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Feature
Get Drugs Straight to the Eye
By Miriam Karmel, Contributing Writer
 
 

Would you like to treat your patient’s eye with a steady dose of an effective drug without systemic toxicities? That ideal may now be possible with a new wave of intraocular implants.

It sounds futuristic. Doctors implant a pellet no bigger than a grain of rice into the eye. Slowly, over the course of years, it releases sight-saving corticosteroids. Well, the future is here.

In April 2005, the FDA approved Retisert, a fluocinolone acetonide intravitreal implant for chronic noninfectious uveitis affecting the posterior segment of the eye. And now Retisert is being tested to treat macular degeneration and diabetic macular edema. Other implantable devices, loaded with different corticosteroids, are in the pipeline.

“This technology is the wave of the future,” said Baruch D. Kuppermann, MD, PhD, who reported study results of a biodegradable polymer device, Posurdex, at the Academy’s 2005 Annual Meeting. Posurdex is an implantable drug delivery system that gradually releases dexamethasone to treat diabetic macular edema.

By targeting drugs to tissues at the back of the eye, sustained-release implants avoid the need for repeated intravitreal injections or systemic drugs. They fill a large unmet need in ophthalmology, said David F. Chang, MD, who participated in clinical trials for a biodegradable implant for the front of the eye (Surodex).

“The ability to implant a delivery system that can provide therapeutic drug levels for up to a year would be enormously beneficial for retinal and optic nerve applications,” he said.

Because steroids appear beneficial in a number of diseases, including diabetic retinopathy, AMD and venous occlusive diseases of the retina, the technology could affect the hundreds of thousands of people with severe vision loss. “If you can get a good drug, an effective drug, that can be released over a long period of time, that is the Holy Grail in retinal medicine,” said Julia A. Haller, MD, another Posurdex investigator.

Idea Whose Time Has Arrived
By all accounts, the search for the intravitreal implant started on several fronts. In the early 1990s, researchers at the University of Kentucky developed the first intraocular sustained-release drug-delivery device, an implantable form of ganciclovir (Vitrasert), which maintained therapeutic levels of the drug  to treat CMV retinitis for eight months. This advance benefitted thousands of HIV-infected patients, nearly half of whom had developed CMV end-organ disease, including chorioretinitis.¹

Vitrasert, approved by the FDA in 1996, established that local therapy was effective for the long-term management of uveitis, said Daniel F. Martin, MD, who played a lead role in the clinical trials that led to FDA approval of both Vitrasert and Retisert. “Intuitively, local therapy made sense,” he said, “but it hadn’t been done before. It was Vitrasert that showed us how potent local therapy could be when compared with systemically administered drugs.”

Controlling the delivery. The first sustained-release biodegradable steroid implant (Surodex) was developed by Vernon G. Wong, MD, to control inflammation after cataract surgery. Dr. Wong, the first clinical director of The National Eye Institute (NEI) and former professor of ophthalmology at Georgetown University, found a way to bind drugs to a biodegradable polymer matrix for intraocular insertion. The drugs are slowly released as the polymer degrades. Alterations to the polymer structure affect the delivery rate, so it’s possible to create devices that release drugs for days or even years. Dr. Wong also developed Posurdex for the treatment of posterior segment diseases, which Allergan later acquired.

And targeting the delivery. Implantable sustained-release devices make sense for another reason. They address a long-standing challenge in retinal medicine—getting drugs to the back of the eye. Since drops don’t penetrate well into the vitreous cavity, doctors had only a few options: frequent and painful injections of steroids into, or around, the eye; or the prescription of large doses of oral steroids or other immunosuppressive therapies, which can create serious systemic side effects.

The problem with systemic treatments, as Dr. Martin noted, is that you end up treating the big toe and the eye with the same amount of drug. “But your big toe doesn’t have problems. So why expose it to the drug?”   

Once researchers were satisfied that local therapy was at least as efficacious as systemic, and possibly less toxic, Dr. Martin said they were faced with the challenge of finding a convenient way to administer drugs.

Here’s what they’ve discovered.

The Devices
Retisert.
In April 2005, the FDA approved the orphan drug fluocinolone acetonide 0.59 milligrams (Retisert by Bausch & Lomb) for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. 

The reservoir drug delivery system consists of a 1.5-millimeter tablet coated with polyvinyl alcohol and silicone laminate, affixed to a polyvinyl suture strut. Overall dimensions are 3 mm x 2 mm x 5 mm. It has been likened to a miniature baseball cap, with the bill getting sutured in the sclera. The cup, which holds the drug, hangs in the vitreous cavity.

The polymer membrane governs the release of the corticosteroid, initially at a rate of 0.6 micrograms per day, then slowly decreasing over about three years.

The 34-week data from a phase 2 randomized, multicenter, masked and controlled clinical trial reported that the recurrence rate of uveitis in eyes with the Retisert implant was 2.9 percent, compared with a 43.7 percent recurrence in the fellow eyes without implants. “The efficacy data for Retisert showed clearly that the device is very effective for controlling uveitis,” said Dr. Martin. “The patient population in that study was the worst of the worst. The fact that we were able to achieve this level of quiescence was remarkable,” he said.

