Inside Duke Medicine

For gout patients, renewed hope

Research by rheumatologist Michael Hershfield has led to a promising new drug to treat the worst cases of gout. Photo by Michelle Gailiun

On June 16, an FDA advisory panel recommended approval of the drug Pegloticase for patients with severe gout for whom other treatments failed.

For Duke rheumatologist Michael Hershfield, M.D., June 16 was a day he’ll never forget. The advisory panel was reviewing work he had begun more than 15 years ago that led to creation of Pegloticase — and to positive results for many patients with advanced gout.

Gout is an inflammatory arthritis that affects about five million Americans. Its hallmark is sudden, searing pain, usually starting (for reasons unknown) in the big toe, followed by formation of knotty
deposits of uric acid around joints and tendons.

In most people, medicines available for decades can ease the pain and prevent progression by reducing uric acid in the blood. But for a small fraction – perhaps as many as 50,000 – nothing works. For them, life is a nightmare of disability and pain.

Hershfield was involved in testing a novel chemically modified enzyme called PEG-ADA, which the FDA approved in 1990 against a very rare, inherited immune deficiency disorder. He saw an opportunity for a new, enzyme-based therapy for severe gout. In 1993 he applied for a grant to develop a PEG-uricase to eliminate uric acid deposits in patients with resistant gout.

The Duke scientists showed that PEG-uricase (today’s Pegloticase) lowered uric acid in animals by converting it into a product easier to excrete. In 1998 the clinical-deVelopment rights to the drug were licensed to Savient Pharmaceuticals. In 2001 the FDA designated it as an orphan drug — a pharmaceutical developed to treat a disease that afflicts relatively few people — for patients with chronic, refractory gout.

The first clinical trials began at Duke in 2001 under the direction of John Sundy, M.D., Ph.D., a rheumatologist with no financial investment in the product.

Several patients felt so strongly about their improvement during the phase III trial that they traveled to Washington, to testify at the June 16 meeting. Pegloticase, to be called Krystexxa if it wins FDA approval, was on the line. Hershfield sat in a “bullpen” awaiting potential panel questions about his laboratory’s research.

Would the benefit to patients demonstrated in the trial outweigh uncertainty about risk? “That’s often the bottom-line question with new drugs, and Pegloticase was in a brand new class of drugs for gout,” said Hershfield.

A vote to recommend approval seemed far from certain. But everything changed when the patients spoke.

“Here were some patients who had been in constant pain and were so debilitated that they couldn’t even walk,” said Hershfield. “Before this drug, some were in wheelchairs, or had entered long-term care facilities. And they actually walked into this meeting and stood at the microphone to say how much this drug had improved their lives.”

Among them was Lonnie Matthews, 76, of Burlington and a former Duke employee. His gout was so bad that he spent most of his time in bed. He couldn’t take care of himself, feed himself, do much of anything, he told the panel.

“After they told their stories, there wasn’t a dry eye in the house,” Hershfield said. “I had a feeling at that point how things would go."

The panel recommended approval by 14-1. It did have reservations about safety and recommended long-term follow-up studies, but Hershfield is optimistic the drug will become available for the patients who need it.

Hershfield said a final FDA ruling is expected in about six weeks.

“There are not many physicians who can point to one — let alone two — discoveries they have made that have dramatically changes patients’ lives,” Sundy said. “Duke is very fortunate to have someone like Mike Hershfield.”