collagenase Clostridium histolyticum - Santyl ointment; Xiaflex
Status: approved; marketed
Organizations involved:
Auxilium Pharmaceuticals Inc.– Manuf.; R&D; Tech.; World mark.
DPT Labs. – Manuf.
DFB Pharmaceuticals Inc. – Parent
HEALTHPOINT, Ltd. – Parent
Pfizer - Former
Advance Biofactures Corp. – Manuf.; R&D; Tech.; Former
Biospecifics Technologies Corp. – Parent; Former
Abbott Labs. – Manuf. other; USA mark.; Former
Smith & Nephew, Inc. – Former
Knoll Pharmaceutical Co. – Former
BASF AG – Parent co.; Former
McNeil Pharmaceutical – Former
Johnson & Johnson Co. – Parent co.; Former
Agricultural Biologicals Corp. – Former
Description: This collagenase is associated with two products, Santyl, no longer manufactured (for the U.S. market at least), and current Xiaflex. Santyl ointment was a topical formulation of collagenase enzyme derived from fermentation of the bacterium Clostridium histolyticum. Xiaflex is a lyophilized (freeze-dried) powder for injection for treatment of patients with Dupuytren’s contracture. This enzyme is able to digest native and denatured collagen (a major structural component of dermal tissues), particularly collagen in necrotic tissue.
Xiaflex contains purified collagenase Clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria. Collagenase AUX-I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 114 kDa and belongs to the class I Clostridium histolyticum collagenases. Collagenase AUX-II is a single polypeptide chain consisting of approximately 1000 amino acids of deduced sequence. It has an observed molecular weight of 113 kDa and belongs to the class II Clostridium histolyticum collagenases.
Unlike Xiaflex, Santyl had a non-articulated composition (not the same as having a variable or non-specific composition, just that the components are not in a defined composition). Note, contrary to general practice, only one INN and one USAN name was assigned to the mixture of enzymes in Xiaflex.
Xiaflex is supplied as a sterile lyophilized powder (white cake) intended for reconstitution with 0.39 mL (for a MP joint) or 0.31 mL (for a PIP joint) of the supplied sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride) prior to intralesional injection into a Dupuytren’s cord. Xiaflex is packaged in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum. Each vial also contains 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine.
Potency (enzyme activity) is determined using an assay based on digestion of undenatured collagen (from bovine Achilles tendon) at pH 7.2 and 37˚C for 24 hours. The number of peptide bonds cleaved is monitored by reaction with ninhydrin. Amino groups digested by a trypsin digestion control are subtracted. One collagenase unit solubilizes ninhydrin reactive material equivalent to 4 micromoles of leucine.
Xiaflex is supplied in single-use glass vials containing 0.9 mg of collagenase Clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
Santyl ointment contained 250 collagenase units/gram in white petrolatum USP. Santyl was marketed in 15 gram and 30 gram tubes of ointment. The dating period for the ointment was four years at temperature ≤ 37˚C. The product is exempt from lot release requirements.
The dating period for Xiaflex (0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder) is 24 months from the date of manufacture when stored at 5 ± 3°C. The dating period for the sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride) shall be 30 months from the date of manufacture when stored at 2-8 °C. The dating period for your drug substance shall be 24 months when stored at ≤ -60°C. The expiration date for the packaged product, collagenase clostridium histolyticum lyophilized powder for reconstitution with calcium chloride dihydrate sterile diluent, is dependent on the shortest expiration date of any component, which is 24 months.
