AIDSWEEKLY Plus; Monday, November 23, 1998
Daniel J. DeNoon, Senior Editor

But the new drug has a very brief half life and, like insulin, can only be administered by twice-daily injections or continuous subcutaneous infusion.

The drug, T-20 (pentafuside, previously dubbed DP-178, Trimeris, Inc., Durham, North Carolina), is a 36-mer synthetic peptide corresponding to a region predictive of the alpha-helical secondary structure of HIV-1 (residues 643 to 678 of HIV-1[LAI]). It specifically prevents HIV from fusing with host cells - which it must do in order to establish infection - by interfering with the gp41 surface molecule HIV uses to penetrate its targets.

University of Alabama, Birmingham, researchers Michael Kilby and Michael S. Saag and colleagues tested T-20 in a pilot study that enrolled 16 HIV infected patients.

"Our findings indicate that over a two-week treatment period, the efficacy of T-20 in blocking de novo virus infection is comparable to that of protease and reverse-transcriptase inhibitors," Kilby et al. wrote.

They published their findings in the journal Nature Medicine ("Potent Suppression of HIV-1 Replication in Humans by T-20, A Peptide Inhibitor of gp41-Mediated Virus Entry," Nature Med, 1998;4(11):1302- 7). Saag reported preliminary study results at the 1997 meeting of the Infectious Diseases Society of America.

Kilby et al. found that at the highest dose (100 mg twice daily) T-20 could reduce HIV viral loads by 99 percent (1.96 log[10]). No safety problems occurred in the two-week study.

Ongoing trials of T-20 have enrolled the type of patient most likely to be treated if the drug proves safe over time: patients with HIV disease who have failed all other available treatments.

"The development of a suitable outpatient drug delivery system for T-20 could result in substantial clinical benefit as a result of inhibiting this additional step in the viral life cycle," Kilby et al. wrote.

In an accompanying commentary article, University of California, San Diego researcher Douglas Richman noted that long-term compliance is a serious issue for a drug that cannot be taken orally.

"HIV infection is chronic and so, too, must be its treatment," Richman wrote ("Nailing Down Another HIV Target," Nature Med, 1998;4(11):1232-3). "Chronic parenteral administration will only be considered for patients who, because of drug resistance, have exhausted more conventional options. In addition, the distribution of a large hydrophobic molecule into critical compartments of HIV replication, such as the genital tract and central nervous system, remains a concern."

Richman asked whether it might be possible to develop a small peptide that could mimic the action of T-20. He suggested that the T- 20 results support such a search, as well as the search for other small molecules that could interfere with HIV/host-cell interactions.

T-20 is derived from a peptide synthesized in an exploration of the structure of the HIV-1 gp41 transmembrane glycoprotein.

Preclinical studies show that T-20 has astonishingly potent anti- HIV activity.

The peptide apparently blocks the transition of HIV gp41 to its fusogenic state by binding to the coiled-coil region of the glycoprotein.

In in vitro studies, T-20 totally blocked HIV-1-mediated cell-to- cell fusion at concentrations below 5 ng/ml. It inhibited HIV at concentrations 10,000 to 100,000 times lower than cytotoxic or cytostatic concentrations. T-20 was 10 to 1,000 times more active against HIV-1 than HIV-2, but was just as effective against primary HIV-1 isolates as it was against laboratory strains.

Pharmacokinetic studies of T-20 show that in the rat it has a rather long half life, with clinically relevant concentrations maintained for six hours. Its bioavailability following subcutaneous or intramuscular injection is 70 percent.

In its current formulation T-20 must be administered intravenously. Clinical trials are exploring the use of a portable infusion pump similar to those used by diabetics for insulin infusion.

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