By Randall Osborne
Isis Pharmaceuticals Inc. said fomivirsen (ISIS 2922), its antisense drug to treat AIDS-related cytomegalovirus (CMV) retinitis, significantly delayed the progress of the disease without serious side effects in a Phase III trial.
"We have a high level of confidence that fomivirsen is working and working well," said Stanley Crooke, chairman and CEO of Carlsbad, Calif.-based Isis. The company plans to submit a new drug application to the FDA in the first part of this year.
CMV retinitis is a late-stage, debilitating complication of AIDS. The infection afflicts 25 percent to 40 percent of AIDS patients.
Twenty-eight subjects were enrolled in the study. Of those, 18 were treated immediately with fomivirsen, which was delivered directly into the vitreous humor of the eye. Dosage was 150 micrograms once per week for three weeks, and once every other week thereafter.
The remaining 10 subjects were assigned to a deferred treatment group and followed to determine progression, as judged by FDA criteria. Then they were treated according to the same regimen as the immediate treatment group (which was also followed, and removed from the study upon progression).
For the immediate treatment group, the median time to disease progression was 71 days, compared with 13 days for the deferred treatment group, according to results of the intent-to-treat analysis, said Jack Chandler, the scientist who presented the data at the 5th Conference on Retroviruses and Opportunistic Infections, in Chicago.
"That's very impressive efficacy results to give to the attendees," along with side effects that "were really quite minor," Chandler said.
No patient was discontinued because of ocular side effects related to the treatment, although increased intraocular pressure was noted in 18.5 percent of patients. Mild to moderate, reversible intraocular inflammation was observed in 15 percent of patients. No incidents of retinal detachment — a risk when treatments enter the eye — occurred.
Protocols were designed "without reference to limiting in any way" the other therapies that might be used, Chandler said.
The trial, called CS2, was designed to test fomivirsen as a monotherapy in patients with newly diagnosed CMV retinitis whose infection did not immediately threaten their sight. Other Phase III trials were designed to evaluate fomivirsen alone and with oral ganciclovir.
A trial called CS3 is testing fomivirsen at the 150 microgram dosage with ganciclovir in patients with smoldering disease or active CMV lesions. Other trials, CS9 and CS12, are comparing two different treatment regimens at 330 micrograms in patients with advanced, active CMV retinitis that is not being controlled by standard therapy.
Preliminary studies of the other Phase III results are ongoing, said Daniel Kisner, president and COO of Isis.
"The time to progression is probably going to be somewhat similar [in those studies]," Kisner said. "This would be a very good bit of news."
Results from all the trials will be used to support a new drug application to the FDA and applications for regulatory approval outside the U.S. "as early as possible this year," Kisner said.
"I won't give a specific date, but it's work that is being done as we speak," Kisner said.
Fomivirsen is the most advanced of the antisense drugs, which work by interrupting the production of disease-causing proteins. An antisense drug binds to a specific sequence of proteins in its mRNA target, preventing formation of the protein encoded by the target mRNA.
Last summer, Isis signed a $20 million marketing deal for the drug with CIBA Vision Corp., of Atlanta, a division of Novartis AG, of Basel, Switzerland. Later in the year, an institutional investor provided Isis with $25 million in a private debt financing. (See BioWorld Today, July 16, 1997, p. 1, and Oct. 28, 1997, p. 1.)
Kisner said the competition for treatment of the disease consists mainly of intravenous drugs with "significant systemic toxicity," whereas fomivirsen has none.
"We think the compound will find a very nice home in the treatment of CMV retinitis," Kisner said.
Isis' stock (NASDAQ:ISIP) closed Thursday at $14.75, up $0.75. *