Cornea
Updates on HSV

Now that Zirgan (ganciclovir ophthalmic gel 0.15%) has been approved by the Food and Drug Administration (FDA) for acute herpetic keratitis, ophthalmologists may wonder how this will fit into their treatment options.
Although the FDA granted orphan drug status to Zirgan, meaning that it recognized the importance of the medication in the treatment of a rare disease—in this case—dendritic ulcers (and thus provided certain incentives to the manufacturer), Zirgan isn’t the first drug that can be used to treat acute herpetic keratitis.
The manufacturer, Sirion Therapeutics (Tampa, Fla.), suggests the drug is unique. “The approval of Zirgan represents a true advance in topical antiviral therapies in the U.S.,” said Sirion CEO Barry Butler in a news release. “Up to this point, no therapy targeting only viral-infected cells was available for topical ocular use. Zirgan provides doctors with a much needed modern treatment for herpetic keratitis.”
However, some U.S. physicians eagerly awaiting the release of the drug into the market—anticipated early this year—are interested in using it mainly because fewer drops are required than other medications for dendritic ulcers, and less toxicity may be experienced, they say.
It is therefore important to understand not just what Zirgan brings to the table, but where its place is relative to other dendritic ulcer medications already there. An understanding of what ophthalmologists have been and are currently using domestically and internationally will provide assistance in this regard.

Fresh off the international boat

The current medication widely used to treat herpetic keratitis in the United States is Viroptic (1% trifluridine, GlaxoSmithKline, Middlesex, United Kingdom). “It’s a nine-times-a-day drop,” said Christopher J. Rapuano, M.D., professor of ophthalmology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, and co-director, Cornea Service, Wills Eye Institute, Philadelphia. “So the main advantage of Zirgan is that it is fewer times a day.”
Worldwide, both ganciclovir and topical aciclovir (various manufacturers) have been available to treat herpetic keratitis for some time. “Colleagues around the world say they are both better than Viroptic, which is hardly used,” he said. “Zirgan is therefore a welcome treatment for dendritic keratitis in the U.S. It’s a five-times-a-day gel drop and is as effective if not more effective than aciclovir. It’s also more comfortable and less toxic than Viroptic.”
According to Sirion Therapeutics, in a 164-patient clinical trial, Zirgan was “non-inferior” to aciclovir in patients with dendritic ulcers. “Clinical resolution (defined as percentage of healed ulcers) at Day 7 was achieved in 77% (55/71) for Zirgan versus 72% (48/67) for acyclovir,” Sirion reported.
Clearly though, using five drops a day still could be burdensome. “Five times a day is still a lot of drops a day,” Dr. Rapuano said. “But it’s a lot better than every two hours.”
In fact, when the epithelium heals, Zirgan can be reduced to three-times-a-day usage, he said.
Dr. Rapuano believes less frequent usage leads to fewer toxicity issues. “I am excited to use it,” Dr. Rapuano said. “Wile Viroptic works, it’s not perfect. It’s used many times a day and is rather irritating to the surface. If you use it more than two weeks it becomes extremely toxic. With usage between 3 and 5 weeks, the corneal surface can become quite damaged from the medication. My understanding is that this is less likely to happen with ganciclovir gel.”
Aciclovir, meanwhile, remains difficult to come by in the United States. “Aciclovir ointment is not available,” Dr. Rapuano said. “[Special] pharmacies may be able to make it up.”

Topical vs. systemic treatment

Systemic aciclovir is available in pill form, Dr. Rapuano said. “But systemic acyclovir is excreted by the kidneys,” he said. “If someone has kidney problems they will either need a lower dose or won’t be able to use it.”
Mark J. Mannis, M.D., professor and chair, Department of Ophthalmology and Vision Science, University of California, Davis, still favors the systemic approach in treating dendritic ulcers, but remains open to various techniques.
“You can effectively eradicate the problem with mechanical debridement, topical medication or oral medication,” he said. “One of the three gives an 85 to 90% chance for achieving resolution of the key problem.”
Dr. Mannis also noted the problems with Viroptic, suggesting that oral Valtrex provides a good alternative. “Viroptic must be used nine times a day and is relatively toxic to the eye,” he said. “Patients who have to use it with frequency also develop toxic side effects.
They primarily turn to valaciclovir [Valtrex, GlaxoSmithKline]. It’s a good first-line drug, is twice daily by mouth and has very little in the way of side effects.” Valtrex, even though it is used in oral form, also penetrates into corneal tissues well, Dr. Mannis said.

Not a blockbuster

John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Virginia Medical School, Norfolk, Va., said the fact that a modest company is bringing Zirgan to market is a great thing, but it likely won’t be a big moneymaker.
“I think that’s a very noble effort by a small startup company to bring a needed product to marketplace in the U.S.,” Dr. Sheppard said. “The profit margins and potential sales for antiviral products are truly minuscule in big picture of pharmaceutical sales.”
Hence, Zirgan “really amounts to being an orphan indication,” Dr. Sheppard said. It will be a very helpful new product, nonetheless, he said. “It doesn’t have to be ordered from a special pharmacy or via transatlantic shipment,” he said. “The fact that it will be available in [regular] pharmacies is very beneficial.”
Dr. Mannis said he runs a “highly concentrated corneal referral practice” and sees two to three herpetic patients per week, who are returning—not new—patients. “The average ophthalmologist is not going to see that many patients,” he said.
Sirion maintains that 20,000 primary cases of ocular herpes are diagnosed in the U.S. each year, and recurrences account for 28,000 additional cases per year.
Beyond the business of dendritic ulcer management, Dr. Sheppard said it’s hard to say at this point whether Zirgan will become the gold standard for such treatment. One thing is for sure: expect more comparisons between Zirgan and Viroptic, considering they will now vie for an already small piece of treatment pie in the U.S. market.

Editors’ note: Drs. Rapuano, Mannis, and Sheppard have no financial interests related to their comments.

Contact information

Mannis: 916-734-6957, mjmannis@ucdavis.edu
Rapuano: 215-928-3180, cjrapuano@willseye.org
Sheppard: 757-622-2200, docshep@hotmail.com