From healthcarecg's reports on the Geneva conference, the following write up on S-1153 PI data, AGPH's recently inlicensed NNRTI (which would compete with Sustiva). Below that, I've copied in Testact's comments on S-1153 for comparison ...
healthcg.com
S-1153: A "Second Generation" NNRTI
In the case of Lexigen Pharmaceuticals1 new non-nucleoside RTI
code-named S-1153, the authors explain that the drug has a 10-fold
greater in vitro potency than either nevirapine or delavirdine, the two
NNRTIs currently licensed in the USA [2]. S-1153's claim to fame is
that, like DuPont Pharma1s efavirenz, it requires more than one amino
acid substitution in order for the IC50 of the drug to be significantly
increased. But patients failing on any of the other NNRTIs will very
likely already possess multiple NNRTI resistance mutations, so if S-1153
is to find a market, it seems it will be for the NNRTI-naive.
This study of S-1153 was also a Phase I dose escalation study, in which
HIV-infected individuals were exposed to seven different doses of S-1153
for either 14 or 28 days. Concomitant antiretroviral therapy with
protease inhibitors or other NNRTIs was not allowed. Of the 25
individuals who received S-1153 for 28 days, four had already "failed"
on protease inhibitor therapies and only 10 were taking concomitant
NRTIs.
A total of 54 patients received S-1153, and the drug was said to have
high bioavailability with or without food. Side-effects reported were
mild nausea and metallic taste which were ameliorated by dosing with
food. No rashes were observed over the 14-28 study period. Target blood
levels of S-1153 were maintained with q8 as well as q12 hour dosing.
Of the 11 patients with plasma HIV RNA levels greater than 10,000
copies/mL who dosed for 28 days, the average viral load decrease on
S-1153 was 1.74 log (range 0.74-2.6). In 12 of the total 25 patients who
received S-1153 for 28 days, plasma viral loads dropped to below the
limit of detection (400 copies/mL). The average CD4+ T cell increase in
these patients was 122 cells/mm3.
The authors concluded that S-1153 administered either BID or TID is
well-tolerated, achieves therapeutic plasma levels and demonstrates
potent antiviral activity in antiretroviral-experienced patients.
However, it may be significant that no data were provided regarding
prior NNRTI exposure and/or failure among this study population. If only
protease and NRTI failures were recruited for this dose escalation
study, results in the clinic among nevirapine, delavirdine or
efavirenz-treated patients might differ significantly.
Testact's comments:
"I spoke with Peter Johnson at the meeting regarding the Shinogi
compound; he obviously is excited about the prospect of it being active
in Sustiva resistant strains. However this in in-vitro data and I am
aware of better pre-clinical compounds than this one. The
pharmakokinetics of this compound and dosing uncertianty (probably BID)
make this a real question mark." |
