Biotechnology's Reach Extends Author's Grasp
Biotechnology's Reach Extends Author's Grasp
Can an injectable biologic really replace a delicate surgery for treatment of Dupuytren’s disease?
Editor’s note: In health care, we deal in numbers so often that unless you are the treating physician, you sometimes cannot appreciate the quality of the personal experience that a successful or failed treatment might have. Here, an exceptionally articulate and knowledgeable patient describes how Xiaflex made a world of difference in treating hand-disabling Dupuytren’s disease. A professional writer, Jack McCain is a regular contributor to Managed Care. His fingers are important to us.
Sometime in the late 1990s, my right hand began looking rather gnarly. I attributed its rugged appearance to various leisure-time activities: tennis, gardening, retrieving stones from the woods and fields and stacking them into rough walls. Then my ring finger began to bend down, and it couldn’t be straightened without applying painful pressure. My primary care physician said the palm and finger certainly looked interesting but he had no idea why. A short time later, during vacation, I showed my hand to a semiretired physiatrist.
As a physiatrist, he dealt with a considerably older patient population, mostly elderly male veterans. It took him just a few seconds to identify the problem. First, he ruled out rheumatoid arthritis. Then he asked me to try to flatten my hand on the picnic table. Seeing that I couldn’t satisfactorily perform the “tabletop test,” he said I had Dupuytren’s disease (see “Fast Facts About Dupuytren’s”) and told me that it probably would get worse and that I’d need surgical repairs.
Author’s left hand, with (A) zigzag scar from open palmar fasciectomy performed in 2004 to correct contracture of the ring finger; (B) site of Dupuytren’s cord into which Jennifer Wolf, MD, injected Xiaflex in 2012, resulting in cord rupture and release of little finger contracture; (C) pit and ridge from diseased tissue not injected; (D) a Dupuytren’s nodule not injected owing to risk of tendon rupture; nodule causes slight bend in finger but does not impair function.
Eventually it became difficult or impossible to perform ordinary activities, such as inserting my hand in a pocket, grasping objects, and washing my face. Washing entailed the risk of poking the bent finger in my eye, which I did more than once. So in 2003, I consulted a hand specialist at the University of Connecticut Health Center, and soon she performed a delicate surgery — open palmar fasciectomy. It took her about 90 minutes to remove the collagenous cord that prevented the finger from being straightened.
Hand in a splint
By design, the procedure resulted in an open surgical wound that required daily care. At night, I slept with my hand in a splint to keep it straight. During the day, I did various exercises to restore function and strength, which were complemented by a long and tedious series of visits to a physical therapist. I experienced little postoperative pain, though my fingertips tingled unpleasantly for months, but while waiting for my PT appointments, I saw some patients in considerable pain. The next year, I went through the same routine with the ring finger on my left hand. At my last visit, my surgeon told me my disease was so active she expected me to need additional treatment eventually.
Her prediction was accurate: About two years ago, new collagen buildup became evident on my left palm, and my little finger began bending. Eventually normal function was impaired — I couldn’t type well, couldn’t apply shaving cream easily, couldn’t play the piano more than a few minutes without discomfort. So I returned to the health center for evaluation to determine if I was a candidate for a new biologic, Xiaflex, instead of surgery. Although I was pleased with the results of the surgeries, I wanted to avoid a third one if at all possible.
Xiaflex (collagenase Clostridium histolyticum; Auxilium Pharmaceuticals) had been in clinical trials when I had my surgeries, but in early 2010 it was approved by the FDA for treatment of adults with Dupuytren’s contracture, provided they have a palpable cord; it’s a recombinant enzyme intended to break up the collagenous deposits. By this time, my original surgeon was no longer with the institution, but her successor, Associate Professor of Orthopedic Surgery Jennifer Wolf, MD, a hand specialist, said Xiaflex would indeed be appropriate.
A few weeks later, after my health insurer had issued prior authorization and a specialty pharmacy had collected my copayment, she made three shallow injections in my palm, directly into the cord, with a very fine needle. It took about 10 seconds for all three, and the discomfort was minimal. I say this as a person with an extreme dislike of needles.
She didn’t inject any collagenase into or near the diseased area along the proximal phalanx because of the risk of tendon rupture at that site. She told me my hand would swell as the collagenase acted, and she wrapped my hand in gauze to protect the area that might become tender. She asked me to return the following morning so she could manipulate the injected area and break the weakened cord.
I drove home by myself, in contrast to being driven home after the outpatient surgeries with my arm in a sling and my head in the asteroid belt, and I attended to some income-generating work — in contrast to sprawling on a bed for the rest of the day while oxycodone dulled the postsurgical pain. In 2003, as the time for the first surgery neared, not knowing what I’d be able to do afterward, I declined a freelance project that might have generated $3,000 or $4,000 in badly needed income — and that decision turned out to be a “good” one.
