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 Dupuytren's - articles

Mar 15, 2010 NY Times:
March 15, 2010

Triumph for Drug to Straighten Clenched Fingers

It took half a century. But a tiny drug maker on Long Island has finally found a potentially lucrative use for its only medicine: straightening clenched fingers. And, if research proves successful, treating a condition that causes bent penises.

The Food and Drug Administration approved the drug, known as Xiaflex, last month as a nonsurgical treatment for Dupuytren’s contracture, a condition in which one or more fingers cannot be straightened.

Hundreds of thousands of Americans have Dupuytren’s, which can make it difficult to type, shake hands, wear gloves, reach into a pocket or perform numerous other tasks. The afflicted have included Ronald Reagan, Margaret Thatcher, the playwright Samuel Beckett and the classical pianist Misha Dichter.

Xiaflex, an injectable drug that goes on sale later this month, will not be cheap, at an estimated average cost per course of treatment of $5,400. But analysts expect sales to reach hundreds of millions of dollars a year.

And that total could go higher, if Xiaflex eventually wins approval for a related condition known as Peyronie’s disease, in which a bent penis makes intercourse painful or even impossible.

About one in 20 men is estimated to have Peyronie’s, but figures are not precise because people with the condition tend not to discuss it publicly.

Although the company selling Xiaflex will be Auxilium Pharmaceuticals of Malvern, Pa., the F.D.A. approval was a belated triumph for the drug’s original developer, BioSpecifics Technologies of Lynbrook, N.Y., on Long Island. Founded in 1957, it struggled for decades to find uses for the product, almost going out of business before licensing the drug to Auxilium in 2004.

“It sort of proves to people that if you really believe in a drug you should never give up,” said Matthew Geller, a biotechnology investment banker who is a member of the BioSpecifics board.

Shares of BioSpecifics closed Monday at $27.61, up from $1 as recently as late 2006.

Some people treated with Xiaflex in clinical trials for the Dupuytren’s hand condition said it had made a big difference in their lives, and had allowed them to avoid painful surgery.

“When I looked down and saw my finger straightened out, I cried,” said Kenneth Nelson, 65, of Indianapolis. “It was to me just like a miracle.”

Xiaflex is an enzyme produced by a gangrene-causing bacterium, Clostridium histolyticum, which uses it to eat away the tissues of its victims. The enzyme, called collagenase, breaks down collagen, a major component of the body’s connective tissue that is found in skin, tendons, cartilage and other organs.

But collagenase by itself does not cause gangrene. And there are times doctors need to break down collagen, such as when an excess builds up in the hand or penis, causing Dupuytren’s and Peyronie’s. The ailments are named for French surgeons who described the conditions in the 18th and 19th centuries.

The enzyme was first extracted from the bacteria around 1950 by Ines Mandl, a young biochemist at Columbia University. Edwin H. Wegman, a Long Island entrepreneur, learned about Dr. Mandl’s work and set up a company called Advance Biofactures, which later became BioSpecifics, to turn collagenase into a drug.

In 1965, the company won approval of an ointment containing collagenase for use in removing dead tissue from skin ulcers and burns. The ointment, sold by licensees under the name Santyl, was a modest success, but the company never truly prospered.

So in the 1970s the company began developing what it thought would be a bigger money-maker, an injectable collagenase. It tested that drug for numerous uses, including herniated disks. Finally, in the early 1990s, two professors of orthopedics at the nearby State University of New York at Stony Brooksuggested using the drug for Dupuytren’s.

The professors, Dr. Lawrence C. Hurst and Marie A. Badalamente, injected the drug into the tails of rats, as a stand-in for human fingers. They found they could dissolve the collagen in tendons, making the tails floppy, without harming nearby nerves and arteries. Then they organized clinical trials in patients and got federal grants to help pay for the work. The professors and Stony Brook will share a royalty of one half of 1 percent of sales of Xiaflex for use in treating Dupuytren’s.

But work was slowed by lack of money, and by 2004, BioSpecifics was about out of cash. In desperation, Ed Wegman’s son Mark, a top computer scientist at I.B.M., called a childhood friend, Laurence Korn, who had been the chief executive of a successful biotechnology company now known as PDL BioPharma.

With Dr. Korn’s help, BioSpecifics licensed the drug to Auxilium in a matter of weeks, receiving $5 million initially.