After 34 weeks, 19 percent to 21 percent of those patients experienced improved visual acuity of 3 lines or more. And the need for adjunctive therapy—corticosteroid and/or immunosuppressive therapy—declined from 59 percent of patients at the start of the trial to 13.7 percent.

The side effects are by now well-known; almost all patients developed cataracts requiring surgery within two years. About 60 percent of patients needed IOP-lowering medication within 34 weeks; 32 percent may need filtering surgery.

Another phase 2 trial, begun in 2001, is testing Retisert in the treatment of patients with the wet form of AMD. And phase 2 and 3 clinical trials are evaluating Retisert in the treatment of patients with DME. 

Medidur. In early October 2005, a phase 3 trial was initiated to treat DME with the delivery system Medidur, using fluocinolone acetonide (the same active ingredient already approved for uveitis and marketed as Retisert).

The tube-shaped device, which is 3 mm long and about 3 mm in diameter, is inserted through an injector. “It is very much like any other intravitreal injection that a retinal surgeon is used to performing in the office,” said Ken Green, PhD, vice president, scientific affairs, Alimera Sciences Inc., which is collaborating with Control Delivery Systems on the device.

A surgeon could aspirate the nonbioerodable implant from the eye, but there is “no anticipated need to remove it once devoid of the therapeutic agent,” Dr. Green said.

In fact, he said that given its size, “It’s pretty reasonable that more than one, over the lifetime of a patient, could be inserted.”

There is a potential to use the implant for a more generalized treatment of diabetic retinopathy, he said.

Posurdex. This implant contains dexamethasone applied in a biodegradable polymer matrix, or “Posterior-Segment Drug-Delivery System” (DEX-PS-DDS from Allergan). The drug is gradually released following insertion into the eye through a small pars plana incision or puncture.

At the Academy’s 2005 Annual Meeting, Dr. Kuppermann reported the results of a phase 2 Posurdex trial that evaluated the response of different patterns of DME to treatment with intravitreal corticosteroids. In patients with persistent, refractory DME, 700 mg DEX-PS-DDS produced clinically and statistically significant improvements in visual acuity and central retinal thickness. A phase 3 trial is in process.

Enrollment is also under way for two further studies involving this delivery system, one to treat macular edema associated with vein occlusions, and the other for DME. Yet another trial will study Posurdex with photodynamic therapy.
 
Surodex. Surodex is to the front of the eye what Posurdex is to the back. The systems and medication are nearly identical, but the dosing is different (60 mg for Surodex, compared with 700 mg for Posurdex), and the application for Surodex is treatment of postoperative inflammation after cataract surgery.

Dr. Chang, a lead investigator for the phase 2 trial, described it as a tiny biodegradable polymer pellet, which, when placed behind the iris, releases a high level of dexamethasone for about one week. The drug level then quickly drops to zero. “Surodex was more efficacious than topical dexamethasone and eliminated topical anti-inflammatory medication for most patients,” Dr. Chang said.

Because such a high and sustained drug dosage was achieved, inflammation was suppressed with only a one-week delivery system and rebound iritis didn’t occur. “The real joy was not having to prescribe, explain, monitor and taper topical anti-inflammatory medications postoperatively,” he said.

But Surodex may have trouble getting to market. Though it could essentially eliminate the need for costlier topical steroids, it must be placed in the eye at the time of surgery. This is an application that Medicare won’t reimburse, Dr. Chang explained, in effect eliminating the market for Surodex.



A Few Sour Notes
Side effects.
Retisert’s side effects—cataract formation and a steroid-induced glaucoma—are well-established (see “Implant In, But Jury Still Out?” page 39). But, said Dr. Martin, referring to the cases at his site, “All the side effects were manageable complications. Are they complications we want? No.” But he said even patients who developed glaucoma and required surgery wanted to keep the implant.

Because IOP can rise suddenly and to very high levels, Dr. Martin recommends that the pressure be checked every four to six weeks.

As for cataracts, Dr. Haller said, “I think, realistically, any type of steroid is going to accelerate cataract formation.”

Big price tag. Cost is another consideration. Retisert, an orphan drug and the only posterior segment implant on the market, costs $18,250 for single implant, which lasts 30 months.

Several observers noted that while that amount seems high, it’s in the “ballpark” when compared to other cutting-edge therapies. For example, Macugen (pegaptanib sodium injection), for the treatment of wet AMD, requires 8.6 injections a year, at $1,000 each. Cost, observers said, likely will limit any off-label use of the implant.

On the Horizon
Although Retisert is the only steroidal implant currently available, others are likely to follow soon.

“I’m hoping that all these technologies will succeed. I’d love to see a wide array of these, with different drugs for different diseases,” said Dr. Kuppermann, adding that Posurdex is still a couple years away from approval. “We’re in the first step of drug delivery to the back of the eye.”

Dr. Martin predicts that both Retisert and Posurdex will have an important role to play in the management of patients with retinal disease. “It’s not picking one or the other. The duration of drug delivery you think you’ll need to manage the disease will drive your treatment decision. The disease we’re trying to treat is going to govern the choice,” he said.

