MS Drug’s Epic Journey From Folklore to Lab

Research Into Ancient Chinese Fungus That Propagates Inside Insects Yields Potential Relief for Multiple Sclerosis

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For centuries Chinese medicine has seen restorative properties in an Asian fungus that invades and destroys insects. Now a drug drawing on that age-old lore is poised to become an important new treatment for multiple sclerosis.

Nature was the first source of medicines to treat human disease and remains an important one. See some of the most successful commercial medicines derived from natural products.

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A Food and Drug Administration panel unanimously recommended this month that the drug called fingolimod be approved as the first oral medicine for MS, an often-debilitating disease in which the body’s own immune system attacks a fatty substance protecting nerve fibers. The drug, assuming it gets final FDA approval, would significantly expand the treatment options for the hundreds of thousands of Americans with MS.

Nature was the first source of medicines to treat human disease and remains an important one. The Japanese scientists who discovered fingolimod added their names to a list that goes back to the European chemists who derived aspirin from a substance in willow bark and Alexander Fleming, who found that a fungus produced a bacteria-killing substance called penicillin.

Fingolimod comes from an idea hatched a quarter-century ago by Tetsuro Fujita, a Kyoto University pharmacology professor who had investigated bitter plants used in traditional Asian medicine. A wonder drug at the time was cyclosporin, which helps tamp down the immune system in transplant patients to reduce the risk of organ rejection. The chemical cyclosporin is derived from a fungus, first isolated from soil samples, that uses the substance to attack other fungi.

 

Researchers in Japan and at Novartis turned a fungus that is deadly to cicadas into a new MS drug. Novartis

Dr. Fujita says he reasoned that an even more powerful immunosuppressant chemical ought to be present in a group of Asian fungi known in Chinese and Japanese as “winter-insect-summer-plants.” These fungi attack insects in the winter with their chemical arsenal. By summertime, the insect is dead and its corpse has been transformed into a vessel for the blooming fungus. Ironically, the same properties that make the chemical deadly in the insect world may also have a helpful side for people suffering from certain autoimmune diseases, in which an overactive immune-system response causes the body to attack its own cells.

Dr. Fujita assembled a team from his university and two Japanese companies to sift through the various fungal products. They found a potent immunosuppressant in a particular kind of winter-insect-summer-plant, called Isaria sinclairii. This fungus victimizes a particular type of cicada found in East Asia, using it as a host in which to propagate. Chinese herbal medicine had long identified Isaria sinclairii as a source of “eternal youth” along with ginseng and deer antlers.

The immunosuppressant isolated from the fungus by the Japanese team was too toxic to give to humans. They needed to tweak it chemically. “Medicine and poison—they’re two edges of the sword,” says the 79-year-old Dr. Fujita by phone from his Kyoto home.

Nowadays, scientists generally rely on test-tube results for initial screening of experimental pharmaceutical drugs. But the Japanese group tried out all its promising drug candidates in rats, giving them skin transplants and seeing how long they survived after the resultant organ rejection. The molecule later named fingolimod proved to be the standout, significantly prolonging survival due to its immunosuppressant effect.

In 1997, Novartis AG NVS +0.16%Novartis AG ADSU.S.: NYSE $73.98 +0.12+0.16% Oct. 16, 2013 4:02 pm Volume (Delayed 15m) : 2.29MU.S.: NYSE $74.00 +0.02+0.03% Oct. 16, 2013 5:26 pm Volume (Delayed 15m): 51,093 P/E Ratio 18.93Market Cap $200.72 Billion Dividend Yield 3.28% Rev. per Employee $453,52709/10/13 FDA Offers Guidance for Advair…08/23/13 European Stocks Beckon to Inve…08/11/13 Novartis Hit by Scandal Over J…More quote details and news » ‘s then-chief executive, Daniel Vasella, flew to Japan to seal a deal under which Novartis licensed the U.S. and European rights to the drug from Yoshitomi Pharmaceutical Industries (now part of Mitsubishi Tanabe Pharma Corp. 4508.TO +0.07%Mitsubishi Tanabe Pharma Corp.Japan: Tokyo ¥1382 +1+0.07% Oct. 16, 2013 3:00 pm Volume : 690,100 P/E Ratio 18.69Market Cap¥775.32 Billion Dividend Yield 2.89% Rev. per Employee ¥47,392,500More quote details and news » ).

After tests, Switzerland-based Novartis dropped the idea of using the medicine for transplant patients because it was no more effective than existing agents. But the company discovered that fingolimod had a powerful effect in multiple sclerosis, reducing the number of relapses in which patients may experience vision problems, fatigue, numbness and other symptoms. Trials in thousands of patients followed.

The FDA, which is expected to make a decision about fingolimod by September, doesn’t have to follow the advice of the expert panel but usually does. In a separate report, FDA staff came to a similar conclusion as the panel. Fingolimod has side effects that include reduced heart rate on the first day of dosing and, in rare cases, swelling in the eye, but the benefits of the drug outweighed the risks, the staff report said.

Jinsuk Kim

Novartis’s head of global development, Trevor Mundel, says fingolimod doesn’t destroy immune cells that are attacking the protective covering around nerve fibers. Instead, the drug works to prevent the immune cells from overreacting in the first place, inducing them to “stay in their home base,” he says. The benefit of this approach, he says, is that it can be reversed more quickly in the event of problems with the drug.

Novartis, taking a hint from products such as fingolimod, has set up a research unit that focuses on finding new drugs from traditional Chinese medicines. “We’re well aware that there are some very interesting compounds that reside in that area,” Dr. Mundel says.