Pipeline
Collagenese has been tested in 11 clinical indications and over 2,200 patients. Three indications are currently in advanced-stage clinical trials: Dupuytren's Disease, Peyronie's Disease and Frozen Shoulder.
Dupuytren's Disease
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Dupuytren's contracture is a deforming condition of the hand in which one or more fingers contract toward the palm, often resulting in physical disability and limiting the range of motion of the fingers. This disease has a debilitating effect on quality of life, and patients often complain about their inability to wash their hands, wear gloves or grasp objects. Dupuytren's contracture has a genetic basis and is most prevalent in individuals of northern European ancestry. Currently, the only available treatment for Dupuytren's contracture is surgery, which generally yields unpredictable results and occasional complications. Recurrence rates can range from 26-80%, and 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 Dupuytren's contracture are older than 60 years of age, there is considerable resistance from patients to surgery, which involves the risk of general anesthesia. An alternative treatment could offer a potential improvement for patients with Dupuytren's contracture. Treatment with XIAFLEX™ requires no anesthesia, is minimally invasive and can be performed in an office setting. It is estimated that one million patients are seeking treatment for this disease annually, with approximately 240,000 new patients in the U.S. and Europe each year. BioSpecifics Technologies Corp.'s market research has shown that hand surgeons are highly receptive to this therapy and have noted that surgery is tedious, lengthy and poorly reimbursed in the U.S. Our strategic partner, Auxilium Pharmaceuticals, Inc.,has reported that U.S.-based hand surgeons would recommend the use of collagenase injection on 76% of patients who were candidates for surgery. This figure confirms an earlier survey of U.S. hand surgeons conducted by BioSpecifics, which found that surgeons would recommend the use of collagenase injection on 80% of patients considered eligible for Dupuytren's disease surgery. Development Status Auxilium's Biologics License Application (BLA) to market XIAFLEXTM in the U.S. for this indication has been accepted for review, and has been granted priority review, by the U.S. Food and Drug Administration. The submission was based on data from a total of 1,082 treated Dupuytren's contracture patients and over 2,600 injections of XIAFLEXTM. On September 16, 2009, the Arthritis Advisory Committee of the FDA unanimously recommended, by a vote of 12 to 0, that the FDA approve XIAFLEXTM for the treatment of Dupuytren's contracture. The primary endpoint of the Phase 3 trial was reduction in contracture to within 0-50 of normal. On average, Dupuytren's contracture patients who achieved the primary endpoint received 1.5 XIAFLEX™ injections. The key secondary endpoints were: greater than or equal to 50% improvement in contracture and change in primary joint degree of contracture. Both the primary endpoint and secondary endpoints were highly statistically significant, overall 25 out of the 26 endpoints in the study were met with statistical significance.
In the Cord I study involving 306 patients in 16 U.S. centers, 203 patients received XIAFLEXTM and 103 received placebo. 64% of XIAFLEXTM patients met the primary endpoint versus 6.8% for placebo (p < 0.001). Additionally, every one of the 26 secondary endpoints in the study were met with statistical significance. The key secondary endpoints were: greater than or equal to 50% improvement in primary joint contracture and change in primary joint degree of contracture. First, four out of five of the patients' primary joint contractures improved by at least 50%. Second, the average degree of improvement in contracture from baseline was 79.3% for primary joints treated with XIAFLEXTM, compared to placebo patients, where the average percent improvement in contracture from baseline was 8.6% (p < 0.001). In the Cord II study involving 66 patients in 5 Australian centers, 45 patients received XIAFLEXTM and 21 received placebo. 44% of XIAFLEXTM patients met the primary endpoint versus 4.8% for placebo. The results were statistically significant with a p < 0.001. These results were published in the September 3, 2009 edition of The New England Journal of Medicine in an article entitled "Injectable Collagenase Clostridium Histolyticum for Dupuytren's Contracture." References:
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Peyronie's Disease
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Peyronie's disease is characterized by the presence of inelastic collagen on the shaft of the penis, which can distort an erection and make sexual intercourse difficult or impossible in advanced cases. Significant psychological distress has been noted in sexually active patients with Peyronie's disease. Currently, there are no effective pharmaceutical therapies for this ailment. Frequent patient complaints include increased pain, painful erections, palpable plaque, penile deformity and erectile dysfunction. Patients with Peyronie's disease have been reported to have an increased likelihood of having Dupuytren's disease, frozen shoulder, plantar fibromatosis, knuckle pads, hypertension and diabetes. It is estimated that more than one million individuals worldwide are affected by this disease, which typically affects males in the range of 40-70 years of age. It is estimated that 475,000 patients seek treatment annually in the U.S. and Europe and 210,000 of these patients would be potential candidates for XIAFLEX™. The cause of Peyronie's disease is unknown, although some investigators have proposed that it may be due to trauma, or an autoimmune component. A number of researchers have suggested that the incidence of Peyronie's disease has increased due to the use of erectile dysfunction drugs. Currently, surgery is the only treatment option available to patients, and the results are variable. Surgery is often painful, requires general anesthesia and can cause a shortening of the penis. There is a general resistance to surgery by surgeons and patients. Our strategic partner, Auxilium Pharmaceuticals, Inc., has reported that of those patients who undergo surgery, 33% are subsequently dissatisfied with the results and frequently require a penile implant. Auxilium Auxilium Pharmaceuticals, Inc. has reported that 90% of urologists would use collagenase injection to delay or avoid surgery, and this finding is consistent with a survey of urologists performed for BioSpecifics Technologies Corp. Development Status BioSpecifics has conducted two Phase 2 clinical trials, Study 1030 and Study 1035, of clostridial collagenase. Study 1030 consisted of a 25 patient open label trial in which patients were administered three injections of clostridial collagenase over a period of seven to ten days. Patients then