By the time I went to bed, I had discarded the gauze. I slept well but awoke around 2 a.m. and, without thinking, stretched the fingers of my left hand. As I did, I heard a rather loud pop emanate from my hand — the sound of the cord breaking! Now very alert, I realized I had straightened all my fingers.
An octave and a third
In the morning, before leaving for my follow-up appointment, I sat down at the piano and discovered I once again could span an octave and a third (10 white keys) — an impossibility on the previous day, and for many months before that — and that I could play without experiencing the discomfort previously induced by only a few minutes of playing.
I thought I was an outlier with respect to my experience with collagenase injections. When I described my experience to a former regional sales director for Auxilium at the time of Xiaflex’s launch, he told me my case sounded fairly typical. The sales director works for another pharmaceutical company now, but he says that in his 36 years in drug sales, Xiaflex stands out as the “funnest” drug he’s ever sold. That’s because positive results often are seen very quickly, to the delight of patient and physician alike.
“Very seldom do you see such dramatic results 24 hours after a person receives a drug,” he says. “I saw hundreds of patients injected with Xiaflex. About 85% had a hand that was close to or nearly flat after the first set of injections, and another 10% needed a second set of injections.” In a small percentage, he says, the injection didn’t work the first time, possibly because the physician prepared the syringe improperly or failed to inject the drug properly, or both.
The former sales director managed a team of seven specialty sales managers in the Pacific Northwest, augmented by a group of three support personnel (reimbursement specialist, medical scientific liaison, market access director). Initially, the sales team encountered healthy skepticism about Xiaflex when calling on hand specialists, whether at teaching institutions or in private practice. We’re surgeons, we’re trained to cut — that was their general reaction. Once they saw how well and rapidly the drug worked, however, their skepticism vanished, he says.
High patient appeal reported
I wondered whether some physicians initially shied away from Xiaflex, consciously or unconsciously, because injecting collagenase is a quick office-based procedure generating less revenue in comparison with palmar fasciectomy. The sales director says that wasn’t the case, because physicians soon realized they could spend more time with other patients if they treated their Dupuytren’s patients with Xiaflex, and because patients who received Xiaflex tended to be very happy.
Further, he says, in contrast to the manufacturer’s expectation that many patients would need two or three separate sets of injections about four weeks apart, most required only one set. Making just one copayment (mine was about $700, but copayments may be considerably higher or lower, depending on the patient’s health plan) instead of three presumably enhances the drug’s appeal to patients.
“I haven’t done a Dupuytren’s surgery in a while,” says Jennifer Wolf, MD, the author’s treating physician. She’d like to see long-term recurrence data published for Xiaflex to support her perception that it’s similar to fasciectomy.
My surgeon, Wolf, says that’s been her experience, too. At UConn, where her patients are drawn from the general population, she sees about 50 or 60 Dupuytren’s patients annually, compared with 150 in a previous position serving veterans. The majority of her patients receiving Xiaflex have needed only one set of injections, and she has yet to provide any patient with three sets.
“I haven’t done a Dupuytren’s surgery in a while,” she said when I recently visited her in my role as freelance writer, noting that one was scheduled for the following week. The few fasciectomies she performs today are for patients with recurrent disease or those whose contracture is caused by a retrovascular cord (on the dorsal side of the fascia and hence not palpable on the palm). On occasion, she performs a fasciectomy for the rare patient who insists on the surgery out of a desire to have all the diseased tissue excised to reduce the risk of recurrence. For the moment, Wolf thinks recurrence rates after fasciectomy or collagenase injections are similar, but she’s eager to see long-term recurrence data published for Xiaflex to support her perception.
On the other hand
As an academician, Wolf says the chief drawback to using injectable collagenase is that it denies her the marvelous opportunity afforded by open fasciectomies to teach students and residents about the intricacies of hand anatomy. Conversely, she says, administering Xiaflex enables her to teach others about an “amazing new technology.”
Wolf says patients who want to make sure they receive Xiaflex if it’s appropriate should consult surgeons with a thorough understanding of hand anatomy and ask them about their familiarity and experience with Xiaflex and whether or not they have completed the training program required under the FDA’s Risk Evaluation and Management Strategy for Xiaflex.
Some physicians may not yet be familiar with Xiaflex because it got off to a slow start.
The former market access director who worked in the Northwest said Xiaflex had to overcome a unique set of challenges when the product was launched. Before the availability of a product-specific J-code for Xiaflex, physicians had to submit lots of documentation to support commercial prior-authorization requests and eventual claim to payment. Even Medicare required billing specification to support reimbursement for a product-unlisted J-code and an unlisted procedural CPT code. In addition, there was the question of how to bill for the post-injection manipulation — a lot of hassle.