Nomenclature: Collagenase [BIO]; Santyl [TR former]; Xiaflex [TR assigned to Auxillium]; collagenase Clostridium histolyticum [FDA]; 9001-12-1 [CAS RN]; 37288-86-1 [CAS RN]; 39433-96-0 [CAS RN]; clostridopeptidase A [SY]; Collagenase ABC [SY]; Cordase [TR reg. by Bio-specifics]; Biozyme-C [TR former]; Novuxol [TR foreign]; NDC 0044-5270-03 and NDC 00044-5270-02 [NDC for Santyl]; NDC 66887-003-01 [NDC for Xiaflex]
Biological.: Collagen, of which their are 27 or more types or molecular variations, is the main structural protein of connective tissue in animals and the most abundant protein in mammals, making up about 40% of the total body protein. It is a long, fibrous protein containing glycine (Gly) at almost every third residue and large amounts of proline (Pro). It also contains two uncommon derivative amino acids not directly inserted during translation of mRNA, hydroxyproline (Hypro) and hydroxylysine, but inserted by post-translational enzyme modification using ascborbic acid (vitamin C)-dependent enzymes. Collagen accounts for about 75% of the dry weight of skin tissue. Collagen strands typically form triple helix structures. If collagen is solubilized and heated, its strand separate into globular, random coils, producing gelatin.
Collagenase enzymatically digests collagen in unhealthy tissue at physiologic pH and temperature, making it useful for wound debridement (cleaning/clearing of necrotic debris). Collagen in healthy and newly formed granulation tissue is largely unaffected by collagenase.
Collagenase is naturally found in some species of Clostridia bacteria. Cruder collagenase (non-pharmaceutical) preparations are commonly used for tissue dissociation, to break tissue down into individual cells. These collagenase preparations contain several collagenases along with sulfhydryl protease, clostripain, a trypsin-like enzyme, and an aminopeptidase. This combination of collagenase and proteinase activity effectively breaks down intercellular matrices. Highly purified collagenase, e.g., as used in Santyl, has minimal secondary proteolytic activities and high collagenase activity.
Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits. Injection of XIAFLEX into a Dupuytren’s cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord. Results of in vitro studies suggest that the collagenases (AUX-I and AUX-II) work synergistically to provide hydrolyzing activity towards collagen. However, there are no clinical data regarding the relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of XIAFLEX in the treatment of Dupuytren’s contracture.
Companies.: Santyl was developed and the enzyme is manufactured by Advance Biofactures Corp. (ABC; originally Agricultural Biologicals Corp; Lynbrook, NY), FDA CBER est. no. 0383, a subsidiary of Biospecifics Technologies Inc. Santyl is currently marketed in the U.S. by Smith & Nephew, which has divested marketing right and will marketit until the end of 2004, with Abbbot Labs. assuming marketing in 2004.
ABC/Biospecifics, now HEALTHPOINT/DFB, originally manufactured the enzyme (Collagenase ABC), and Abbott Labs. performs further manufacture and finishing of Santyl ointment under contract to the company. Starting in June 2001, ABC/Biospecifics began manufacture of the bulk enzyme at facilities in Curacao, the Netherlands Antilles. A new, upgraded ABC/Biospecifics enzyme manufacturing facility in Curacao was expected to come online in late 2002. ABC/Biospecifics’ stockpile of enzyme previously manufactured (at the older, FDA-approved site) for further manufacturing by Abbott was depleted by July 31, 2002, with Abbott then holding inventories of enzyme and Santyl sufficient for marketing (by Smith and Nephew) sufficient through April 2003. The Curacao facility was approved by FDA in June 2003, and major supply disruptions were avoided.
Santyl was originally marketed in the U.S. by Knoll Pharmaceuticals (then a subsidiary of BASF Pharma, acquired by Abbott Labs. in 2001) and co-marketed by Ortho-McNeil Pharmaceuticals, a subsidiary of Johnson & Johnson Co. In Feb. 2000, Smith & Nephew plc acquired exclusive North American marketing rights for Santyl from Knoll/BASF for $121.4 million.
On Jan. 1, 2004, Abbott Labs. (Ross Products div.) assumed all U.S. marketing and distribution. Smith & Nephew continued to market Santyl in the U.S. through the end of 2004, after which it switched its U.S. marketing to Gladase, a papain (pinapple-extracted enzyme; generally considered a natural product, not a biopharmaceutical) enzyme plus urea wound debridement product, which it acquired from Stiefel Laboratories Inc. Outside the U.S., Smith & Nephew continues to market its own collagenase product under the brand name Iruxol, using collagenase supplied by an unspecified manufacturer.
