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Duke researcher's persistence pays off with new drug for gout
(News & Observer, The (Raleigh, NC) Via Acquire Media NewsEdge) Nov. 2--The line of work Dr. Mike Hershfield has pursued for most of his 32-year research career at Duke University is basically scientific social service.
He adopts orphans.
Specifically, he takes on so-called orphan diseases -- afflictions so rare that the big pharmaceutical companies have no financial incentive to develop treatments.
Hershfield and his team at Duke are among more than a dozen research groups at Duke, UNC-Chapel Hill and private biotech companies in the Research Triangle Park area that have contributed to a wave of new treatments for people suffering from diseases such as immune disorders, rare cancers and cystic fibrosis. Each disease afflicts fewer than 200,000 Americans, but all the orphan diseases added together strike an estimated 25 million.
Under the federal Orphan Drug Act, passed 25 years ago, grants and exclusive marketing rights are extended to researchers who develop drugs for rare diseases. But the work of finding treatments is still often patched together with small grants, fragile collaborations with private companies -- and a tiny group of patients desperate for a breakthrough.
For Hershfield, 15 years of work culminated last week in an announcement at a scientific meeting that the drug he helped develop for people with untreatable gout proved effective in a large trial. Perhaps as early as 2009, the treatment may be available to an estimated 40,000 people who suffer from gout and get no relief from the predominant therapy.
"My goal from the very beginning was to provide treatment for people who had absolutely nothing else," Hershfield said. In his clinical work as a rheumatologist, he said, he often tends patients in desperate pain from untreatable gout.
Like many who delve into research on rare diseases, Hershfield got involved through a combination of expertise and coincidence.
A medical doctor who also has an appointment in the biochemistry department at Duke, he had worked on another treatment at Duke in the 1980s. It was for babies born with an exceptionally rare enzyme deficiency that resulted in a failed immune system.
A new approach
A child at Duke had not been cured of the immune disease despite two bone-marrow transplants. Doctors wanted to test a new approach -- replacing the missing enzyme by attaching it to a large molecule called a polymer and infusing it into the child's bloodstream.
After treatment, Hershfield's lab tested the enzyme levels in the child's blood. He found that the polymer, which isn't absorbed by the body, enabled the enzyme to circulate much longer and work more effectively. The child was saved, and the technology of fusing the so-called PEG polymer with biological therapies began to be applied in other long-lasting treatments.
By happenstance, Hershfield learned that the company that had produced the lifesaving drug for the immune disorder had developed another potential therapy with the polymer. It was for gout -- a disease in which uric acid builds up in the joints, causing inflammation and pain. Hershfield knew firsthand how such a therapy would help his patients. He urged the company to fine-tune its approach so that a drug could be tested in people.
After six years, however, the company decided it wasn't interested in pursuing the drug, so in 1993, Hershfield decided to press forward on his own. To qualify for a small grant from the National Institutes of Health, he needed to line up another company.
Finally, a startup company in California, Mountain View Pharmaceuticals, indicated it was interested. By 1996, Hershfield and his research partner at Duke, Susan Kelly, won more federal grant money and began testing the technology on mice that had been specifically bred to have gout.
"In mice, it was a fatal disease," Hershfield said. "Uric acid would build up, and it was so insoluble it would crystallize in their kidneys and they'd die in a few weeks."
When mice were treated with Hershfield's experimental drug, they were cured. "They lived to be old mice," he said.
Finding a drug maker
By 1998 -- five years after he started -- Hershfield still had not advanced to human trials. To do so, he needed to license the drug. He found Savient Pharmaceuticals of New Jersey, which paid Duke and Mountain View a licensing fee for their roles in developing the therapy. Savient also sought a designation for treatment-resistant gout as an orphan disease.
The designation was critical. Under the Orphan Drug Act of 1983, the Food and Drug Administration classifies a disease as an orphan if it afflicts fewer than 200,000 people in the United States. That is too few for big drug makers to justify the expense and time needed to develop therapies.
