Vitrase for the Treatment of Vitreous Hemorrhage
A discussion of new treatments and the viability of Vitrase as a pharmacotherapy option.
BY ABDHISH R. BHAVSAR, MD

INDICATION AND BACKGROUND

Vitrase (hyaluronidase ovine, ISTA Pharmaceuticals, Inc.) is FDA-approved as a spreading agent and received an approvable letter for the treatment of vitreous hemorrhage in 2003. However, to date it is not FDA-approved for intravitreous use. Vitrase is highly purified ovine hyaluronidase. It has been studied thus far in humans as a single intravitreous injection for the treatment of vitreous hemorrhage and for induction of posterior vitreous detachment. Vitrase has been under development for approximately 10 years and approximately 1500 patients have been treated at 131 sites in 13 countries.

VITREOUS HEMORRHAGE

The incidence of vitreous hemorrhage in Europe is 7 new cases of dense spontaneous vitreous hemorrhages per 100000 population annually. In the United States, this translates to approximately 20000 new cases of vitreous hemorrhage occurring each year.¹

Common causes of vitreous hemorrhage include proliferative diabetic retinopathy, posterior vitreous detachment, retinal tears and detachment, trauma, retinal vein occlusions, and age-related macular degeneration.

Typical mechanisms of vitreous hemorrhage may include tear of a normal retinal blood vessel, retinal neovascularization, traction on active or fibrotic neovascularization, or breakthrough of subretinal or choroidal hemorrhage. The general characteristics of vitreous hemorrhage include rapid bleeding and dispersion, but relatively slow clearance.

The sequelae of vitreous hemorrhage typically include decreased visual acuity (VA), obstruction of visualization of the retina, and prevention of treatment for potentially sight-threatening pathology.

The natural history of untreated vitreous hemorrhage has been documented in 3 studies. These studies include a natural history study from the United States, a natural history study from Spain, and the Diabetic Retinopathy Vitrectomy Study (DRVS). The study from the United States included 85 eyes with untreated large vitreous hemorrhage, and 70% of patients had VAs of worse than or no better than 5/200 at 3–10 years of follow-up.² The study from Spain showed that 63% of patients with massive vitreous hemorrhage had unchanged VA and only 26% of patients improved. At 2 years without treatment, 49% of patients had worse than hand motion (HM) VA, and only 21% of patients had better than HM VA.³ The DRVS involved 312 eyes with severe vitreous hemorrhage that had onset within 6 months of randomization. Visual acuity at entry ranged from 5/200 to light perception. The delayed treatment group involved the delay of vitrectomy surgery for 1 year. In the delayed treatment group, 22% of patients had clearance of the vitreous hemorrhage at 1 year and vitrectomy surgery was not required. Eleven percent of patients required vitrectomy for traction retinal detachment and 5% of eyes were inoperable due to retinal detachment or neovascular glaucoma.⁴

CURRENT THERAPIES

The current therapies for the management of vitreous hemorrhage include observation or vitrectomy surgery. There is no approved pharmacotherapy for vitreous hemorrhage at this time. The major concerns associated with vitrectomy surgery are that it is a major intraocular surgery, some patients are at increased risk, and there are substantial costs and potentially serious complications.

The goals of a new therapy for the management of vitreous hemorrhage could include:

• offers good safety profile/low risk to treated eyes
• speeds hemorrhage clearance
• restores visual function
• allows early treatment of underlying pathology
• can be performed as an office procedure.

VITRASE

Vitrase is a lyophilized preparation of highly purified ovine testicular hyaluronidase. It is preservative-free and reconstituted with 0.9% sodium chloride injection USP.

Vitrase Pharmacokinetics

The pharmacokinetics of an intravitreous injection of Vitrase are derived from animal studies. The half-life of Vitrase in the eye is between 60–112 hours, whereas the plasma half-life is 49 hours. The highest concentration is found in the vitreous followed by the retina.

Vitrase Mechanism of Action

Vitrase cleaves the glycosidic bonds of hyaluronan and leads to collapse and liquefaction of the vitreous, thereby facilitating diffusion of molecules and proinflammatory chemotactic factors. This, in turn, promotes the ingress of phagocytic cells and egress of red blood cells and proteins. In a rabbit model of vitreous hemorrhage, saline injection alone at 3 days postinjection shows some disruption of the clot. At 3 days postinjection, Vitrase shows marked disruption and liquefaction of the clot.⁵

Phase 3 Clinical Trial Program

The phase 3 clinical trial program for Vitrase included 2 phase 3, double-masked, placebo-controlled clinical trials conducted at 131 sites in 12 countries. The primary objective of the study was to determine the safety and efficacy of a single intravitreous injection of vitrase for the treatment of severe vitreous hemorrhage.