In June 2004, BioSpecifics granted exclusive worldwide development and commercialization rights to Auxilium Pharmaceuticals Inc. for collagenase for injection all non-topical uses including use in treating in Dupuytren’s disease, Peyronie’s disease, and Frozen Shoulder. Auxilium exercised rights to Frozen Shoulder in Dec. 2005 based on positive clinical results in a Phase III trial. BioSpecifics, now HEALTHPOINT/DFB, receives license and manufacturing fees, and is eligible for milestones and royalties.
With the 2010 full BLA approval, Auxilium Pharmaceuticals manufactured the enzyme at its facility in Horsham, PA.
In Dec. 2010, approval was granted to manufacture commercial supplies at DPT Laboratories, a subsidiary of DFB Pharmaceuticals, Inc., a subsidiary of HEALTPOINT, in Lakewood, NJ (a 2nd manufacturing facility)
On Feb. 28, 2011, the EU granted approval to Xiapex.
In Nov 2012, Auxilium ended a marketing deal with Pfizer Inc, regaining the rights to sell the Xiaflex in Europe.
Pfizer, which had the right to negotiate marketing other Xiaflex indications in the European Union, had been scheduled to return the rights to the Dupuytren's contracture treatment by April 24, 2013.
FDA class: Biologic PLA BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19650604; PLA/ELA; granted to Agricultural Biologicals Corp. for collagenase powder for export for further manufacture of collagenase ointment
Date = 19991106; PLA supplement; Indication = manufacture in a then undisclosed new facility [Abbott Labs.]
Date = 20030629; BLA supplement; Indication = approval of major renovations to the Curacao, Netherlands Antilles, manufacturing facility, utility systems, and process equipment
Date = 20100202; full BLA (125338) granted to Auxilium Pharmaceuticals
,
Date = 20101208; BLA supplement; Indication = approval to manufacture commercial supplies at DPT Laboratories, a subsidiary of DFB Pharmaceuticals, Inc., facility in Lakewood, NJ (a 2nd manufacturing facility)
Status: FDA review documents note that the original approval (for export of powdered enzyme) was based on very limited clinical testing. A June 19, 1971 memo notes, “The clinical data submitted for license was based more on subjective evaluations than objective. There was evidence that the ointment might be useful in debridement of wounds, ulcers and burns. There was nothing in the clinical data in the clinical data indicating a safety hazard.” Changes in labeling to include more cautious statements and instructions for use were made in 1971 and product lots were released.
Supplementary approval was granted in Oct. 1999 for manufacture in a new facility (Abbott), including compounding, filling, precision packaging, and cartoning.
On Feb. 2, 2010, Auxilium received full BLA approval for Xiaflex it manufactures for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.
On Nov. 9, 2012, Auxilium filed a sBLA with requested Priority Review designation for the treatment of Peyronie's disease. If approved by the FDA, Xiaflex will be the first and only biologic therapy indicated for the treatment of Peyroniea's disease, an excess of inelastic collagen causing penile curvature deformity. Xiaflex was granted orphan drug designation in the US by the FDA in January 1996 for this indication. I
n Aug. 2013, FDA extended the Prescription Drug User Fee Act ("PDUFA") goal date for the sBLA for XIAFLEX for the treatment of Peyronie's disease ("PD") from September 6, 2013 to December 6, 2013. During the course of product label discussions, Auxilium had submitted revisions regarding the proposed Risk Evaluation and Mitigation Strategy (REMS) program and other aspects related to the proposed label. The FDA determined that this submission qualified as a major amendment filed during the final three months of the review and extended the PDUFA goal date to December 6, 2013. The FDA did not request any additional clinical studies be performed prior to the revised PDUFA action date.
On Dec. 9, 2013, FDA granted sBLA approval for treatment of Peyronie's disease.
Indications: [Santyl, now legacy, full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
Collagenase Santyl Ointment is indicated for debriding chronic dermal ulcers and severely burned areas.
[Xiaflex full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.