Auxilium was interested because of Peyronie’s disease. It already was selling a gel for men with low testosterone and had learned from urologists about the need for better treatments for bent penises.

“From talking with surgeons and patients who have Peyronie’s, neither of them wants to do the surgery,” said Will Sargent, a spokesman for Auxilium.

Two years ago, the drug giant Pfizer, which sells the erectile dysfunction drug Viagra, licensed the European rights to Xiaflex from Auxilium for an initial payment of $75 million. BioSpecifics got $6.4 million of that amount and will receive 8.5 percent of additional payments of up to $410 million that Pfizer might make.

Auxilium sought approval for treating Dupuytren’s first because it was easier to measure success in straightening fingers. But the company hopes to begin late-stage trials of Xiaflex for Peyronie’s disease later this year. In a midstage trial, injections of Xiaflex into the collagen plaque in the penis reduced the curvature. But the drug did not reduce pain or discomfort during intercourse by a statistically significant amount.

While collagenase itself is not patented, the companies do have patents on the use of the enzyme to treat Dupuytren’s and Peyronie’s. They are also shielded from competition for seven years under a federal law aimed at spurring development of drugs for rare, or “orphan,” diseases — even though newer estimates suggest these two diseases are not as rare as thought when the drugs were given orphan status.

Auxilium and BioSpecifics hope that the half-century-old collagenase might eventually become as versatile as Botox, another bacterial product. They are looking at uses that range from loosening up immobile “frozen shoulders” to eliminating fat bulges and cellulite.

With its belated success, BioSpecifics has sold off its ointment business. It now has only five employees and a business of collecting a roughly 11 to 12 percent royalty on sales of Xiaflex.

“We will be a cash machine going forward,” said Thomas L. Wegman, the president and the other son of the company founder. “We don’t have to pay for marketing. We don’t have to pay for manufacturing.”

The Wegman family — the two sons and the founder’s 75-year-old wife, Toby — controls about 25 percent of the company’s stock.

Ed Wegman, the company’s founder, did not live to see the F.D.A. approval, dying at age 87 in 2007. On Feb. 2, the day the drug was approved, one BioSpecifics director sent an e-mail message to the others saying, “Well done. Hope Ed is looking on.”

Meanwhile, Dr. Mandl, the biochemist who first isolated collagenase from the bacteria, is nearing 93. Last year, when BioSpecifics stock rose above $30, she sold the last 1,000 shares she had been given for serving as a consultant to the company over the years.

Unfortunately, she had sold most of her holdings years earlier for a relative pittance. “If I still had what I originally had,” she said. “I’d be very rich.”

Feb 15, 2010, S.F. Chronicle:

Pianist Misha Dichter to perform at Stanford

Monday, February 15, 2010

Today, Misha Dichter calls himself the happiest pianist in the world. But only three years ago, Dichter, who will perform Wednesday at Stanford University, said he had "zero hope" for his career. Faced with a debilitating hand condition, he was afraid he might never play again.

Dichter was born in 1945 in Shanghai and emigrated from Poland to the United States with his parents when he was 2. Four years later, he began piano lessons, and by the time he enrolled at Juilliard, he was practicing piano 12 hours a day.

In his busiest performing years, Dichter performed 100 concerts a year all over the world. But he always played in the shadow of a specter: His father had suffered from Dupuytren's contracture, a condition that disfigured his hands, and Dichter knew the condition was genetic.

Dichter received the official Dupuytren's diagnosis in 2007, but he began experiencing symptoms of the disease years earlier. It started with a small dimple on the palm of his right hand. Over time, his ring and little fingers curled toward his palm and impaired his hand movement. Dichter was terrified he would face the same fate as his father.

Father had surgery, too

"My father had two botched surgeries," Dichter said by phone from his New York City home. "His hands were curled up and looked like horrible claws. Remembering what Dad went through, I was not about to have surgery."

Instead, he modified his technique, adjusting the fingering so he could play his repertoire with only nine fingers, or with only his left hand. He said his right hand "felt like someone had poured cement under my skin."

Dichter managed to compensate for his ailing right hand for several years, but in early 2007, before a weekend concert in New Orleans, the condition became too much to bear any longer. He had been working on a Tchaikovsky piece he was scheduled to play with the Chicago Symphony three months later, but he couldn't play anything with his right hand. He decided it was time to call a surgeon.