Another hurdle that physicians faced was determining how to acquire the drug. Did they want to emulate oncologists and engage in “buy-and-bill,” laying out a lot of their own money up front, or did they want to have their patients go through specialty pharmacies? As orthopedic and plastic surgeons, the physicians lacked familiarity with buy-and-bill and prior authorization, and so did their staffs.
Yet another formidable barrier was that Auxilium was trying to introduce a foreign concept to surgeons: “We were telling surgeons to put down their scalpels and pick up a syringe,” the former market access director says. “It wasn’t easy to change their approach.”
Moreover, although there’s a substantial population in the U.S. with Dupuytren’s, initially far fewer patients sought treatment with Xiaflex than the company expected, he says. So Auxilium turned to direct-to-consumer advertising in places with an older population that includes a substantial percentage of people of northern European descent, good payer coverage, and a solid “injector base,” chiefly hand specialists.
Greater Pittsburgh, where I was born and raised, is a good example of a community meeting these criteria, and Auxilium sometimes runs full-page ads in the Pittsburgh Post-Gazette to alert readers to the availability of Xiaflex. The ads feature a large photograph of a hand with a crooked ring finger and a discernible cord, presumably to catch the attention of people who recognize the condition but don’t know its name.
Keith Denkler, MD, a clinical professor of plastic surgery at the University of California – San Francisco with a private practice in Larkspur, Calif., was one of the first physicians in the U.S. to use Xiaflex after its FDA approval, and to date he’s used 400 vials to treat patients with Dupuytren’s. He also was the first physician on the West Coast to perform percutaneous needle aponeurotomy, having performed over 3,500 since learning the procedure in 2005 through a training program in Paris. Although he’s a paid speaker for Auxilium, he doesn’t steer patients toward Xiaflex. Instead, he says, he helps patients determine the best therapeutic approach by asking them which factor they regard as most important (see “Ranking Xiaflex, Percutaneous Needle Aponeurotomy, and Palmar Fasciectomy” on page 42). Today he treats about half of his Dupuytren’s patients with needle aponeurotomy and half with collagenase injections, sometimes using aponeurotomy and Xiaflex in combination (an approach that isn’t an FDA-approved application for Xiaflex).
Only a small percentage of Denkler’s Dupuytren’s patients undergo fasciectomy — in his office, under local anesthesia (Denkler 2005) — and only for primary disease. If a patient previously treated with fasciectomy presents with recurrent disease, Denkler uses Xiaflex the second time because he likes the way the enzyme breaks up scar tissue. He said he shuns fasciectomy for recurrent Dupuytren’s because the risk of serious complications (digital artery and nerve injuries) is about 10 times as high in patients with recurrent disease as in primary disease, roughly 20% vs. 2% (Denkler 2010).
Xiaflex is likely to gain favor in managed care organizations for treatment of Dupuytren’s because of its diminished complication rate, which should result in savings, says Keith Denkler, MD, clinical professor of plastic surgery at the University of California–San Francisco.
When Denkler uses Xiaflex, he uses the whole vial instead of discarding unused collagenase. Since this involves five or six injection sites and sometimes more, instead of the usual three injection sites, he numbs the area prior to injection. Although this is not an FDA-approved application for Xiaflex, he’s confident in his unorthodox approach: “So far I’ve used 400 vials without hitting the nerve and without tendon rupture or infection,” he says.
“Spreading out the injections makes it less likely to dissolve deep in any one area and cause tendon injury,” he explains. It is his first choice for patients who have already had surgery since, he says, it dissolves scar tissue and Dupuytren’s without injuring neurovascular structures containing a different type of collagen that Xiaflex does not affect. He also recommends Xiaflex as an excellent first step for severe proximal interphalangeal (PIP) contractures (Denkler 2012).
Denkler expects Xiaflex to gain favor among managed care organizations for treatment of Dupuytren’s because of its diminished complication rate, which he says should result in savings. He also says MCOs should be alert to increased use of radiation therapy to treat early Dupuytren’s. Some patients with early disease but no impairment are so anxious about experiencing any loss of function that he refers them to a therapeutic radiologist; the expensive treatment seems to quiet the disease process in about 1/3 of patients. The former managed care director says that from a payer’s perspective, the cost of collagenase injections is approximately equal to that of fasciectomy plus physical therapy, but from the patient’s perspective, taking quality of life and lost income into consideration, Xiaflex often is the clear winner. Overall, Wolf and Denkler both agree that Xiaflex is a welcome addition for treating Dupuytren’s contracture and will lessen the need for invasive hand surgery with its long rehab and increased complication risk.
