Status: marketed in U.S.; pending in EU

Organizations involved:

ISTA Pharmaceuticals Inc. – R&D; Tech.; USA mark.; Intl. mark.

Bausch & Lomb – Parent

Biozyme Laboratories Ltd. – Manuf.; Tech.

Theratase plc – Parent

SP Pharmaceuticals, Inc. (SP) – Manuf.

Schering-Plough Corp. – Parent

Allergan, Inc. – Europe mark.

Otsuka Pharmaceutical Co., Ltd. – Japan mark.

Cardinal Health, Inc. – Manuf. other

Cross ref.: See the entry above for hyaluronidase, bovine (Wydase), a previously marketed product. See also the Hyaluronic Acid Products entry (#925) for information about hyaluronic acid, which is broken down by hyaluronidase.

Description: Vitrase refers to lyophilized (freeze-dried) and aqueous formulations of hyaluronidase, an enzyme that breaks down hyaluronic acid (hyaluronan), extracted from the testes of sheep. Hyaluronidase cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acid mucopolysaccharides of the connective tissue. Hyaluronic acid is a major constituent of the intercellular matrix of connective tissue, and is found at high concentrations in the aqueous and vitreous humor of the eye, under the skin, and in the synovial fluid in joints. The exact chemical structure of ovine hyaluronidase is unknown, but the amino acid sequence for the primary structure of the enzyme has been deduced from the sequence of purified peptides. Ovine hyaluronidase has a molecular formula of 58.17 kDa and a calculated molecular formula of C2600H4040N696O774S23. Vitrase is used a spreading or diffusing substance to increase the permeability of connective tissue through the hydrolysis of hyaluronic acid (HA), and for the other indications: for which the other animal-derived hyaluronidase products have received approval.

Vitrase is available in vials containing 200 USP Units/mL in sterile solution and 6,200 USP Units/mL as lyophilized powder. A new 3 mL vial containing 150 Units (50 Units/mL) lyophilized powder was approved in Dec. 2004. Each 5 mL vial contains 6,200 USP units of hyaluronidase along with 5 mg lactose, 1.92 mg potassium phosphate dibasic, and 1.22 mg potassium phosphate monobasic. A 1 mL syringe and a 5 µm filter needle are supplied in the Vitrase kit. Prior to injection, Vitrase is reconstituted with Sodium Chloride Injection, USP. Vitrase is reconstituted in its vial to a concentration of 1,000 Units/mL by adding 6.2 mL of Sodium Chloride Injection, USP solution to the vial. Reconstituted solution has an approximate pH of 6.7 and osmolality of 290-310 mOsm. The product contains no preservatives. Vitrase is currently required to be stored under refrigerated conditions prior to its use.

Nomenclature: hyaluronidase, ovine/ISTA [BIO]; Vitrase [TR]; Vitragan [TR Europe]; hyaluronidase (glycoprotein, sheep testis isoenzyme) [CAS]; hyaluronidase (sheep testis isoenzyme) [CAS]; 488712-31-8 [CAS RN]; mucinase [SY]; hyaluronate 4-glycanohydrolase [SY]; hyaluronoglucosidase [SY]; HYO6A [SY]; hyaluronate lyase [SY]; ovine hyaluronidase [SY]; EC 3.2.1.35 [EC]; NDC 67425-001-02

Companies.: ISTA Pharmaceuticals Inc. developed Vitrase, including conducting trials and filing for approvals in the U.S. and Europe. The enzyme is manufactured by Biozyme Laboratories Ltd., a subsidiary of Theratase plc, with filling and packaging by Cardinal Health, Inc. In June 2004, Theratase and ISTA modified their supply agreement.

ISTA has a supply agreement with Biozyme for cGMP-grade hyaluronidase for use in ophthalmic applications. This calls for ISTA to annually purchase a minimum of $750,000 (total) over the next three years; and ISTA acquired a license for Biozyme manufacturing technology for $1.1 million, payable over three years. ISTA transfered to Biozyme ownership of manufacturing equipment it had purchased (then already in use at Biozyme). Hyaluronidase is lyophilized (freeze dried) by Biozyme and shipped to Cardinal Health for filling and packaging.