"The receptionist put me on hold, and the hold music was the very same Tchaikovsky piece I was supposed to be learning," Dichter said. "It was a sign."

The surgeon Dichter called was orthopedic hand specialist Dr. Scott Wolfe, chief of the Hand and Upper Extremity Service at Manhattan's Hospital for Special Surgery who also spent 10 years directing the hand and upper extremity program at Yale University. Wolfe rearranged his schedule and performed Dichter's delicate, two-hour surgery within two weeks of his first visit.

"Scott was a genius," Dichter said. "He was so wide-eyed and optimistic. This surgery was nothing for him."

Two days later, Dichter began physical therapy with Caryl Johnson, a therapist who had experience working with musicians. Recommended by Wolfe, she too was a Juilliard-trained pianist.

Rapid recovery

Knowing Dichter still planned to perform with the Chicago Symphony in three months, Johnson agreed to work with Dichter three to four days a week.

"At first, he was only allowed to practice five minutes a day," said Dichter's wife, Cipa. "I had to watch him like a hawk. I would be outside the door and burst in after five minutes. This for him was the hardest thing. He has no sense of time when he practices."

Johnson's strict regimen worked. Dichter performed publicly for the first time only seven weeks after surgery, and met his goal of performing with the Chicago Symphony.

"Ordinarily, I would have needed a year to prepare the Tchaikovsky piece," Dichter said. "But I prepared it in three weeks. I don't think my therapist thought I would make it."

Dr. Amy Ladd, chief of the Chase Hand & Limb Center at Stanford University, has spent 20 years treating patients with Dupuytren's contracture. She met Dichter by chance at the 2008 Aspen Music Festival, a year after his surgery. A master pianist herself, she heard Dichter tell the Aspen audience about his hand condition and knew immediately he was talking about Dupuytren's contracture. She met Dichter backstage after the performance, and the two realized they had a lot in common.

"Dr. Wolfe is a good friend of mine, and he was the perfect person to do Misha's surgery," she said. "Misha was someone who solely uses his hands for his profession, so the surgery was life-changing. And his recovery, frankly, has been extraordinary."

Treatment advances

She added that treatment for Dupuytren's contracture has changed a lot since Dichter's father had surgery.

"Today, treatment is more early and aggressive," she said. "My guess is that Misha's father's disease might have been fairly progressive, and by the time he had surgery, he had passed the point of no return. Fortunately, Misha hadn't reached that point yet."

Ladd, who sees about three new cases per week in her Stanford clinic, said the disease affects between 1 and 2 percent of the U.S. population, but that figure varies by region because it almost exclusively attacks people of Northern European or Australian heritage.

"In severe cases like Misha's, it's like there are cords wrapped around the nerves and arteries of the finger like stripes on a candy cane," Ladd said. "You definitely need a hand surgeon - someone who understands the anatomy of the hand - because the surgery is so delicate. If something goes wrong, you could damage the nerves or the blood supply to the fingers."

Ladd said it is possible for Dupuytren's contracture to recur, or develop in Dichter's other hand, but since the surgery, he shows no signs of the disease in either hand.

"It's a credit to his genes and his surgeon," Ladd said.

"Misha was always very compulsive," Cipa said, recalling their college days at Juilliard where they first met. "I would arrive to begin practicing piano at 8 a.m., and he would say 'How do you expect to be a pianist if you start practicing so late?' "

The two married in 1968, and performed their first concert together at the Hollywood Bowl four years later. They now have two grown sons, both of whom dallied in piano as children, but neither of whom stuck with the instrument.

Video tells story

A member of the American Society for Surgery of the Hand, Ladd wanted to share Dichter's story of triumph with other doctors in the group. Dichter agreed, and in October 2008, Ladd flew to New York to film a video chronicling his journey.

The video, which is now available on YouTube, took on a life of its own. As a result, Stanford University invited Dichter to perform Wednesday. It will be his first performance in California since his surgery.

"The first piece I'll be playing (at the Stanford recital) is by Brahms," Dichter said. "It has a chord that I couldn't play before my surgery, and now, every time I play it, it gives me a special little smile."

Misha Dichter: Recital. 8 p.m. Wed. Dinkelspiel Auditorium, Stanford University. $40-$46. (650) 725-2787. livelyarts.stanford.edu.

E-mail Kathryn Roethel at datebookletters@sfchronicle.com.

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