Gene Expression Modulator 92 (GEM 92) is an experimental drug designed to inhibit HIV using genetic technology. Developed by an American research company Hybridon, it is an antisense oligonucleotide agent. Antisense drugs are short pieces of synthetic DNA or RNA that affect disease at the genetic level. These drugs are designed to stop the production of proteins which cause disease.

GEM 92 is a second generation, orally administered, anti-sense oligonucleotide directed against the gag gene in HIV. It is a follow-up compound to GEM-91 or Trecovirsen, which was discontinued due to toxicities and patchy anti-HIV activity.

Current use

GEM-92 is undergoing phase I safety and dosing trials. In cell cultures, GEM 92 significantly inhibited HIV replication and showed increased stability in comparison with GEM-91.

Preliminary tests showed that GEM 91 could get inside HIV-infected cells in laboratory tests and substantially reduce HIV replication. Doses were then reduced until they were 100 times lower than those initially used, but the virus remained unable to reproduce. Despite these encouraging test-tube results, development of GEM 91 was halted in July 1997 after a phase II study in people showed inconsistent responses to treatment and a reduction in platelet counts. Phase I/II studies of GEM 91 demonstrated a decrease in cellular viraemia (the amount of infectious HIV within circulating blood cells), but moderate increases in HIV RNA (the amount of HIV particles in the circulation).

Key research

Agrawal reported that GEM 91 showed anti-HIV activity in acutely infected cells, chronically infected cells, long-term cultures using H9 and Molt 3 cells and primary peripheral blood lymphocytes and macrophages using laboratory strains and clinical isolates. Plasma half-life is up to 30 hours in rats and 50 hours in monkeys when administered intravenously. Byrn reported that a range of 14 clinical isolates, including AZT-resistant and ddI-resistant strains, were equally sensitive to GEM 91 in vitro.

Lisziewicz reported that GEM 91 inhibited viral replication in long-term culture for over 80 days. After pre-treatment of cells, the concentration of the antisense oligodeoxynucleotide could be decreased by greater than10-fold and still maintain inhibition of viral replication.

Papp reported that there was no significant loss of sensitivity to GEM 91 in vitro after 15 passages over a period of 187 days.

Sereni treated 24 patients with GEM 91 (0.1, 0.3, 0.5 and 1 mg/kg). Participants received a single dose either intravenously or subcutaneously, then fourteen days later received a second dose by the alternative route (except for the 1 mg/kg dose which was always given by IV). No renal, neurological, hepatic or cardiac toxicities were observed. 6/18 participants developed localised painful nodules at the site of subcutaneous injection.

Hybridon (1997a) reported that in phase Ib/II in which eight people received placebo and 14 received GEM 91 (3.2 to 4 mg/kg/day over 8 days), cellular viraemia increased during the first four days in all participants, but thereafter generally decreased among GEM 91 participants for the duration of treatment. HIV RNA levels increased modestly, during treatment, with a sharp reversal on discontinuation.

References

Agrawal S et al. GEM 91 therapeutic agent for AIDS based on antisense oligonucleotide principle. 9th Intl Conf AIDS, Berlin, abstract A17-4, 1993.

Byrn RA et al. In vitro antiviral activity of GEM 91 against diverse clinical isolates of HIV-1. 2nd Natl Conf on Human Retroviruses, Washington, abstract 477, 1995.

Hybridon. Hybridon unblinds clinical trial results of GEM 91 showing activity against advanced HIV and AIDS. Company press release, 4th April 1997.

Hybridon. Hybridon stops development of GEM 91 for AIDS. Company press release, 25th July 1997.

Lisziewicz J et al. Long-term treatment of human immunodeficiency virus-infected cells with antisense oligonucleotide phosphorothioates. PNAS 90:3860-3864, 1993.

Papp B et al. Failure to generate HIV-1 resistance in vitro to the antisense therapeutic agent GEM 91. 2nd Natl Conf on Human Retroviruses, Washington, abstract 469, 1995.

Sereni D et al. Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects. Journal of Clinical Pharmacology 39(1):47-54, 1999.

Zheng R et al. Technology evaluation: GEM-92, Hybridon Inc. Current Opinions in Molecular Therapy 1(4):521-523, 1999.