In March 2000, ISTA granted Allergan exclusive rights to market Vitrase for uses in the posterior segment of the eye in the U.S. and all international markets, except Japan. In Sept. 2004, prior to the launch of Vitrase, ISTA reacquired U.S. and many other marketing rights from Allergan. ISTA paid $10 million to Allergan, and pays royalties in its U.S. sales of Vitrase for use in the posterior segment of the eye. ISTA has responsibility to file Vitrase for vitreous hemorrhage in the EU, and Allergan will have an option to commercialize Vitrase in Europe subsequent to EU approval. If Allergan does not exercise its option, European rights will revert to ISTA, and Allergan will be paid a royalty on ISTA’s European sales of Vitrase for use in the posterior segment of the eye.

Otsuka Pharmaceuticals has exclusive development and marketing rights in Japan.

ISTA has entered into a letter of intent and is negotiating a definitive agreement with SP Pharmaceuticals, Inc. (SP), a subsidiary of Schering-Plough Corp, for the manufacture of commercial quantities of Vitrase. Both SP and Biozyme will supply enzyme to ISTA.

Ista was acquired by Bausch & Lomb in March 2012.

Manufacture: Hyaluronidase, the active pharmaceutical ingredient used in Vitrase and Keratase, is sourced from ovine testes and processed in several stages to produce a highly purified raw material for formulation. Biozyme extracts the enzyme from the testes of New Zealand sheep at its facilities in Blaenavon, Wales, U.K. Bulk highly purified enzyme is shipped about twice every month to Cardinal Health, Inc. in the U.S. for formulation and filling of vials. Bulk enzyme from Biozyme formulated into Vitrase used in earlier clinical trials was originally formulated and vialed by PrimaPharm, which now markets its own bovine hyaluronidase, Hydase (see related entry).

The export of each shipment of hyaluronidase from the U.K. requires the Ministry of Agriculture, Fisheries and Food (MAFF) to issue an export permit (due to transmissible spongiform encephalitis/prion contamination concerns). An annually renewed import permit from the U.S. Department of Agriculture (USDA) is required to import the product into the U.S.

FDA class: Drug NDA 505(b)(2)

Approvals: Date = 20040504; NDA first approval under 505(b)(2) regulations.

Date = 20041203; NDA supplement; Indication = approval of new lyophilized 150 Units (50 Units/mL) vial

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Vitrase (hyaluronidase for injection) is indicated as an adjuvant to increase the absorption and dispersion of other injected drugs; for hypodermoclysis; and as an adjunct in subcutaneous urography for improving resorption of radiopaque agents.

Status: In Jan. 2002, ISTA started submitted portions of its original NDA for spreading agent indications: and treatment of vitreous hemorrhage (bleeding into the vitreous humor or fluid of the eye) as these sections were completed (having received “fast-track” designation). In Dec. 2002, FDA accepted the chemistry, manufacturing and controls (CMC) section of the NDA. FDA approved Biozyme’s manufacturing facilities in Feb. 2003.

On March 17, 2003, FDA’s Dermatologic and Ophthalmic Drug Advisory Committee voted 7 to 5 that the benefits of Vitrase outweigh the risks in some subgroups, but voted 8 to 4 that insufficient data were available to support approval, voted 8 to 4 that Vitrase can cause iris irritation, and suggested further analysis of the two Phase III trials, and possibly new trial(s). In April 2003, FDA issued an “approvable letter” requesting an additional clinical trial, with this resulting in the ophthalmic indication removed from the active NDA. On Aug. 20, 2003, FDA granted the NDA priority review status, and FDA accepted the NDA for filing on Oct. 5, 2003, with a priority review target date of within six months. In Feb. 2004, the FDA notified ISTA that it was extending the PDUFA action date 90 days to May 5, 2004. The NDA was approved with New Chemical Entity (NCE) status on May 4, 2004; approval time = 8 months; .75 years).

Vitrase, like other recently FDA-approved animal-derived hyaluronidase products, has not received centralized European Union approval.

On Aug. 2, 2003, Biozyme filed a supplemental NDA seeking approval for use of a new, single-use, 150 Units (50 Units/mL) vial of lyophilized Vitrase as a spreading agent to facilitate the dispersion and absorption of other drugs, and for approval of directions for reconstitution of Vitrase for potential treatment applications in the back of the eye. The company believed this will dosage form to be more convenient and cost effective for use as a spreading agent.

