Article Date: 7/1/2005

Retisert: A Step Forward in Treating Chronic Noninfectious Posterior Uveitis

Though chronic noninfectious posterior uveitis is a relatively uncommon disease, affecting an estimated 175 000 people in the United States and approximately 800 000 worldwide, it exacts a socioeconomic cost about equal to diabetes, though the incidence of diabetes is much higher.1 This is because the disease primarily strikes people in their prime working years between the ages of 20 and 50, causing years of vision loss for each individual and eventually leaving about 22% of those afflicted with the disease legally blind in at least 1 eye. Approximately 46% of patients diagnosed with posterior uveitis experience severe visual impairment.

The Retisert implant is about the size of a grain of rice.

Chronic noninfectious posterior uveitis is difficult to categorize. It encompasses a range of inflammatory diseases, many of which can be traced to idiopathic and/or systemic origins. The chronic episodes of inflammation lead to cellular destruction, eventually progressing to the structural destruction that causes vision loss from such complications as cystoid macular edema, cataracts, or both. The damage that can be caused by repeated bouts of inflammation cannot be overstated. It is critical that inflammation must be controlled over the longer term and that each episode of inflammation be dealt with promptly if patients are to avoid severe vision loss or blindness.

Until now, systemic corticosteroids have been the treatment of choice for posterior segment uveitis, administered either systemically or via periocular injections of Kenalog (triamcinolone acetonide, generic) given every 2 to 4 months.2 Coticosteroid treatments have proven effective in managing the disease, but because of their toxicity they often lead to a myriad of side effects that are both debilitating and detrimental to patients' quality of life. The most common side effects of these corticosteroid treatments are diabetes, hypertension, osteoporosis, weight gain, and changes in appetite. In addition, repeated periocular injections can result in perforation of the globe, orbital fibrosis, and ptosis.3

Some posterior uveitis patients who cannot tolerate corticosteroids have been treated with such nonsteroid drugs as methotrexate, cyclophosphamide, and cyclosporine. These therapies have their own specific side effects. For example, methotrexate can cause bone marrow suppression, cyclophosphamide can lead to hemorrhagic cystitis, and cyclosporine can cause hypertension and kidney damage.

Given these significant drawbacks, retinal specialists have long desired a new delivery system for drugs that can be effective in treating chronic noninfectious posterior uveitis.

Because the disease is chronic and often confined to the eye, logic dictated that the most advantageous method of drug delivery should be intravitreal and that the therapy should be continuous. Here, I will explain why the recent approval by the Food and Drug Administration (FDA) of the drug-delivery system Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch & Lomb, Rochester, NY) represents a major step forward in the treatment of chronic noninfectious posterior uveitis.

A NOVEL DRUG-DELIVERY SYSTEM

Restisert, which has just become available for use by retinal specialists, is now the only FDA-approved agent for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. The Retisert delivery system can best be characterized as a second-generation sustained-release platform. The implant itself is a 1.5-mm tablet coated with polyvinyl alcohol (PVA) and silicone laminate, and affixed to a PVA suture strut. The overall dimensions of the implant are 3 mm x 2 mm x 5 mm. A silicone elastomeric membrane allows the drug to leach out. The release characteristics are a nominal initial rate of 0.6 μmg per day, with dosage decreasing over the first month to a steady rate of 0.3 μg to 0.4 μg per day over approximately 30 months.

The low solubility of fluocinolone acetonide allows for slow release and long duration of action.4 The agent also has potent anti-inflammatory activity5 and minimal, if any, risk for systemic exposure.

Implantation of Retisert should not be difficult for retinal specialists who have experience with the Vitrasert (ganciclovir, Bausch & Lomb) implant. The implantation technique is similar, with Retisert actually being easier to insert because it is a smaller device than Vitrasert. Wound-healing problems are potentially more of an issue with Retisert than with Vitrasert because the Retisert device places corticosteroids (which inhibit wound healing) in close proximity to the implantation incision.

Complications that can result from the implantation of Retisert include retinal detachment, intraocular infection, vitreous hemorrhage, and wound dehiscence.

BENEFITS CAN BE SIGNIFICANT

Two pivotal clinical studies of Retisert have demonstrated impressive benefits to patients, particularly in terms of reduced disease recurrence, improved visual acuity, and elimination of the need for systemic corticosteroids and/or periocular injections. The continuous steroid therapy provided by Retisert did result in 90.3% of study eyes developing cataracts (which were extracted) and about 64% of patients displaying high IOP (generally managed by topical medications and/or filtering procedures). A small percentage of patients developed glaucoma. These complications were anticipated given the nature of the disease and the type of drug used.

