Merck Annual Report 2000

    Cancidas: Powerful New Drug
    to Combat Killer Fungi
    For more than 20 years, boxes full of samples of soil and other organic matter from all over the world have descended on MRL’s CIBE natural products laboratory in Madrid, Spain. “CIBE screens thousands of such samples each year looking for organisms with the potential to evolve into commercial medicines,” explains Dr. Dennis Schmatz, executive director, Infectious Disease Research in Rahway, N.J.
    The testing occasionally identifies a winner. Natural product discoveries have played a key role in the development of several Merck products, including the cholesterol-lowering medicine Mevacor and the anti-parasitic ivermectin.
    With so global an outlook, it is perhaps only human that Spanish researchers exhibited skepticism at the possibility of finding a winner in their own backyard. So, when their screens detected antifungal properties in an organism isolated from a local pond, they promptly repeated the studies. They saw the same results. The sample was promptly shipped across the Atlantic to Rahway for closer investigation. Working closely with the microbiologists, the isolation chemists in New Jersey identified the active component in this extract, a novel natural product from a family of structures known as echinocandins.

    Tackling a killer
    Some fourteen years later, Merck has just launched a close relative of that original natural product structure for the treatment of patients with aspergillosis who fail traditional therapy for this disease. Called Cancidas, Merck’s newest medicine is the first in a new class of drugs designed to counter fungal infections caused by Aspergillus, a fungus that flourishes in the soil, decaying vegetation, foods and other organic materials. It causes fewer infections than other more common fungi, such as Candida, but some 50 to 90 percent of Aspergillus infections are fatal.
    Merck is studying the use of Cancidas against Candida, the cause of 80 percent of all serious fungal infections. Candida exists naturally in our bodies. If our immune systems are functioning fine, Candida does no harm. But when someone’s immune system is compromised, the fungus can cause severe problems and even kill. Many AIDS patients, for example, contract esophageal candidiasis when the Candida that occurs naturally in their throats grows out of control because their immune systems can’t stem the infection.
    Given that Candida is the far more common infection, one might wonder why Merck did not pursue an indication for Candida first. The reason is simple: Aspergillus is more deadly, so the medical need is greater.

    Decades of work
    MRL has researched the antifungal field since the late 1970s. Yet, even the arrival of that promising sample from Spain brought no breakthrough. True, it led to the development of compounds that tested favorably in animals. But these proved effective against only a narrow spectrum of fungi and, because of the large size of the molecule, were restricted to intravenous delivery.
    The program for Cancidas came to life in the late 1980s, when a substantial number of people began developing fatal fungal infections. The common thread connecting these patients was the suppression of their immune systems. That is when Merck research mounted an intensive program to find a preventative, treatment or cure for AIDS. Sensing this might take years, MRL President Dr. Edward Scolnick pressed Merck scientists to also seek medicines for the opportunistic infections killing many infected by the HIV virus. One particularly serious infection is caused by Pneumocystis carinii, then presumed to be a protozoa parasite. Dr. Schmatz, a parasite specialist, went to work on Pneumocystis carinii because the drugs that existed to treat it were only partially effective or came with unpleasant side effects.

    Once in a lifetime
    Pneumocystis carinii posed a challenge. “You can’t grow the organism in a lab,“ explains Dr. Schmatz. “So instead of employing whole organism screens, we began examining potential mechanisms to target for a drug discovery effort. We targeted the organism’s cell wall.” Returning one day from a scientific meeting featuring a lively debate over whether Pneumocystis carinii was a parasite or a fungus, Dr. Schmatz decided to take one of those old echinocandins developed to combat fungi off the shelf and try it on the organisms. It worked. The cell walls protecting the fungi collapsed and the organisms exploded when they tried to grow.
    Dr. Schmatz quickly found himself heading a team of Merck scientists assigned to an antifungal project. The chemists and their microbiology associates manipulated the molecule to add potency, create solubility and improve its activity in humans until they produced a compound ready for testing in the clinic. Results prompted the U.S. Food and Drug Administration to fast-track review of the medicine for use in patients with aspergillosis. And it all began in a little Spanish pond.

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