“I think that there is a tremendous technology out there yet to be applied, and others to be developed that will simplify how we deliver drugs locally to the eye,” Dr. Martin said. “This is very much in its infancy.”

_______________________________
1 Hoover, D. R. et al. N Engl J Med 1993;329(26):1922–1926.

Implant In, But Jury Still Out
The original study of Retisert demonstrated that a tiny drug reservoir designed to deliver sustained levels of fluocinolone acetonide to the back of the eye worked.

“But it did not demonstrate how well it worked relative to standard therapy,” said Douglas A. Jabs, MD, MBA. “Although the studies that led to the licensing of the implant demonstrated that it worked, it’s never been compared to systemic therapy in a head-to-head fashion.”

Proof by comparison. Now, Retisert is going up against conventional treatment in the Multicenter Uveitis Steroid Treatment (MUST) Trial. The five-year, NEI-sponsored trial, which began September 2005, is comparing the effectiveness of oral corticosteroids with fluocinolone acetonide implant therapy for the treatment of severe cases of noninfectious intermediate uveitis, posterior uveitis or panuveitis. Four hundred patients will be randomized into one of the two groups at 20 centers in the United States and one center in Canada. 
 
MUST is designed to answer the question of how to treat a patient who presents with severe posterior or panuveitis. “Should you treat them systemically with what we’ve known for 20 years is an effective approach? Or should you use the new implant?” asked Dr. Jabs, who co-heads MUST. “Ophthalmologists are nervous about systemic side effects from immunosuppressive drugs,” Dr. Jabs said. “They should be. But that doesn’t mean that these drugs should be avoided.”

And Retisert is not benign. Almost everyone in the Retisert trials developed a cataract within two years. About two-thirds developed elevated IOP that required drugs, while one-third required filtering surgery.

Better, or just not as bad? Daniel F. Martin, MD, who tested the implant, said such side effects are manageable and may be preferable to those associated with conventional treatment. “You’re displacing systemic adverse events, which virtually every patient in the study would gladly trade,” he said.

But Dr. Jabs argued that the side effects associated with systemic treatment are avoidable. “People who say systemic side effects are so terrible are working off of old paradigms.” He explained that “side effects occurred because doctors tended to prescribe too much prednisone for too long, and did not move to immunosuppressive drugs.” 

Modern treatment with corticosteroids and immunosuppressive drugs can achieve good visual outcomes with acceptable side effect profiles, which occur in a limited number of patients, Dr. Jabs said. “We’ve learned that when people use the immunosuppressive drugs early, the side effects can be avoided.” 

Dr. Jabs’ advice: 1 milligram/kilogram of prednisone up to 60 mg/day, until the eye is quiet, or up to one month. If the eye is quiet, taper off prednisone, hopefully to nothing, and add an immunosuppressive drug of the physician’s choice. That regimen results in a 7 percent to 10 percent rate of cataract and glaucoma side effects. With the implant, the rate for cataract is 50 percent each year. The glaucoma rate is nearly 60 percent within two years.

Hopefully, the MUST Trial will reveal which treatment results in better visual acuity. “We don’t know which will be the result,” Dr. Jabs said. “The implant may prove to provide better visual outcomes than systemic therapy, or it may provide worse outcomes. We need to compare them.”
Enrollment in the MUST Trial is under way. For more information contact the Johns Hopkins University Center for Clinical Trials, 413-287-3170.

Implant Roster: One in Use, Three in Trials
Retisert. Fluocinolone acetonide 0.59 milligram tablet. Approved for the treatment of chronic noninfectious uveitis in the posterior segment.
 
Medidur. Fluocinolone acetonide in a tube-shaped delivery system. Under study for the treatment of DME.

Posurdex. Dexamethasone 700 mg in a biodegradable polymer matrix. Under study for the treatment of macular edema associated with vein occlusions and for DME.

Surodex. Dexamethasone 60 mg in a biodegradable polymer pellet for placement behind the iris. Under study for the treatment of postoperative inflammation after cataract surgery.

MEET THE EXPERTS

David F. Chang, MD Clinical professor of ophthalmology, University of California, San Francisco. Financial interests: None.

Ken Green, PhD Vice president, scientific affairs, for Alimera Sciences.

Julia A. Haller, MD Professor of ophthalmology, Johns Hopkins University. Financial interests: Is a consultant to Allergan and Bausch & Lomb, and has received research funds from both as an investigator.

Douglas A. Jabs, MD, MBA Professor of ophthalmology, medicine and epidemiology at Johns Hopkins University. Financial interests: None. Bausch & Lomb is providing a limited number of implants for the MUST Trial.

Baruch D. Kuppermann, MD, PhD Associate professor of ophthalmology and biomedical engineering and director of the retina service, University of California, Irvine. Financial interests: Is a paid consultant to Allergan and Bausch & Lomb.

Daniel F. Martin, MD Professor of ophthalmology, director of the retina service at Emory University. Financial interests: Is a consultant for Bausch & Lomb and is on the advisory boards of Alcon and Allergan. 



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