Re: NATAP/Entry Wksp: New Fusion Inhibitor TRI-1144
Brian Mailman
> *Preclinical Work Suggests Advantages of New Fusion Inhibitor Versus
> Enfuvirtide
>
> *Targeting HIV Entry: 3rd International Workshop
> December 7-9, 2007
> Washington, DC
>
> /Mark Mascolini
>
> /Early lab and animal work by Trimeris suggests that an experimental
> fusion inhibitor labeled TRI-1144 has a higher barrier to resistance
> than enfuvirtide, retains activity against enfuvirtide-resistant virus,
> may need only once-daily--or perhaps once-weekly--dosing, and may cause
> fewer injection site reactions than enfuvirtide [1]. Like enfuvirtide,
> TRI-1144 is synergistic with an array of other antiretrovirals [2].
>
> Before reporting the resistance and synergy findings at the HIV Entry
> Workshop, Donna Davison from Trimeris mentioned pharmacokinetic work
> supporting the viability of once-daily TRI-1144 injections. In a
> question-and-answer session after her talk, Trimeris's Michael Greenberg
> said the company wants to see early pharmacokinetic data in humans
> before deciding whether to pursue a once-weekly dosing option.
>
> Davison also noted that Trimeris scientists developed a more soluble and
> stable solution for TRI-1144 that could eliminate the need for
> reconstitution, a necessary step for people injecting enfuvirtide. In
> animal studies TRI-1144 causes fewer injection site reactions, a nagging
> problem with enfuvirtide.
>
> Testing TRI-1144 and enfuvirtide against 50 HIV isolates collected from
> patients, Trimeris recorded similar geometic mean 50% inhibitory
> concentrations (IC50s) with TRI-1144 (42 ng/mL) and enfuvirtide (33
> ng/mL), but the new drug had a tighter range of IC50 values (8 to 218
> ng/mL versus 2 to 749 ng/mL with enfuvirtide).
>
> Next Davison and colleagues pitted TRI-1144 against 24
> enfuvirtide-resistant viruses, 11 of them collected from people with
> resistance to enfuvirtide and 13 of them generated in the lab. Compared
> with a geometric mean fold change in IC50 of 63.9 for enfuvirtide, the
> mean fold change in IC50 for TRI-1144 measured only 0.99. Trimeris
> believes the experimental fusion inhibitor's activity against
> enfuvirtide-resistant virus suggests TRI-1144 and enfuvirtide have
> distinct resistance profiles.
>
> In vitro selection experiments that continued until the concentration of
> TRI-1144 or enfuvirtide reached 50 micrograms/mL generated an average of
> 1.8 enfuvirtide-associated mutations and 1.4 TRI-1144-associated
> mutations. However, the geometric mean fold change in IC50 measured 39.7
> for enfuvirtide in these experiments, compared with only 5.8 for
> TRI-1144. It took virus 49 days to evolve the average 1.8 mutations that
> conferred 39.7-fold resistance to enfuvirtide. In contrast, it took HIV
> 223 days to mount a comparable 42.6 fold-change in resistance to
> TRI-1144 (Table). An average 5.2 mutations had to accumulate to confer
> this level of resistance to TRI-1144, compared with the average 1.8
> mutations needed to make HIV resistant to enfuvirtide.
>
> *Summary of In Vitro Selection Studies with TRI-1144 and Enfuvirtide
>
> *///
> /
>
> Finally, Davison tested TRI-1144 against virus that she engineered to
> carry one, then three, then four of the resistance mutations that arose
> in the in vitro selection experiments. Virus with only one mutation had
> no change in IC50, and virus with three mutations had only a 9-fold
> change in IC50. But virus with four mutations was fully resistant to
> TRI-1144, with almost a 150-fold change in IC50.
>
> These findings led Trimeris to propose that TRI-1144 has a higher
> barrier to resistance than enfuvirtide. After Davison's talk, University
> of Utrecht resistance expert Charles Boucher cautioned that these lab
> findings do not necessarily mean that TRI-1144 will have a higher
> barrier to resistance than enfuvirtide when the drug gets tested in humans.
>
> A separate set of studies determined that TRI-1144 is synergistic with
> AZT, 3TC, lopinavir, and darunavir at combination index values of 0.53,
> 0.59, 0.51, and 0.62 respectively. TRI-1144 was "moderately synergistic"
> with efavirenz at a combination index of 0.83. These combination indices
> are similar to those found between enfuvirtide and these other
> antiretrovirals.
>
> In January 2004 Trimeris ended development of another second-generation
> fusion inhibitor candidate, T-1249.
>
> *References
> *1. Davison D, Medinas R, Mosier S, Greenberg M. In vitro selections
> with fusion inhibitor peptide TRI-1144 exhibit a high genetic barrier to
> resistance. Targeting HIV Entry: 3rd International Workshop. December
> 7-9, 2007. Washington, DC. Abstract 18A.
> 2. Stanfield-Oakley S, Davison D, Greenberg, M. Enfuvirtide and
> TRI-1144: Fusion inhibitors with synergistic interactions with
> antiretroviral drugs in vitro. Targeting HIV Entry: 3rd International
> Workshop. December 7-9, 2007. Washington, DC. Abstract 18B.
>
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