Two
Novel Fusion Inhibitors Demonstrate In Vitro Activity against HIV New
fusion inhibitors, which block the attachment of HIV to host cells, represent
a promising avenue for drug development. Only one
fusion inhibitor, T-20 (enfuvirtide, Fuzeon) is currently approved. At
the XVI International AIDS Conference in Toronto, researchers from Trimeris presented
data on two "next generation" candidates in this class, TRI-1144 and
TRI-999. TRI-1144
and TRI-999 are peptides derived from the gp41 HR2 domain of the HIV envelope,
closer to the N-terminal than T-20. (Trimeris
also developed T-20, though it is marketed by Roche.) These compounds, the
researchers wrote, "demonstrate substantial improvements in potency, genetic
barrier to resistance, and pharmacokinetics," compared with T-20. Pharmacokinetics TRI-1144
and TRI-999 were evaluated in sustained-release formulations (including microspheres
and gels), in the hope that these may allow for a dosing frequency of once daily
or less, compared with the current twice daily for T-20. Results 
TRI-1144 and TRI-999 had IC50s (50% inhibitory concentrations) against fusion
inhibitor-sensitive clinical HIV isolates of 7 and 1 nanomoles (nM), respectively.
Tested against a panel of peptide fusion inhibitor-resistant HIV isolates, TRI-1144
and TRI-999 had geometric mean IC50s that were 150-fold and 250-fold lower, respectively,
than that of T-20.
TRI-1144 and TRI-999 had pharmacokinetic clearance values that were 4-fold and
6-fold slower, respectively, than that of T-20.
In vitro release profiles of these peptides in sustained-release formulations
demonstrated steady release of 90% at time periods greater than 1 week.
Various sustained-release formulations produced steady or delayed release in rats
and rabbits.
Preliminary in vivo release profiles of early formulations of these peptides in
monkeys provided evidence for release at time periods greater than 1 week.
Conclusion The
researchers concluded that TRI-1144 and TRI-999 demonstrated "(1) potent
in vitro antiviral activity, (2) high genetic barrier to generation of in vitro
resistance, and (3) slow clearance properties in monkeys." They
added that, "Current progress in developing a sustained release formulation
provides evidence that extended-release of [next generation fusion inhibitor]
peptides is achievable." Work continues towards identification of refined
formulations that will allow for "patient friendly" once-weekly dosing. Drug
Resistance In
another study, researchers analyzed the development of resistance to TRI-1144
and TRI-999. Three types of cells were infected with 8 HIV isolates and cultured
with increasing concentrations of T-20 or T-1249 (an experimental fusion inhibitor
candidate that was discontinued in 2004) to select for resistance, then the virus
was subject to genotypic resistance testing. Results
12 isolates with resistance to T-20 were still sensitive to T-1249, TRI-999, and
TRI-1144.
11 isolates with resistance to both T-20 and T-1249 remained sensitive to TRI-999
and TRI-1144.
Conclusion In
conclusion, the researchers wrote, "TRI-999 and TRI-1144 retained activity
against [T-20]- and T-1249-resistant isolates. Those results, combined with a)
an inability to observe virus breakthrough in concentrations of TRI-999 and TRI-1144
over 30-fold lower than with [T-20] or T-1249, along with b) higher numbers of
mutations required to generate resistance suggest these next generation fusion
inhibitors have enhanced genetic barriers to resistance." 08/29/06 References M
Delmedico, B Bray, N Cammack, and others. Next generation fusion inhibitor candidates
TRI-1144 and TRI-999 have improved pharmacokinetics: progress towards once / week
dosing. XVI International AIDS Conference. Toronto, August 13-18, 2006. Abstract
THAA0303. D K
Davidson, R J Medinas, S M Mosier, and others. New fusion inhibitor peptides,
TRI-999 and TRI-1144, are potent inhibitors of enfuvirtide and T-1249 resistant
isolates. XVI International AIDS Conference. Abstract THPE0021/13377.
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