received a second series of three injections twelve weeks later. Patients were evaluated at three, six, and nine months post-injection. The positive results from this trial were published in the Journal of Sexual Medicine in January 2008. The results showed that significant decreases from baseline were achieved in the mean penile deviation angle at months three (P = 0.0001) and six (P = 0.0012) as well as plaque width at months three (P = 0.0018) and six (P = 0.0483). More than 50% of patients in this trial considered themselves “very much improved” or “much improved” at all time points in the study, and the clostridial collagenase treatment was generally well tolerated. Study 1035 consisted of a ten patient open label trial in which patients were administered three injections of clostridial collagenase in a three-treatment series. Patients were administered one injection per day, separated by at least one day each, over a seven day period. Patients then received two additional series of three injections, each separated by six weeks. The mean baseline deviation angle at the time the trial commenced was 50.2 degrees. At the nine month follow-up period (post-first injections), 25% or greater reduction in deviation angle was achieved in eight out of nine patients (or 89%) who completed the study (one patient had 24% reduction in deviation angle). 67% of patients in this trial considered themselves “very much improved” or “much improved” at all time points in the study, and the clostridial collagenase was generally well tolerated. The most common adverse events reported in Studies 1030 and 1035 were local administration site reactions that were mild or moderate in severity, non-serious, and resolved in time without medical attention. The Company's strategic partner Auxilium Pharmaceuticals, Inc. recently reported top-line efficacy and safety results from a U.S. Phase 2b trial of XIAFLEXTM in the treatment of Peyronie’s disease. In the Phase 2b trial, XIAFLEXTM demonstrated a statistically significant change overall compared to placebo at 36 weeks in both improvement in penile curvature (p=0.001) and the Patient Reported Outcome (PRO) Peyronie's disease bother domain (p=0.046). There was no statistically significant change in mean scores between XIAFLEXTM and placebo in the PRO penile pain, intercourse discomfort or intercourse constraint domains. XIAFLEXTM was well-tolerated and the most common treatment-related adverse events in the Phase 2b study were consistent with adverse events reported in previous Peyronie's disease trials with XIAFLEXTM, which included injection site bruising, edema and pain. In patients who received XIAFLEXTM during the Phase 2b study, a mean improvement of 29.7% in penile curvature from baseline to 36 weeks was seen (54.4 to 38.2) versus an 11.0% mean improvement in curvature seen in placebo patients (50.6 to 45.1); (p=0.001). In patients who received XIAFLEXTM, 60.5% of patients achieved the endpoint of at least a 25% reduction in angle of curvature compared with 25.0% of patients receiving placebo who achieved this endpoint. In the PRO Peyronie's disease bother domain, the overall XIAFLEXTM treatment arm experienced a benefit in mean change in score from baseline to 36 weeks that was significantly better than the overall placebo arm benefit (p=0.046). Auxilium Pharmaceuticals Inc. expects to meet with the U.S. Food and Drug Administration in the second quarter of 2010 to further discuss these results and its plans for Phase 3. References:
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Frozen Shoulder
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Frozen Shoulder (adhesive capsulitis) is an inflammation and thickening of the shoulder capsule. It is known to be caused by trauma but there are other unknown causes. It is estimated to affect between 20 and 50 million individuals worldwide with a slightly higher incidence in women. It typically occurs in patients between the ages of 40-70 years of age. Individuals with insulin-dependent diabetes have been reported to have a 36% higher incidence rate and have a greater likelihood of bilateral symptoms. One common therapy currently available is manipulation, which is painful and requires general anesthesia. It is estimated that 700,000 patients visit doctors annually in the U.S. for this clinical syndrome. Development Status: Positive results of a Phase II randomized, placebo-controlled and double-blind dose-response study were discussed in an oral presentation at the annual meeting of the American Academy of Orthopedic Surgeons (AAOS) in March 2006. Sixty patients were enrolled in the protocol: 47 women and 13 men. All patients received a randomized, placebo-controlled single injection of 0.5 mL of placebo or 0.145 mg, 0.29 mg, or 0.58 mg collagenase diluted in physiologic saline. Outcome measures including function score, pain score, strength and stability were evaluated using a form by the American Society of Shoulder and Elbow Surgeons. Results demonstrated a clinically meaningful difference in return to normal shoulder motion and function with drug treatment compared with placebo. Patients who received additional open-label 0.58 mg collagenase injections had improvements in shoulder motion, function and pain. These improvements occurred one day post-injection, and at one month, improvements were comparable to normal values. References:
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Additional Indications
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In addition to our lead product candidates, collagenase has been tested in the following clinical indications, some of which may also have promising veterinary applications: Lipomas Lipomas are benign fatty tumors that occur as bulges under the skin. An open-label Phase I clinical trial has been completed for treatment of lipomas utilizing a single injection of collagenase. This trial was designed based on observations made during preclinical studies that a collagenase injection decreased the size of fat pads in animals. Favorable initial results, demonstrating that 10 out of 12 patients had a 50-90% reduction in the size of the lipomas, were presented at a meeting of the American Society of Plastic Surgeons. Cellulite Cellulite is a condition characterized by dimpling of the skin typically affecting the thighs and buttocks. It is due to irregular and discontinuous subcutaneous connective tissue. An open-label study has been completed to assess whether injectable collagenase can restore the cellulite-affected areas to a more cosmetically acceptable appearance. An abstract of an article titled, "Collagenase Injection in the Treatment of Cellulite," by A. Dagum and M. Badalamente, describing the promising results of this study, was published in Plastic and Reconstructive Surgery on September 15, 2006. Other clinical indications for which collagenase has been tested include the following:
- Keloids |
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