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First-generation HIV-Antisense Oligonucleotide Trials Halted
On Friday, July 28, 1997, Hybridon Inc., of Cambridge, Massachusetts, announced that is halting development of GEM91, its first-generation antisense oligonucleotide directed against the HIV gag gene, because of platelet depletion in trial patients. The company will focus efforts on GEM92, a second-generation antisense compound, which also targets the gag site of the viral genome.
Earlier trials indicated that GEM91 significantly reduced viremia in HIV-positive patients treated for up to eight days. However, in the latest Phase IIb trial, 3 of 9 patients with advanced HIV infection experienced a decrease in platelet count after ten days of treatment.
This finding led to the decision to halt development of the compound. In a company communication, Hybridon VP Dr. Russell Martin said, "...even if efficacy could be demonstrated, the results of this Phase II clinical trial indicated that chronic therapy for advanced HIV patients with GEM91 in combination with other antiretrovirals likely would require periodic interruption of drug administration."
The second-generation antisense products being developed by Hybridon, unlike the first-generation phosphorothioates, are mixed backbone oligonucleotides. "We believe these second generation oligonucleotides will have a substantially greater therapeutic index," said Hybridon Chairman E. Andrews Grinstead. He added, "The growing population of AIDS patients who...develop resistance to triple combination therapy may be helped by GEM92."
GEM92 is expected to enter clinical trials in October. So far, animal studies show that it causes substantially fewer platelet and liver changes than GEM91, and that it has the potential for oral administration. Dr. Martin said he hopes GEM92 will have "...increased potency, reduced frequency of dosing administration and an improved safety profile, as compared to first generation antisense compounds."
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