Tech. transfer: Patents related to Santyl include U.S. 5,514,370, “High Dosage Topical Forms of Collagenase,” Stern, H and Yee, D., May 7, 1996, assigned to Advanced Biofactures Corp. Other U.S. patents include U.S. 5,422,103.
Trials: Collagenase injection is in Phase III trials with for treatment of Dupuytren’s disease, and in Phase II trials for Peyronie’s disease. Positive Phase II results have been reported for treatment of Frozen Shoulder.
Disease: Frozen Shoulder syndrome is a disorder of diminished shoulder motion, characterized by restriction in both active and passive range of motion of the shoulder joint. Frozen Shoulder usually affects patients aged 40-70 years. It is estimated that 3% of people develop Frozen Shoulder over their lifetime. Women tend to be affected more frequently than men. The condition may affect both shoulders, either simultaneously or in sequence. Recurrence of Frozen Shoulder is common within five years of onset. The most common treatments for Frozen Shoulder are extensive physical therapy, corticosteroids, and/or arthroscopy. Drugs are used to control pain, but none have been shown to have an impact on the underlying disease process. Likewise, medications have not been shown to affect the duration of disease or the severity or duration of joint contracture.
Trials: Early phase II trial(s) for frozen shoulder have shown efficacy and tolerability. The study was a randomized, placebo-controlled, and double-blind dose-response study in 60 patients - 47 women and 13 men. All patients received a first 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 were conducted using a form by the American Society of Shoulder and Elbow Surgeons. Function score, pain score, strength, and stability were measured. There was a clinically significant difference in return to normal shoulder motion and function with Xiaflex 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. Ongoing trials are planned to assess the optimal dosing and dosing regimen.
In June 2008, Auxillium reported that each of its CORD I and II trials Phase III trials with Xiaflex for treatment of Dupuytren’s contracture successfully met the primary endpoint, a reduction in the angle of a patient’s joint contracture to = 5 degrees of normal, as measured by digital goniometry, 30 days after the last injection. A Pharmacokinetic (PK) Study also showed the lack of systemic exposure of Xiaflex in patients treated for Dupuytren’s contracture. The most common adverse events in the CORD I and II and PK studies were consistent with adverse events reported in previous trials and included pain, swelling, bruising and pruritis at the injection site and transient lymph node swelling and pain. In over 2,000 Xiaflex injections administered in ~850 patients through the end of May 2008, a total of 7 serious adverse events possibly related to study drug had been reported, five of which were related to tendon or ligament injury (rate per injection = 0.24%).
CORD I was the largest placebo-controlled study ever conducted in Dupuytren’s contracture patients and the second U.S. pivotal Phase III study for Xiaflex in Dupuytren’s contracture. A total of 306 patients enrolled, with 203 patients receiving XIAFLEX and 103 receiving placebo in the double-blind portion of the study. The joints were stratified 2:1 Metacarpal Phalangeal Joint, or MP joint, to Proximal Intra-Phalangeal, or PIP joint. The primary endpoint was met with 64% (130 of 203) of patients’ primary joints treated with Xiaflex achieving = 5 degrees of normal contracture, compared to only 6.8% (7 of 103) of patients’ primary joints treated with placebo (p<0.001). On average, Dupuytren’s contracture patients who achieved the primary endpoint received 1.5 Xiaflex injections. In addition to the primary endpoint, there were 26 secondary endpoints that were measured, each of which was met with statistical significance. These included the difference between the pre- and post-treatment contracture angles and whether patients achieved at least a 50% reduction in their contracture compared to baseline.
CORD II enrolled 66 Dupuytren’s contracture patients in five sites across Australia. Forty-five patients received Xiaflex and 21 received placebo in the double-blind portion of the study. The joints were stratified 1:1 MP to PIP. The primary endpoint was met, with 44.4% (20/45) of patients’ primary joints treated with Xiaflex achieving = 5 degrees of normal contracture, compared to only 4.8% (1 of 21) of patients’ primary joints treated with placebo (p<0.001). On average, Dupuytren’s contracture patients who achieved the primary endpoint received 1.5 Xiaflex injections. The average percent improvement in contracture from baseline was 70.5% for primary joints treated with Xiaflex. For placebo, the average percent improvement in primary joint contracture from baseline was 13.6% (p<0.001). A >/= 50% reduction from baseline in the affected joint’s contracture was achieved in 77.8% of patients (35/45) of all primary joints treated with Xiaflex compared to 14.3% of patients (3/21) for joints treated with placebo (p<0.001).