With the approval of Vitrase, hyaluronidase was officially removed from FDA’s drug shortage list, where it had been listed since 2001 (due to the discontinuation of Wydase). However, until approval (in Dec. 2004) of the 150 Units/mL lyophilized formulation, only limited samples of Vitrase were being distributed free, i.e., the product had not yet been commercially launched. This sNDA was approved in Dec. 2004.

Vitrase was originally approved under 505(b)(2) regulations, the same as used for approval of many generic drugs. Various hyaluronidase products sourced from mamalian testicular material have been available in the U.S. as drug products for over 50 years. 505(b)(2) approval means that some of the data relied on to support that application was from studies that were not conducted by the applicant or for which the applicant did not have a right to reference (e.g., cited Wydase references in the literature). These approvals are based on demonstrating similarity or equivalence to an already-approved product, , including aspects affecting bioavailability and pharmacodynamics. 505(b)(2) approvals are not based on proof of safety and efficacy, usually based on large-scale Phase III trials. Note, most generic drugs are approved under 505(j) applications.

Ista claimed in the cover letter for its NDA as a spreading agent, “The Vitrase formulation differs from the Wydase formulation only in that it is of ovine origin and is preservative-free. This proposed formulation would provide a safe, consistent and reliable supply of this product as an alternative to the existing supply, which is provided by compounding of bovine hyaluronidase by individual pharmacies. Wydase was previously approved for and marketed by Wyeth Laboratories. ISTA’s 505(b)(2) application relies on the Agency’s previous findings of safety and efficacy for Wydase...For nonclinical pharmacology and toxicology information and for clinical data, this 505(b)(Z) application cross-references Wydase NDA 6-343 to which ISTA has not obtained a right of reference. For chemistry, manufacturing, and controls data and supportive nonclinical and clinical safety data, this NDA cross-references ISTA’s NDA 21-414 and all amendments thereto for Vitrase, which is for the same formulation of ovine hyaluronidase administered by a different route (ophthalmic intravitreal injection) and for a different indication, i.e., for the treatment of vitreous hemorrhage...” As discussed in the Wydase entry, Wydase’s prior status as an approved drug was based on FDA’s previous findings of safety and efficacy through the Drug Efficacy Study Implementation (DESI) program, which reviewed grandfathered products, so Wydase apparently never received modern/conventional NDA approval.

In many respects the approval of Vitrase under 505(b)(2) generic drugs regulations is similar to proposed biogeneric, biosimilar, biocomparable, follow-on protein (FOP), etc. approvals, with approvals based on abbreviated trials showing bioequivalence to a comparator/reference product, rather than full Phase III safety and efficacy trials. Thus, in some respects Vitrase may be considered to be a generic form of Wydase and other hyaluronidase products. In fact, animal-derived hyaluronidase has characteristics which many opponents of development of formal biogeneric regulations consider problematic, including it being considered “uncharacterizable” due to its complexity. Hyaluronidase, even as a pure recombinant product, is a large complex molecule - about double the size of erythropoietin/EPO) with considerable microheterogeneity, with the molecule being glycosylated or having variable carbohydrate polymer chains attached at often varying amino acids of the its sequence. Although the animal-derived hyaluronidase products have been and continue to not be well characterized, FDA has determined that the generic U.S. Pharmacopeia assay for hyaluronidase “is a valid surrogate for enzymatic activity and thus may be used to establish the effectiveness of new hyaluronidase products.”

In Sept. 2004, FDA granted three years of New Chemical Entity (MCE)/New Molecular Entity (NME)-based market exclusivity for Vitrase (as ovine hylauronidase) for use as a spreading agent to facilitate the dispersion and absorption of other drugs. U.S. market exclusivity was extended until May 5, 2007. Prior to this date, the FDA could not approve any other hyaluronidase in the U.S. for this indication. On Oct. 28, 2004, FDA further extended market exclusivity from three years to five years for use as a spreading agent to facilitate the dispersion and absorption of other drugs (with Vitrase receiving 5 years exclusivity, as have the other recently approved hyaluronidase products). ISTA’s U.S. market exclusivity now extends until May 5, 2009. The FDA based this extension on its granting Vitrase new molecular entity (NME) status [under 21 CFR 314.108(b)], “because there was inadequate information to determine whether any moiety in Vitrase is the same as any previously approved moiety.” NME-based exclusivity is a bar to FDA acceptance of certain 505(b)(2) applications and ANDAs, i.e., biogeneric, biosimilar, biocomparable, follow-on or other generic biopharmaceutical versions of ovine hyaluronidase.

