compounds that block fungal growth?

The answer is yes. Leading the way is Merck, which recently wrapped up human testing of its most potent drug in this class, Cancidas. The drug, which is given once a day intravenously, is safe and well-tolerated and does not interact with other commonly prescribed medicines. Merck recently submitted its findings on Cancidas to the Food & Drug Administration. Approval could come as early as this time next year. According to Kelly, the potential market size for Cancidas is roughly $500 million.

Not too far behind are Fujisawa's FK-463 and Versicor's V-Echinocandin, both in late-stage clinical trials. Kelly expects both compounds to become serious competitors in the next 12 to 24 months. And he estimates that the market potential for FK-463 could be at least $150 million.

Versicor's compound, VEC, is particularly intriguing to researchers. In a study of patients with esophageal fungal infections, Versicor scientists found that a low dose of VEC wiped out infections of Candida 85% of the time. Results of a separate study indicated that a higher dose was safe and had no serious side effects. The company is now measuring VEC's effectiveness at this higher dose to see if it can boost the patients' response rates to nearly 100%.

The echinocandins aren't likely to be panaceas, though. Because they must be injected, their utilization is probably going to be limited to hospital settings and doctors' offices. And with prolonged usage, resistance could become a problem, too. That's one reason why doctors are eagerly awaiting the arrival of exotic new compounds such as the ones from Peter McCarthy's sponge. For the millions of patients with life-threatening Candida or Aspergillus infections, these could be true elixirs.

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