Pipeline
Dupuytren's Contracture
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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 is most prevalent in individuals of northern European ancestry. XIAFLEX is the first and only FDA-approved nonsurgical treatment for Dupuytren's contracture. Previously, the only proven therapeutic option was 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. Development Status On February 2, 2010, the U.S. Food and Drug Administration (FDA) approved XIAFLEX for the treatment of adult Dupuytren's contracture patients with a palpable cord with no restrictions to the number of joints or limitations on the contracture severity. Phase 3 clinical trials yielded highly significant data regarding clinical endpoints. The primary endpoint of the Phase 3 trial was reduction in contracture to within 0-50 of normal. 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 XIAFLEX® and 103 received placebo. 64% of XIAFLEX 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 XIAFLEX, 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 XIAFLEX and 21 received placebo. 44% of XIAFLEX patients met the primary endpoint versus 4.8% for placebo. The results were statistically significant with a p < 0.001. The Cord I 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." The Cord 2 results were published in the December 2010 online edition of The Journal of Hand Surgery. 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 contracture, 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. 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 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. The Company's strategic partner Auxilium Pharmaceuticals, Inc. initiated a randomized, double-blind, placebo-controlled Phase 3 program in October 2010 and target enrollment was completed in March 2011. Over 800 patients are enrolled and the Company expects to report top-line results in the second quarter of 2012. This global Phase 3 program includes two randomized, double-blind, placebo-controlled Phase 3 studies with 800 patients at 70 sites in the U.S. and Australia. There is also one open label study, with 250 patients, at 30 sites in the U.S., E.U. and New Zealand, and one pharmacokinetic study, with 16 patients. In this global Phase 3 trial, XIAFLEX is administered two times a week every six weeks for up to four treatment cycles (2 x 4). Each treatment cycle is followed by a penile modeling procedure. Patients are followed for 52 weeks post-first injection in the double-blind studies and for 36 weeks in the open label trial. Auxilium previously reported top-line efficacy and safety results from a U.S. Phase 2b trial of XIAFLEX in the treatment of Peyronie’s Disease. In the Phase 2b trial, XIAFLEX 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 XIAFLEX and placebo in the PRO penile pain, intercourse discomfort or intercourse constraint domains. XIAFLEX 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 XIAFLEX, which included injection site bruising, edema and pain. In patients who received XIAFLEX 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 XIAFLEX, 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 XIAFLEX 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). 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: BioSpecifics reported positive results of a Phase II randomized, placebo-controlled and double-blind dose-response study in which 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. Auxilium has initiated a Phase IIa trial of XIAFLEX for the treatment of Frozen Shoulder and top-line results are expected in 1H13. This Phase IIa study is an open-label, controlled dose-ranging study designed to assess the safety and efficacy of XIAFLEX in comparison to an exercise-only control group. The study will involve approximately 50 adult men and women at approximately 9 sites throughout the US.
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Lipoma
Lipomas are benign fatty tumors that occur as bulges under the skin. There is a strong need for a minimally invasive approach for humans and canines.
Canine Lipoma:
Lipomas are found in 1.7 million dogs in the U.S. annually. As with humans, surgery is the most frequent option but it is risky, especially for older dogs, due to the need for general anesthesia. Based on BioSpecifics veterinarian market survey, each veterinarian peformed an average of 25 surgeries/lipoma excision annually. The survey concluded an estimate that veterinarians would use injectable collagenases on 22 dogs per year. The approximate current cost of treatment annually is believed to be $635M.
Chien-802 was designed to evaluate the efficacy of injectable collagenase in canine lipoma in four healthy dogs with subcutaneous lipomas. Inclusion criteria required the lipoma to be benign, superficial and easily measureable. All dogs had a second lipoma that was untreated and used as a control. At 90 days post injection, in the three evaluable dogs, the lipoma size was 0%, 0% or 7% of the original size as measured by a CT scan. By contrast, the untreated lipomas were 129%, 113% and 128% of the original size at day 90. Thus, the treated lipomas showed a 97% reduction in the size of the lipoma and an increase in the size of the untreated controls of 23%.
BioSpecifics plans to initiate Chien-804, a placebo controlled, single injection randomized clinical trial to evaluate the efficacy of XIAFLEX for treatment of benign subcutaneous lipoma shortly after receiving FDA (CVM) approval of the clinical trial protocols. The study will evaluate 32 dogs randomized 1:1 XIAFLEX to placebo.
Human Lipoma:
There are 575,000 U.S. patients diagnosed annually.
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 lipoma, were presented at a meeting of the American Society of Plastic Surgeons.
BioSpecifics will initiate a 14 patient, single center dose escalation study for the treatment of human lipomas shortly.
Cellulite
Cellulite, or edematous fibrosclerotic panniculopathy, is a condition characterized by dimpling of the skin typically affecting the thighs and buttocks. It results from collagen fibrous septae held in an irregular pattern that causes skin dimpling and affects 85-98% of women. There are no FDA approved medical therapies available today.
An open-label study has been completed to assess whether injectable collagenase can restore the cellulite-affected areas to a more cosmetically acceptable appearance. Ten female subjects were treated with a single 0.58 mg dose divided equally and given at 5 separate injection sites in a pilot open label study. A 76% reduction in the physician reported appearance of cellulite and a high patient satisfaction score was reported for this study.
Auxilium plans to initiate a Phase 1b study in which subjects will receive a single dose of XIAFLEX, which will be equally divided and given at 10 separate injection sites. The first of seven cohorts of subjects is planned to start in the first quarter of 2012 with subjects followed for 90 days. Auxilium hopes to identify the appropriate dose or doses of XIAFLEX that would result in improvements in cellulite noticed by both physicians and patients. Top-line proof of concept results are expected in the fourth quarter of 2012.
Additional Indications
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In addition to our lead product candidates, collagenase has been tested in the following clinical indications:
- Keloids
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