The US Food and Drug Administration (FDA) has accepted Auxilium Pharmaceuticals' filing for supplemental Biologics License Application (sBLA) for Xiaflex (collagenase clostridium histolyticum or CCH), a novel, in-office biologic therapy for the potential treatment of Peyronie's disease (PD).

With this the US FDA has also granted standard review status to Xiaflex. Under the Prescription Drug User Fee Act (PDUFA), the FDA is expected to take action on the application by September 6, 2013.

Xiaflex is currently approved in the US, EU, Canada and Switzerland for the treatment of adult Dupuytren's contracture patients with a palpable cord.  Xiaflex for the treatment of PD was granted orphan designation in the US by the FDA in January 1996 and, if approved by the FDA, is expected to be the first and only biologic therapy indicated for the treatment of PD.

"We are very pleased that Xiaflex was accepted for review as we believe there is a significant unmet need for a safe and effective treatment with proven results for patients exhibiting the classic penile curvature deformity and patient-reported bother associated with Peyronie's disease," said Adrian Adams, chief executive officer and president of Auxilium. "We look forward to working with the FDA as it reviews the application."

The sBLA submission of Xiaflex for the treatment of PD is based on data from the clinical studies known by the acronym IMPRESS – The Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies – and other controlled and uncontrolled clinical studies, in which over 1,000 PD patients were enrolled and received over 7,400 injections of Xiaflex. In the two identical phase III double-blind placebo-controlled IMPRESS studies, Xiaflex demonstrated statistically significant improvement in the co-primary endpoints of penile curvature deformity and patient-reported bother versus placebo. In IMPRESS I at 52 weeks, the co-primary endpoints met statistical significance with a 37.6 per cent mean reduction in penile curvature deformity for Xiaflex subjects (p=0.0005) and a 3.3 point improvement in the Peyronie's Disease Questionnaire (PDQ) bother domain for Xiaflex subjects (p=0.0451). In IMPRESS II at 52 weeks, the co-primary endpoints met statistical significance with a 30.5 per cent mean improvement in penile curvature deformity for Xiaflex subjects (p=0.0059) and a 2.4 point improvement in the PDQ bother domain for Xiaflex subjects (p=0.0496). Xiaflex was generally well-tolerated. The most common treatment related adverse events reported in the phase III studies were local to the treatment site and consistent with adverse events reported in previous PD trials with Xiaflex, which included injection site hematoma, pain and swelling.  Serious adverse events included corporal rupture (penile fracture) in 3 subjects in the placebo controlled studies.

PD is the development of collagen plaque, or scar tissue, on the shaft of the penis that may harden and reduce flexibility, causing the penis to deform in a bend or arc during erection. PD is commonly associated with significant disease bother, emotional distress, loss of self-esteem, and depression in addition to difficulty with sexual intercourse.  PD is a heterogeneous disease with an initial inflammatory component.

Auxilium's late stage global development plan for Xiaflex consists of four clinical studies and is known by the acronym IMPRESS – The Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies. There are two identical randomized, double-blind, placebo-controlled phase III studies, which enrolled over 800 patients combined at 64 sites in the US and Australia in less than five months, with a 2:1 ratio of Xiaflex to placebo. There is also one open label study, which enrolled at least 250 patients, at approximately 30 sites in the US, EU and New Zealand, and one pharmacokinetic study, which enrolled approximately 20 patients who were then enrolled into the open label study. Xiaflex was administered two times a week every six weeks for up to four treatment cycles (2 x 4). Each treatment cycle was followed by a penile modelling procedure. Patients were followed for 52 weeks post-first injection in the double-blind studies and were followed for 36 weeks in the open label and pharmacokinetic trials.

The trials' co-primary endpoints are percent improvement from baseline in penile curvature deformity compared to placebo and the change from baseline (improvement) in the PD bother domain of the PDQ compared to placebo. The PDQ also has two additional domains as secondary endpoints, which include severity of psychological and physical symptoms of PD, and penile pain. Safety measurements include adverse event monitoring and clinical labs. Immunogenicity testing was also performed.

The PDQ is a 15-question assessment of the impact of PD on a subject using 3 domains: PD bother, psychological and physical symptoms of PD, and penile pain (administered at screening, week 24, and week 52). The PDQ is a proprietary questionnaire that Auxilium developed with the FDA, starting in 2004, and evolved through the Xiaflex clinical PD studies into a validated tool for measuring PD bother.

Xiaflex (collagenase clostridium histolyticum or CCH) is a biologic approved in the US, EU, Switzerland and Canada for the treatment of adult Dupuytren's contracture (DC) patients with a palpable cord. Xiaflex is a minimally invasive treatment for this condition and consists of a highly purified combination of two subtypes of collagenase, derived from Clostridium histolyticum, in specific proportion. Together, the collagenase sub-types work synergistically to break the bonds of the triple helix collagen structure more effectively than human collagenase. An sBLA for Xiaflex for the treatment of PD has been accepted for standard review by the FDA. Additionally, CCH is in phase IIa of development for the treatment of Frozen Shoulder syndrome (adhesive capsulitis) and in phase Ib of development for the treatment of cellulite (edematous fibrosclerotic panniculopathy). Xiaflex has been granted Orphan status in the US by the FDA for DC and PD. Auxilium also has rights to pursue additional indications for CCH.

Auxilium Pharmaceuticals, Inc. is a specialty biopharmaceutical company with a focus on developing and marketing products to predominantly specialist audiences.