 |
|
|
| |
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.
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.
|
| |
|
|
|
|
|