Medical: Santyl ointment is applied once daily , or more frequently, if dressing is soiled. The skin may be cross-hatched or etched with a sharp blade to increase surface contact with necrotic tissue. Treatment is halted once debridement of necrotic tissue is complete and granulation tissue is well established.
Market: The 2005 Average Wholesale Price (AWP) is $30.85/15 g tube, with a Direct Cost (DC; manufacturer’s discount price) of $25.71; and $56.64/30 gram tube, with DC of $48.87 (Red Book, 2005). These AWPs are unchanged from 2004.
In Nov. 2012, Auxilliim reported expecting between $153 million and $163 million in Xiaflex sales for 2012. Sales of Xiapex in Europe accounted for 22% of the company's total sales in its third quarter
Biospecifics reported, historically, ~90% of its net sales and royalties have been derived from Santyl Ointment sales in the U.S. Sales to Abbott and Santyl royalties accounted for $3,196,000 and $7,199,000 in the company’s FY2003 and FY2002, respectively, with this revenue approximately 78% and 87% of company revenues during FY2003 and FY2002, respectively. North American 1999 sales of Santyl exceeded $37 million. Biospecifics received $2.5 million in royalties from Santyl sales by Knoll in FY1998.”
Santyl is reimbursed by Medicaid in all 50 states.
It is expected that Xiaflex will offer a strong therapeutic alternative to surgery and could potentially become the new first-line treatment option for Dupuytren’s contracture.
Competition: Santyl competes with other enzymatic wound debridement products. For example, on Nov. 5, 2003, Smith & Nephew, the former distributor of Santyl, launched Gladase containing papain, a pineapple-derived proteolytic enzyme (considered to be a natural product drug). This will become the company’s primary wound debridement product marketed in the U.S. (after dropping Santyl), while the company will continue to market outside the U.S. collagenase (as Iruxol) obtained from an alternate manufacturer (not ABC/Biospecifics).
Ongoing: BC/Biospecifics has conducted Phase II trials with a new injectable collagenase formulation (Cordase) for treatment of Du-puy-tren’s disease, which restricts the extension of one or more fingers. Trials have also been conducted for treatment of lipoma reduction. Clinical and laboratory studies were also investigating the potential role of collagenase and its pharmacological activity for wound healing
In late 2008, Auxillium is conducting Phase II trials with Xiaflex for treatment of Peyronie’s disease and Frozen Shoulder syndrome (Adhesive Capsulitis).
Financing, manufacturing and other problems have slowed product development by ABC/Biospecifics.
Companies involvement:
Full monograph
612 Collagenase
Nomenclature:
Collagenase [BIO]
collagenase Clostridium histolyticum [FDA for Santyl]
Cordase [TR reg. by Biospecifics]
Santyl [TR reg. by Knoll]
Xiaflex [TR US]
Xiapex [TR in EU]
Novuxol [TR outside U.S.]
37288-86-1 [CAS RN]
39433-96-0 [CAS RN]
9001-12-1 [CAS RN]
clostridopeptidase A [SY]
Collagenase ABC [SY]
Biozyme-C [TR former]
Iruxol [TR foreign]
NDC 0044-5270-03; NDC 00044-5270-02 [NDC]
NDC 66887-003-01 [NDC for Xiaflex]
molecular weight (kDa) = 113
FDA Class: Biologic BLA
Year of approval (FDA) = 2010
Date of 1st FDA approval = 20100202
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
enzymes
beef heart infusion
bovine Achilles tendon
Clostridium hisolyticum
calcium chloride
collagen, porcine dermal
hydrochloric acid (HCl)
petrolatum
sodium chloride
sucrose
trisodium citrate
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
octoxynol (Triton X-100)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
Copyright© 2020, Biotechnology Information Institute