Dupuytrens disease is a deforming condition of the hand in which one or more fingers contract toward the palm, often resulting in physical disability. The onset of Dupuytrens disease is characterized by the formation of nodules in the palm that are composed primarily of collagen. As the disease progresses, the collagen nodules begin to form a cord causing the patients finger(s) to contract, making it impossible to open the hand fully. Patients often complain about inability to wash their hands, wear gloves, or grasp some objects. Dupuytrens disease has a genetic basis and it is most prevalent in individuals of northern European ancestry. Well-known individuals with Dupuytrens disease include President Ronald Reagan and Prime Minister Margaret Thatcher.
The only proven treatment for Dupuytrens disease is surgery. Recurrence rates can range from 26-80%. The post surgical recovery is often associated with significant pain, delayed return to work, and extended periods of post-operative physical therapy. Because many of the individuals with Dupuytrens disease are older than 60 years of age, there is considerable resistance from the patients to undergo the surgical procedure, which also involves the risk of general anesthesia. We anticipate that many of the patients who are now willing to live with the disease, given the current treatment options, would be receptive to an alternative treatment involving an injection into the hand that could be performed in an office setting.
Hand surgeons note that the Dupuytrens disease surgery is
tedious, lengthy and poorly reimbursed in the United States
(the U.S.). Average cost of surgery for Dupuytren's Disease
are $5,000 in the U.S. and $3500 in Europe. Auxilium has reported
that U.S. based hand surgeons would recommend the use of collagenase
injection on 76% of the patients who were candidates for surgery.
This figure confirms an earlier survey of U.S. hand surgeons
conducted by us, which found that they would recommend the
use of collagenase injection on 80% of patients considered
eligible for Dupuytrens disease surgery.
Phase 2 Trials
A Phase 2 clinical study was designed to evaluate the relative safety and efficacy of collagenase compared to placebo injection in improving the degree of flexion deformity, and range of finger motion in patients with Dupuytrens disease. The investigation was carried out as a randomized, double-blind placebo-controlled clinical trial using collagenase or placebo. Thirty-six metacarpophalangeal (MP) patients and thirteen proximal intraphalangeal (PIP) patients were enrolled in the study. The success rate was determined one month after the first injection of collagenase or placebo.
The overall success rate, defined by the primary endpoint of reduction in contracture to 05, was approximately 80% (fourteen out of eighteen patients) for MP joints (p=0.001) and approximately 70% for PIP joints. Adverse events reported during this protocol included pain and swelling of the hand, bruising, and post-injection self-limiting swelling of the lymph nodes. Some patients experienced transient increases in blood pressure on the day of injection, which were attributed to anxiety in anticipation of the treatment. Only one serious adverse event was reported and it was not attributed to the product by the clinical investigator.
This study demonstrated a statistically significant reduction in contracture to within 0-5 of normal and improved range of motion at 7 and 14 days and at one month after a single injection of collagenase into the cord affecting the MP joint. The placebo treatment group did not show statistically significant improvement in degrees of contracture, range of motion or grip strength.
A second Phase 2 study designed as a double-blind, randomized, parallel group, placebo-controlled, dose response clinical trial was conducted. Fifty-five MP patients and twenty-five PIP patients with a mean baseline fixed flexion deformity of forty-nine degrees were enrolled in the study at two centers. Patients were treated with low (2,500), mid (5,000) or high (10,000) number of units of collagenase or placebo. The overall success rate and primary endpoint was defined as reduction in contracture to 0 5 one month after the first injection.
Eighteen out of the twenty-three patients (78%) who received the high number of units returned to normal extension (0-5) at one month post-treatment as compared to ten out of twenty-two (45%) in the mid number of units group, and nine out of eighteen (50%) in the low number of units group. There was no response to placebo in any patient. For PIP joints, five out of seven (71%) patients who received the high number of units of collagenase returned to normal extension at the one month post-treatment as compared to four out of seven (57%) patients in the mid number of units group, two out of four (50%) in the low number of units group and zero out of seven (0%) in the placebo group. For MP joints, thirteen out of sixteen (81%) patients who received the high number of units group of collagenase returned to normal extension at the one month post-treatment as compared to six out of fifteen (40%) patients in the mid number of units group, seven out of fourteen (50%) in the low number of units group and zero out of ten (0%) in the placebo group.
None of the serious adverse events that occurred were attributed by the investigators to the study drug.
Pivotal Trial
Auxilium announced on June 21, 2006 the results of a pivotal trial. They stated:
The randomized, double-blind, placebo-controlled pivotal efficacy study showed that a local injection of AA4500 [injectable collagenase] was highly effective in the treatment of Dupuytrens Contracture. In this trial involving a total of 35 patients, 23 patients were randomized to receive AA4500 (up to three injections) and 12 patients were randomized to receive placebo, with the goal of reaching therapeutic success. Therapeutic success was defined as reaching a reduction of the contracture of the affected joint to less than five degrees, essentially allowing the hand to be flat when placed on a table. AA4500 achieved a 91% success rate for the primary endpoint of less than five degrees of contracture in treated joints, both Proximal Intra-Phalangeal, or PIP, joint and Metacarpal Phalangeal, or MP, joint, after up to three injections, compared to a 0% response rate in the placebo group (p<0.001). The mean number of injections per joint was 1.4. These results were consistent with those from a Phase II study published in The Journal of Hand Surgery (2002:27A: 788-798).
The results observed after a single injection of AA4500 showed that 70% of subjects achieved therapeutic success; no patients responded to placebo (p<0.001).
The most commonly reported adverse events were pain and swelling (edema) of the hand at the injection site, and post-injection temporary swelling of a modest nature in the lymph node area of the armpit was reported in 30% of subjects. There were no serious adverse events reported that were judged by the investigator to be related to treatment with AA4500.
Development Status
On August 16, 2007, Auxilium announced that the Company has
received clearance from the U.S. Food and Drug Administration
("FDA") to resume its phase III clinical trials for XIAFLEX (clostridial
collagenase for injection), formerly referred to as AA4500, in
the treatment of Dupuytren's contracture.
Currently, the only proven approach to treating Dupuytren's disease is
through surgery. Clinical trials are in progress to investigate non-operative
therapy for Dupuytren's disease using BioSpecifics injectable Collagenase (AA4500).
The FDA has accorded "Orphan Drug Status" to this usage and a U.S.
patent has been granted. The phase III clinical trial is now underway by
our licensee, Auxilium Pharmaceuticals (Nasdaq: AUXL).
Dupuytren's Disease References
Useful Websites:
http://www.pncl.co.uk/~belcher/dupuytrn.htm
http://www.centerwatch.com/studies/STU2496.HTM
http://www.lahey.org/orthopaedisurgery/updates/dupuytrens.asp
Dupuytren's Disease Patient
Discussion Forum
Literature:
1. Badalamente, M.A., Hurst, L.C. Enzyme Injection as a Nonoperative
Treatment for Dupuytren's Disease. Drug Delivery, 3:35-40, 1996
2. Starkweather, KD., Lattuga, S., Hurst, L.C., Badalamente, M.A., Stony
Brook, NY, Guilak, F., Durham, NC, Sampson, S.P., Dowd, A., Stony Brook, NY,
Wisch, D., Torrington, Ct. Collagenase in the Treatment of Dupuytren's Disease:
An In Vitro Study. The Journal of Hand Surgery, 1996; 21A: 490-495.
3. Badalamente, M.A., Hurst, L.C. and Hentz V.
Collagen as a clinical target: Nonoperative treatment of Dupuytren's
disease. The Journal of Hand Surgery, 2002; 27A: 788-798.