|Ranking Xiaflex, percutaneous needle aponeurotomy, and palmar fasciectomy|
|Source: Keith Denkler, MD|
Fast facts about Dupuytren’s
- Benign connective tissue disorder of the palmar fascia that may lead to disabling contracture of one or more fingers, owing to formation of collagenous cords along fascia
- Joints commonly affected: metacarpophalangeal (MCP), proximal interphalangeal (PIP)
- Most commonly affects people of northern European descent; about 3% to 6% of white adults will develop Dupuytren’s in their lifetime
- Other risk factors: tobacco use, diabetes, alcohol use, HIV
- Usually emerges in middle age, affecting both hands in many patients
- Diagnoses per year, U.S.: 300,000
- Surgeries per year, U.S.: 70,000
- Most common physician-reported complications in patients with primary disease: wound-healing complications and pain
- Most common physician-reported complications in patients with recurrent disease: injuries to digital nerve or artery (about 20%, vs. 2% in primary disease)
- All interventions are corrective, not curative
- Open palmar fasciectomy — the leading surgical approach
- Percutaneous needle aponeurotomy — office-based procedure more common in Europe than U.S.A.
- Xiaflex — recombinant collagenase injected into cord in office-based procedure
- Famous people who’ve had Dupuytren’s: President Ronald Reagan, U.K. Prime Minister Margaret Thatcher, Scottish actor David McCallum (Man From U.N.C.L.E., NCIS), English actor Bill Nighy, Irish playwright Samuel Beckett, Scottish author and playwright James Barrie (Peter Pan), classical pianist Misha Dichter (of Polish-Jewish descent), who feared Dupuytren’s had ended his career but eventually regained virtually all his skills after surgery in 2007
Dupuytren’s disease timeline
c 1000 BC — An Egyptian dies with Dupuytren’s contracture in the left hand, as determined by examination of the mummified remains in 2010.
1500s — “Curse of the MacCrimmons” is said to afflict the little finger on the right hand of renowned bagpipers on the Isle of Skye, causing their fingers to bend so deeply into their palms that they can’t play their instruments.
1614 — A Swiss doctor, Felix Plater, describes a stonemason whose left ring finger and little finger were contracted into his palm, but he incorrectly ascribes the condition to a problem with the tendons.
1777 — The eminent English surgeon and anatomist Henry Cline Sr. describes finger contractures caused by the fascia (as opposed to tendons); he later proposes a surgical approach — palmar fasciectomy.
1822 — Astley Cooper, a student of Cline’s, describes a surgical treatment for the condition now known as Dupuytren’s contracture (which just as easily could have been named Cline-Cooper’s contraction).
1831 — The famous French anatomist and surgeon Baron Guillaume Dupuytren presents a lecture, in which he, like Cline, reports that the fascia is the cause of the contractures. During his lecture he performs an open fasciectomy on a 40-year-old coachman.
1971 — “Enzyme fasciotomy” using trypsin and hyaluronidase is employed during surgery to treat Dupuytren’s but without producing satisfactory long-term results.
1972 — A specialized fibroblast, the myofibroblast, is implicated in the pathogenesis of Dupuytren’s disease.
1980s — At Stony Brook University Medical Center, Lawrence Hurst, MD, and Marie Badalamente, PhD, begin investigating novel noninvasive treatments for Dupuytren’s contracture.
1996 — In vitro study by Hurst, Badalamente, et al. suggests the possibility of using collagenase injections to treat Dupuytren’s.
2007 — Start of CORD I (NCT00528606), a phase 3 trial comparing collagenase injections vs. placebo in 308 patients with Dupuytren’s contracture (Hurst 2009).
2009 — Hurst, Badalamente, and Edward Wang, MD, receive the Orthopaedic Research & Education Foundation Clinical Award for two decades of research suggesting that collagenase injections could be used to treat Dupuytren’s contracture.
2010 — FDA approves Xiaflex (collagenase Clostridium histolyticum) for treatment of Dupuytren’s contracture in patients with a palpable cord.
2013 — Final data collection for CORDLESS (NCT00954746), a long-term assessment of the durability of the response to collagenase injections in patients who received at least one injection of collagenase in trials sponsored by the manufacturer, Auxilium Pharmaceuticals.
2013 — University of Alberta begins recruiting 300 patients for a trial (NCT01776892) comparing collagenase injections with needle aponeurotomy; study also will compare the combination of aponeurotomy and collagenase injections with each individual treatment; it is expected to be continued until 2020 to allow long-term evaluation.
Jack McCain is a freelance medical writer and editor in Durham, Connecticut.
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