The main eligibility criteria included presence of vitreous hemorrhage for at least 1 month, severe vitreous hemorrhage at entry that obscured visualization of the fundus and best-corrected visual acuity (BCVA) worse that 20/200 in the study eye. The density of the vitreous hemorrhage assessed by a new standardized grading scale had to be grade 3 or 4 in 12 clock hours. The main exclusion criteria included presence or history of retinal tears or detachment, ocular trauma, prior vitrectomy, organized vitreous hemorrhage, or no light perception in either eye.

An independent Data Safety Monitoring Board reviewed the outcomes throughout the course of the study.

The randomization groups included 3 different intravitreous doses of Vitrase: 7.5 IU (North American Study only), 55 IU, and 75 IU, as well as a saline intravitreous injection control group. The etiology of the baseline vitreous hemorrhage included proliferative diabetic retinopathy in more that 60% of the cases. The mean duration of the baseline vitreous hemorrhage was approximately 4 months. The baseline BCVA was off chart (light perception, HM, counting fingers) in over 90% of the cases.

The combined efficacy and safety results were published in the online American Journal of Ophthalmology in July 2005 and subsequently in the hard-copy journal. In summary, the primary efficacy endpoint was not met at 3 months. However, the primary efficacy measure at months 1 and 2 was statistically significant in favor of Vitrase. In addition, all of the secondary endpoints (ie, improvement in BCVA and reduction of vitreous hemorrhage density) of the studies were met in a statistically significant manner in favor of Vitrase over saline injection control.

The most significant key adverse events included iritis in approximately 60% of Vitrase-treated eyes and approximately 30% of saline injection control eyes. Sterile hypopyon occurred in approximately 2%–5% of Vitrase-treated eyes and did not occur in saline injection control eyes. Most cases of retinal detachment were cases of tractional retinal detachment. Rhegmatogenous retinal detachment occurred in approximately 1%–2% of eyes and was not statistically significant when comparing vitrase to saline control eyes.

Clinical Use of Vitrase Today

Because Vitrase is approved by the FDA for use as a spreading agent, it is clinically available for use in the ophthalmic setting. For example, an approved ophthalmic use for Vitrase is in preparation of a local retrobulbar block. However, Vitrase is not FDA approved for intravitreous use. However, with appropriate knowledge of the safety and efficacy of Vitrase, I do include it in my armamentarium of methods of managing vitreous hemorrhage. For appropriate patients with vitreous hemorrhage, I discuss the off-label use of Vitrase and then offer treatment. Vitrase can be prepared in the office by reconstitution with normal saline for injection USP and is administered by standard intravitreous injection.

It is important to keep in mind that other hyaluronidase compounds on the market have not been studied in the vitreous. Importantly, a preparation of ovine hyaluronidase containing thimerosal was found to be toxic to the retina when administered by intravitreous injection into rabbit eyes at doses up to 30 units.⁶

Vitrase offers a pharmacotherapeutic option for the management of vitreous hemorrhage. However, it is currently not FDA approved for this use.

Abdhish R. Bhavsar, MD, is director of clinical research at the Retina Center, PA in Minneapolis, Minn. Dr. Bhavsar receives research funds from and is a consultant to ISTA Pharmaceuticals, Inc. He can be reached at bhavs001@umn.edu.

REFERENCES

1. Lindgren G, Sjodell L, Lindblom. A prospective study of dense spontaneous vitreous hemorrhage. Am J Ophthalmol. 1995;119:458-465.

2. Ziemianski MC, McMeel JW, Franks EP. Natural history of vitreous hemorrhage in diabetic retinopathy. Ophthalmol. 1980;87:306-312.

3. Cordido M, Fernandez-Vigo J, Fandino J, Sanchez-Salorio M. Natural evolution of massive vitreous hemorrhage in diabetic retinopathy. Retina. 1988;8:96-101.

4. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial.Report 2. Arch Ophthalmol. 1985;103:1644-1652.

5. ISTA Pharmaceuticals, data on file.

6. Gottlieb JL, Antoszyk AN, Hatchell DL, Saloupis P. The safety of intravitreal hyaluronidase. A clinical and histologic study. Invest Ophthalmol Vis Sci. 1990;31:2345-2352.