By Lisa Seachrist
BETHESDA, Md. — Despite the company's inability to enroll patients into clinical trials, an FDA advisory panel voted 5 to 2 to recommend approval for Isis Pharmaceuticals Inc.'s antisense drug for treatment of cytomegalovirus (CMV) retinitis.
In backing the first antisense drug for market approval, a subcommittee of the Dermatologic and Ophthalmic Drugs Advisory Committee offered a mixed recommendation on whether or not Vitravene (fomivirsen) should be cleared as a first-line therapy. The committee asked Isis to conduct Phase IV studies to determine the most appropriate dose and define the drug's role in the current CMV armamentarium. CMV retinitis is a serious and debilitating complication of AIDS that leads to blindness.
"Clearly, the advisory committee felt fomivirsen was safe and effective," said Stanley Crooke, CEO and chairman of the board for the Carlsbad, Calif.-based firm. "They also clearly sympathized with the limited number of patients which we could enroll. This is a seminal day in the development of antisense therapies."
Isis readily acknowledged trials of fomivirsen weren't completely enrolled. They pointed out that as highly active antiretroviral therapy with protease inhibitors has become the norm, the incidence of AIDS-related CMV retinitis has dropped significantly.
"CMV retinitis has become a distinctly rare disease," said Daniel Kisner, president and chief operating officer for Isis. "Our ability to enroll patients effectively fell to zero in 1997. These patients, thank heavens in many ways, disappeared."
Nevertheless, as HIV begins to develop resistance to the new drug cocktails, the incidence of CMV retinitis is likely to increase once more.
Fomivirsen is an antisense DNA molecule that targets the CMV RNA, stymieing its ability to replicate. The drug is injected directly into the eye.
The company presented data from trials testing fomivirsen in patients with newly diagnosed and advanced disease. In the first study of previously untreated patients, 28 were treated with 165 micrograms of fomivirsen once a week for three weeks and once every other week thereafter. Eighteen patients received treatment immediately, whereas 10 patients received the drug only after their disease had progressed.
Patients receiving the drug immediately had a median time to disease progression of 71 days compared with 13 days for the delayed treatment group.
In a second study, 54 patients with advanced CMV retinitis were given 330 micrograms of fomivirsen in two different regimens. Thirty-four patients received an aggressive dosing regimen that involved fomivirsen injections once a week for three weeks followed by once every other week thereafter. Twenty patients received the fomivirsen fortnightly from the outset. Both treatment groups experienced a median time to disease progression of 90 days.
Overall, Isis said, 330 patients have received fomivirsen in a number of clinical studies.
The company reported there were no systemic adverse events as a result of fomivirsen ocular injections. There were side effects found in the eye, which include anterior chamber inflammation, uveitis and intraocular pressure. However, the company maintained the side effects were mostly mild or moderate and usually resolved over time.
"Based on the data we've accumulated for fomivirsen, I believe it is both safe and efficacious for the treatment of CMV retinitis," said Jack Chandler, an ophthalmologist and consultant to Isis. "I believe very firmly that this is a drug that has an important place in the management of CMV retinitis."
The FDA, however, had questions about the number of patients available for making a determination of safety and efficacy.
A significant problem for the FDA's Wiley Chambers, deputy director of the Division of Anti-inflammatory, Analgesic and Ophthalmologic Drug Products, was the failure to enroll the scheduled number of patients in various trials, including both studies presented by the company.
Data Inadequate For First-Line Therapy, Official Says
"In my opinion, addition clinical studies should be done. Whether they need to be done as Phase III or Phase IV studies is something I hope you can advise me on," Chambers told the panel. "I don't believe [the data] is adequate to support a first line therapy. I could see an indication in patients who had failed prior therapies."
Chambers noted the natural variability involved in reading the retinal photographs that documented progression of the disease meant the results the company found may not be as significant as the calculated p-values indicated.
While concurring with the FDA the science could be stronger, the advisory committee felt Isis demonstrated the drug was efficacious within the confines of a very low incidence of the disease.
"It's going to be really difficult to do a well-powered study of this disease," said panel member Donald Fong, of Kaiser Permanente Medical Center in Baldwin Park, Calif. "I think the best we can do is look at post-market analysis."
The FDA isn't bound by the recommendations of its advisory panels, but the agency usually follows the advice.
Trading in Isis' stock (NASDAQ:ISIP) was halted Wednesday. It closed Tuesday at $13.438. *