By Steve Sternberg
Special To BioWorld Today
Two experimental antisense compounds for use in AIDS patient have passed key clinical hurdles, their manufacturers said Thursday.
The compounds are Hybridon Inc.'s GEM91, a synthetic strand of oligonucleotides designed to inhibit replication of HIV, and Isis Pharmaceuticals Inc.'s fomiversen, an intraocular compound intended to halt the progression of cytomegalovirus (CMV) retinitis.
An analysis of unblinded data from Hybridon's ongoing Phase Ib/II trial of GEM91 found "a statistically significant decrease in cellular viremia between treated and untreated patients with advanced HIV disease," said Russell Martin, vice president for clinical research at Hybridon, of Cambridge, Mass.
Based on the analysis, by Victor Gruttola, a professor of statistics at the Harvard School of Public Health, Hybridon plans to conduct a confirmatory Phase II clinical trial in advanced HIV patients, who seemed to benefit most from treatment.
"We're not claiming efficacy here, I want to make that clear," said Robin Hogen, the company's vice president for corporate communications. "We've got very intriguing results, and we want to confirm them."
The Phase Ib/II trial is a double-blind comparison of the GEM91 vs. placebo that has lasted two years. The confirmatory trial would involve about two dozen patients, who would take the compound for 14 days. Hogen said Hybridon expects to report the results of the smaller trial in May. Later this year, the company plans to initiate pivotal trials and apply to the FDA for a treatment investigational new drug application.
Robert Coombs, an associate professor of laboratory medicine at the University of Washington, in Seattle, who has been quantifying cellular viremia for the GEM91 studies, characterized the results so far as "encouraging." Both men spoke at the Oligonucleotide and Gene Therapy-based Antisense Therapeutics meeting in San Diego.
Martin also noted that the compound concentrates in macrophages, which may account for the seeming improvement in late-stage patients. Researchers have demonstrated that these cells are an important site of viral replication in the late stages of HIV disease.
Since protease inhibitors don't penetrate macrophages, Hagan said, GEM91's apparent ability to stem HIV replication in macrophages could make the strand of 25 oligonucleotides an effective therapy of last resort, either alone or in combination with other drugs.
The antisense compound could also prove useful earlier in the course of the disease for patients who develop resistance to other antivirals and those who can no longer tolerate the multidrug cocktails that have become the norm in HIV treatment.
Hybridon's stock (NASDAQ:HYBN) gained $0.875 Thursday to close at $7.
Fomiversen Outperforms Ganciclovir
In another presentation at the meeting, Daniel Kisner, president and chief operating officer of Isis Pharmaceuticals, in Carlsbad, Calif., reported that the company's compound, fomiversen, "continues to demonstrate an attractive safety profile and rapid and long-term control of CMV retinitis." The results emerged from an open-label uncontrolled trial in people with advanced CMV retinitis whose infections survived other agents. Kisner told the meeting that fomiversen has, so far, outperformed ganciclovir and newer anti-CMV drugs.
Fomiversen is a 21 oligonucleotide complement for CMV's messenger RNA. It is delivered directly into the vitreous humor of the eye once a week for three weeks, and then every other week for maintenance. The antisense sequence acts by blocking production of two proteins that are necessary for CMV replication, said Jane Green, the company's senior director of investor relations. "It is a local therapy for a local disease," Green said.
Although the preparation cannot heal damaged tissue, or restore sight in people with existing retinal lesions, the compound has demonstrated that it can halt the progression of CMV disease, and preserve a person's vision. Isis plans to complete Phase III trials later this year.
Isis stock (NASDAQ:ISIP) closed Thursday at $16, up $0.375. *