This approval with NCE/NME status provides five years of market exclusivity. However, as discussed above in the Amphadase entry, this has little or no meaning for hyaluronidase products, since FDA considers each unique, granting each NCE/NME status, with market exclusivity not applying to other products with NCE/NME status.

In “The FDA’s assessment of follow-on protein products: a historical perspective,: in Nature Reviews Drug Discover, published online April 13, 2007, FDA explained and rationalized it prior biogeneric/follow-on protein-like approvals. Regarding animal-derived hyaluronidase products, FDA noted, “The FDA has approved follow-on versions of hyaluronidase based on assay data showing that the product has enzymatic activity consistent with USP–NF standards (this activity is also the mechanistic basis for product effectiveness), clinical data assessing the immunogenicity of the product, and information establishing that the manufacturing process ensures consistency of the drug product. Evidence of enzymatic activity permits reliance on the existing body of clinical data and experience from other hyaluronidase products that have demonstrated similar enzymatic activity. Clinical testing of the immunogenicity is important here because products derived from different sources may be more or less immunogenic.”

On Dec. 3, 2004, an NDA supplement was approved for the 150 Units/mL lyophilized formulation, designed for use as an ophthalmic spreading agent. With this, Vitrase was launched in the U.S. on Jan. 6, 2005.

In 3rd quarter 2005, ISTA filed a centralized Marketing Authorisation Application (MAA) seeking European market approval of Vitragan for the treatment of vitreous hemorrhage. This was accepted for review on Jan. 12, 2006, A decision was expected in summer 2007.

ISTA reports that it may terminate the development of Vitrase for severe vitreous hemorrhage due to the preliminary results of its Phase III clinical trials (see the Trials section below).

Tech. transfer: Hyaluronidase patents assigned to ISTA include U.S. 6,551,590 covering the use of certain preparations of hyaluronidase derived from any source (including bovine and ovine sources) for ophthalmic administration and enzymatic methods for accelerating the clearance of hemorrhagic blood from the vitreous body of the eye; and 5,866,120 and 6,039,943 in March of 2000, both covering methods for clearing blood from the vitreous humor using hyaluronidase. U.S. 6,551,590 includes claims for hyaluronidase induction of liquefaction of the vitreous humor. U.S. 6,737,075 includes claims for elimination of corneal collagen fiber disorganization to improve vision, e.g. for treatment of corneal scars, corneal opacification and corneal haze, and for treatment of accidental traumatic injury to the cornea and from refractive surgery for such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK).

Trials: Vitrase has been studied in clinical trials for use as a spreading agent and treatment of ophthalmic vitreous hemorrhage. An NDA was filed for the later indication (see Status section), but FDA is requiring additional trial analysis and an additional trial based on this analysis. Vitrase has also been studied for the treatment of diabetic retinopathy.

In March 2002, ISTA (related to its original NDA) reported that despite significant improvements in the clinically important surrogate endpoint of visual acuity in two Phase III trials, no significant difference was observed between the treatment and placebo for the primary (surrogate) endpoint of vitreous hemorrhage clearance. Vitreous hemorrhage is a serious condition affecting the back of the eye, an indication for which there are currently no therapeutics available. Clinically relevant changes in best-corrected visual acuity (“BCVA”), but no significant clearing in the eye, were observed. In Jan. 2003, integrated data were reported from two double-masked, placebo-controlled Phase III clinical trials of Vitrase for the treatment of vitreous hemorrhage (VH) in patients with diabetes. At baseline, nearly 80% had a history of diabetes and about 90% could not read any letters on a standard vision exam wall chart. In the diabetes subset, after as little as one month following a single intravitreous injection, more than twice the number of Vitrase patients vs. placebo recipients had a reduction in hemorrhage density, with this often allowing physicians to see the back of the eye to diagnose the underlying cause of the hemorrhage and begin laser treatment, if appropriate. Among patients with proliferative diabetic retinopathy as the apparent cause of hemorrhage, more than twice the Vitrase vs. placebo patients were able to begin laser treatment within one month following Vitrase injection.