To build incentives, the legislation enabled the FDA to provide research grants, tax breaks and market protection to groups that develop treatments for orphan diseases.
"Originally the struggle was just to get somebody interested in these diseases and get companies involved in research and trials and bring drugs to market," said Mary Dunkle, vice president of communications for the National Organization for Rare Disorders. The group, based in Connecticut, is credited with galvanizing small groups of patients around the country to win support for the 1983 legislation.
Since the act was passed 25 years ago, nearly 300 orphan drugs have won FDA approval, and thousands of them are in development. Dunkle said the act has helped millions of people and given attention to diseases that had long been ignored.
Still, getting drugs to market is difficult, as the Duke team learned.
"There is not enough attention" to orphan diseases, said Dr. John Sundy, who led Duke's clinical trials of the gout drug, called PEG-uricase. That's especially evident, he said, in immune disorders and diseases that afflict the joints -- such as gout.
Relieving gout pain
Millions of people suffer from gout. It's among the oldest disorders described in literature, yet doctors still don't know why uric acid crystals begin building up in some people's joints. For more than 40 years, a drug called allopurinol has been the main source of relief.
"Everybody assumed gout was taken care of," Hershfield said. But some people -- perhaps 40,000 Americans and many of the people who showed up in Hershfield's office in Durham -- can't tolerate the drug, or it loses effectiveness.
As Savient moved the drug to human trials, Hershfield took a back seat to avoid a conflict of interest, because he retains a share of royalty rights if the drug goes to market. Sundy began running the human tests.
A small, first-phase trial in 2002, in which the drug was injected, was halted when patients broke out in hives. Hershfield despaired that Savient's interest would wane, but the group switched gears and had better results with intravenous infusions.
Last year, Savient launched advanced phases of testing -- enrolling more than 200 patients at multiple sites around the nation. At a conference of rheumatologists last week, Sundy reported that uric acid levels declined within hours for all patients treated with the drug and remained low months later in about 40 percent of patients.
Janet Wheeless, 63, of Nashville, N.C., was enlisted in the trial at Duke on a referral from her doctor at UNC Hospitals. She had suffered gout for 25 years but could take only a small dose of allopurinol because it harmed her already weakened kidneys.
Four years ago, she developed red-hot painful joints, swollen to the point of popping. Her index finger "looked like ET's," she said, and she couldn't use her hands.
"I was crippled," she said. Her husband had to help her use the restroom, dress her, open doors.
Six weeks after beginning twice-monthly infusions of the therapy, she said, her gnarled and painful fingers began feeling better. Now they're normal, and she has no pain at all. The turnaround came just in time.
In April, her husband of 34 years, Bobby, suffered a stroke, and she was able to tend to him in his last days, just as he had tended to her.
"I'm thankful I was able to do that," Wheeless said through tears. "This drug saved my life, and my sanity."
That, for Hershfield, is worth 15 years of paternal persistence.
ORPHAN DRUG ACT
The Orphan Drug Act enabled the Food and Drug Administration to give grants, exclusive marketing rights and other perks to researchers who develop drugs for rare diseases, called orphan diseases, which by definition afflict fewer than 200,000 people in the United States.
WHY WAS IT NEEDED? Rare diseases had long been ignored by large pharmaceutical companies, which had little financial incentive to spend millions researching treatments for drugs marketed to a tiny population. By providing small companies with incentives, the act spurred research.
HAS IT BEEN SUCCESSFUL? Most agree it has. In the 10 years before the act was passed, the FDA reports, only about 10 drugs were approved for rare diseases. Since then, nearly 300 drugs have been approved and thousands more are in development, providing treatment to an estimated 14 million patients.
DOES IT HAVE DRAWBACKS? Some say it has created an environment for drug developers to gouge patients desperate for help -- one drug costs patients more than $200,000 a year. Others say the exclusive, seven-year marketing rights stifle competition, especially when therapies become used for more mainstream diseases, prompting sales to skyrocket.
savery@newsobserver.com or 919-829-4882
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