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Auxilium’s (NASDAQ:AUXL) Xiaflex FDA Advisory Panel will likely be focused on a surgeon education and training program that will be in place to limit side effects from improper use, such as tendon rupture and digital nerve damage, hand surgeons told Pharmawire.
The FDA’s Arthritis Advisory Committee will tentatively review Xiaflex on 16 September 2009. The FDA advisory committee is looking at including hand and/or orthopedic surgeons on the panel, but the breakdown has not been revealed, according to Will Sargent, vice president of investor relations and corporate communications at Auxilium.
Regardless of the FDA pathway, Auxilium believes that educating the surgeon base about the proper technique for injecting Xiaflex is important, Sargent said. The company is planning a “robust” education program that it plans to share with the FDA, and is in a dialogue now, he said. The education program would ensure that surgeons are aware of the risk/benefit profile and are aware of what worked best in clinical testing, he added.
Dr Srinath Kamineni, a consultant orthopedic surgeon and elbow, shoulder, hand and wrist specialist in London, said that extensive training is needed - citing the potential risks of tendon rupture and nerve damage with injections. Tendon rupture is a huge concern because if Xiaflex is injected in the wrong place, it could lead to tendon breakdown, he said.
In the CORD I and II studies, the open-label JOINT I and II studies and the pharmacokinetics study, there were a total of three confirmed tendon ruptures (rate per injection = 0.14%); one reported tendon rupture remains unconfirmed (rate per injection = 0.05%).
The rate of tendon rupture is probably acceptable, according to Dr Roy Kulick, associate professor of orthopedic surgery at Albert Einstein School of Medicine and director of orthopedic hand surgery at Montefiore Medical Center in New York. If the cord is on top of a tendon, ruptures could occur if the injections are deep but they do not happen often, he said.
Tendon rupture is a major concern, said Dr Robert Szabo, professor of orthopedic and plastic surgery at the UC Davis School of Medicine. The clinical trials have been performed by surgeons who are more familiar with the disease so the results are better than they will be once Xiaflex is available to the public. The concern is that Xiaflex will have to be limited to surgeons, he said. If it is marketed to everyone, there will be a lot of problems, he added.
It is really a question of training, said Dr Larry Hurst, chief of hand surgery and chair of the department of orthopedics of the Health Science Center at the State University of New York at Stony Brook, and primary investigator of the CORD trials, noting that certain trials in Australia were done by rheumatologists.
The rate of tendon rupture was reasonable, said Dr Roy Meals, a clinical professor of orthopedic surgery at the University of California, Los Angeles, and an investigator for Xiaflex. Tendon rupture is partly technique dependent, he said. Education will probably start in hand surgery, where surgeons will be taught the potential risks and benefits of Xiaflex so they can use it safely, he said.
Xiaflex should be approved but with some reservation about widespread use, noted Dr William Townley, a plastic surgeon at Salsbury District Hospital in the UK. The agent will probably have the best safety if given by qualified hand/plastic surgeons with the appropriate anatomical knowledge, experience and ability to deal with complications, as well as awareness of surgical alternatives, he said.
The technique should be relatively easy to pick up, but the company will need to tell doctors to learn it well or else might Xiaflex may cause tendon rupture, said Dr F. Thomas Kaplan, a surgeon at the Indiana Hand Center.
Meals said many physicians hope that Auxilium will restrict the distribution of Xiaflex to prevent rheumatologists and dermatologists from using it because there would probably be more tendon ruptures if they did. These specialties have not seen the cord of tissue that causes the contracture and do not have a good spatial understanding of the hand, he said. “It is a scary thought,” he added.
However, the severity of the rupture depends on which tendon is affected since some patients would not even know that a tendon ruptured if it did not disrupt motion, Meals said, noting that these patients already have limited motion from the contracture and that if Xiaflex brings the contracture towards normal a tendon rupture is much less of a consequence.
Yet a surgeon who spoke on the condition of anonymity said that since some authors are reporting tendon ruptures, he believed that “the nails are in its coffin.” Fasciectomy or fasciotomy seem much safer, he added. The surgeon was not aware of any cases of neurolysis, but said that the occurrence is feasible.
Dr Bing Siang Gan, a surgeon at the Hand and Upper Limb Centre at the University of Western Ontario, agreed that any tendon rupture is one too many.
With nerve damage, the risk becomes higher as one injects distally, similar to traditional surgery, Kamineni explained. In over 1000 patients and over 700 injections, there was no nerve damage, Hurst said. Kaplan also described nerve injury as surprisingly low and added that no one reported temporary numbness.
However, in Dupuytren’s, nothing is standard and predictable and while the cord can be palpated, it is not possible to feel the nerves so a physician would know where to inject but would not know where not to inject, Szabo cautioned.
There are different forms of collagen and some are resistant to collagenase, Meals said when asked about the potential for neurolysis. Some patients have experienced skin lacerations with Xiaflex, he noted.
One plastic surgeon noted that improper injection could result in serious consequences. If improperly injected into a digital artery, patients can lose a finger since Xiaflex works through dissolution, he said. He also noted that accidents may result in skin loss.
Vessel rupture is also a concern since many vessels are covered in collagen, said Kamineni, who explained that this could result in hematomas. There is a potential complication of hitting normal tissue with Xiaflex that is depends on on how and how often it is given, said Dr Scott Zashin, a rheumatologist and clinical associate professor of medicine at the University of Texas, Southwestern Medical School.
According to Sargent, while nerve damage appeared to be an issue in vitro, Xiaflex does not appear to affect the nerve, large arteries, or veins.
Kamineni said that lack of proper training is the “quickest way to go wrong” for the company but believed that Xiaflex genuinely has a place in treating Dupuytren’s contracture.
Physicians are optimistic about approval, but there is a concern that problems may emerge if patients who do not need Xiaflex get treated with it due to the convenience of administration, Szabo said.
Meals agreed that hand surgeons were enthusiastic over the potential for Xiaflex, but noted that many adverse effects are often identified after an agent comes to market. However, he said that Xiaflex seems remarkably safe.
Auxilium has a market cap of USD 1.33bn.
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