In quantifying the benefits of Retisert, the two clinical studies demonstrated that implantation of Retisert reduced disease recurrence after 34 weeks from the 40% to 54% range to the 7% to 14% range. In addition, the clinical studies showed that 19% to 21% of Retisert recipients had improved visual acuity of more than 3 lines after 34 weeks and 15% to 17% of these individuals maintained that improvement after 1 year. Retisert also reduced the percentage of patients requiring systemic corticosteroid therapy after 34 weeks from the 47% to 63% range to the 5% to 10% range.6

Because locally delivered Retisert dramatically reduces the percentage of patients who need either systemic steroids or corticosteroid-sparing agents, most patients are able to avoid the aforementioned systemic side effects caused by these potent drugs. The elimination of periocular injections for many patients spares them the discomfort and risk associated with intravitreal procedures. In addition, patient convenience is enhanced because use of the Retisert implant requires fewer office visits.

THE COST EQUATION

Despite its $18 250 cost for an implant that provides 30 months of continuous therapy, Restisert is reasonably priced when compared to other highly specialized and "orphan" drugs used to treat systemic and ophthalmic diseases. For instance, Remicade (ifliximab, Centocor) for rheumatoid arthritis and Crohn's disease costs about $43 000 for 3 years of treatment, and Avastin (bevacizumab, Genentech) for colorectal cancer costs approximately $4 500 for 1 month of treatment.

In the area of ophthalmic drugs, Vitrasert costs about $20 000 for 30 months of treatment, Macugen (pegaptanib sodium injection, Eyetech Pharmaceuticals/Pfizer Inc.), the newly approved drug for wet AMD, costs about $20 000 for 30 months of treatment, and Visudyne (verteporfin, QLT Inc./Novartis) costs approximately $12 600 for 30 months of treatment.

Aside from the initial cost of the drug, Retisert also creates savings and efficiencies by eliminating the need for systemic corticosteroids and/or periocular injections in most patients, by requiring fewer office visits, and by allowing patients in their prime years to be far more productive because their vision is better and they avoid the debilitating side effects of systemic steroids. Not all of these benefits are immediately quantifiable in terms of dollars and cents, but they are real.

Thus far, insurance companies have found cost no impediment to approving Retisert for reimbursement. These plans are paying for the drug because they, too, believe that its use is offering patients a better quality of life while saving the payers money.

When submitting reimbursement claims for Retisert implantation, use CPT procedure code 67027 (implantation of intravitreal drug-delivery system, includes concomitant removal of vitreous). See "Coding Q and A" on page 20 of this issue for additional information on coding for Retisert.

SUMMARY

Clinical results from 2 extensive pivotal studies have demonstrated that Retisert provides long-term control of inflammation, and significantly reduces disease recurrence. Additionally, a greater percentage of patients who were implanted with Retisert experienced an increase in visual acuity compared to those in a control group. Of equally great importance is the fact that adjunctive therapy with corticosteroids and/or immunosuppressives was required for far fewer patients who had received the Retisert implant.

The primary side effects of Retisert — including cataract, elevated IOP, and glaucoma — though a concern, are manageable and tolerable considering the significant benefits provided by this therapy.

In summary, Retisert represents a major step forward in the treatment of an extremely difficult and frustrating disease.

Henry L. Hudson, MD, FACS, is in private clinical retina practice in Tucson, AZ. Dr. Hudson has no financial or consultant relationship with Bausch & Lomb.

REFERENCES

1. Durrani, et al. Degree, duration, and causes of vision loss in uveitis. Br. J Ophthalmol. 2004;88:1159-1162.

2. Anglade E. Whitcup SM. The diagnosis and management of uveitis. Drugs. 1995;49:213-223.

3. Haupert CL, Jaffe GJ. New and emerging treatments for patients with uveitis. Int Ophthalmol Clin 2000;40:205-220.

4. Ruelle P. et al. Hydrophobic and solvation effects on the solubility of hydroxysteroids in various solvents: quantitative and qualitative assessment by application of the mobile order and disorder theory. Perspect Drug Discov Des. 2000;18:61-112.

5. Brattsand R., Thalen A, Roempke, K, Kallstrom L, Gruvstad, E. Influence of 16 alpha, 17 alpha-acetal substitution and steroid nucleus fluorination on the topical to systemic activity ratio of glucocorticoids. J Steroid Biochem. 1982; 16:779-786.

6. Data on file. Bausch & Lomb, Inc.

 



Retinal Physician, Issue: July 2005