The vitreous hemorrhage (VH) MAA filing was based on existing clinical trial data, including results from two randomized, double-masked, placebo-controlled, international, Phase III trials. The pooled analyses of these two studies demonstrated a statistically significant reduction in VH density as early as one month that persisted through three months following a single intravitreous injection of Vitrase when compared to a single injection of saline solution. This reduction allowed investigators to see into the back of the eye to diagnose the underlying cause of the hemorrhage and treat with laser therapy when appropriate. The results also demonstrated that Vitrase has a favorable safety profile, with no serious safety issues reported following a single intravitreous injection of Vitrase. The Phase III trials also demonstrated that patients receiving a single intravitreous injection of Vitrase showed improvement in best-corrected visual acuity (BCVA) of three or more lines on an eye chart as early as one month and through three months when compared to a single injection of saline solution. There also was a decrease in the density of the vitreous hemorrhage that was clinically meaningful and statistically significant as compared to placebo as early as one month and through three months following a single intravitreous injection of a 55 IU (68 USP Unit) dose of Vitrase.

Medical: The Dosage and Administration section of the product insert provides directions for the reconstitution of Vitrase in five different dose concentrations from a single 6,200 Units vial, facilitating its use for different conditions. Vitrase is used at dilutions of 50 Units/mL (0.05 mL of reconstituted 1,000 Units solution); 75 Units/mL (0.075 mL); 150 Units/mL (0.15 mL); and 300 Units/mL (0.3 mL).

Vitrase solution can be administered directly into the vitreous humor through a single-dose injection. Absorption and dispersion of other injected drugs may be enhanced by adding 50-300 Units, most typically 150 Units, of hyaluronidase to the injection solution. When injected into the vitreous humor, Vitrase breaks down the proteoglycan matrix, causing the vitreous humor to liquefy.

Vitrase is useful for hypodermoclysis (clysis), the subcutaneous injection of replacement fluids. Intradermal (under the skin) injection of Vitrase breaks down hyaluronic acid in the skin, increasing the ability of fluids to spread and diffuse under the skin and into deeper tissue.

When hyaluronidase is added to a local anesthetic agent, e.g., added to lidocaine and injected in the vitreous humor during intraocular surgery, it hastens the onset of analgesia and tends to reduce the swelling caused by local infiltration. However, the wider spread of the local anesthetic solution increases its absorption; this shortens its duration of action and tends to increase the incidence of systemic reaction.

Vitrase is also used in conjunction with subcutaneous urography (injection of dyes for x-ray visualization of the urinary tract). The subcutaneous route of administration of urographic contrast media is indicated when intravenous administration cannot be successfully accomplished, particularly in infants and small children. With the patient prone, 75 Units of Vitrase is injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.

Vitrase repeated use may induce hyaluronidase-neutralizing antibodies. A preliminary skin test for hypersensitivity to Vitrase can be performed, involving intradermal injection of 0.02 mL (3 Units).

Market: The 2005 Average Wholesale Price (AWP) is $1,007.50/6200 U vial, with a Direct Cost (DC; manufacturer’s discount) of $806.00; and $32/50 for the 1.2 ml, 200 U/mL vial, with a DC of $26.00 (2005 Red Book).

To support the launch of Vitrase in the U.S., ISTA converted the sales representatives of Ventiv Pharma Services (a company it acquired) that were then promoting its Istalol product to ISTA employees. ISTA continued to use Ventiv Pharma Services for sales force administration and other services. ISTA also expanded its sales force from 28 representatives to 50 during the first quarter of 2005 to reach the over 7,000 ophthalmologists in the U.S.

Competition: Hydase competes for its approved indications: with each of the other approved animal-derived hyaluronidase products and with Hylenex, recombinant hyaluronidase.

Ongoing: ISTA is developing two other products containing ovine hyaluronidase – Keratase for treatment for corneal opacification and Keraform for treatment of abnormalities of the cornea (Keratoconus) . Both are in early clinical trials.