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Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naïve HIV-1-infected patients
Presented by Sherene Min (United States).
J. Lalezari1, L. Sloan1, E. Dejesus1, T. Hawkins1, L. Mccurdy1, I. Song2, J. Borland2, R. Stroder2, S. Chen2, Y. Lou2, M. Underwood2, T. Fujiwara3, S. Piscitelli2, S. Min4, ING111521 Investigators
1ING111521 Investigators, Research Triangle Park, United States, 2GlaxoSmithKline, Research Triangle Park, United States, 3Shionogi & Co., Ltd., Osaka, Japan, 4GlaxoSmithKline, Infectious Diseases Medicine Development Center, Research Triangle Park, United States
Background: S/GSK1349572, a novel integrase strand transfer inhibitor, has demonstrated potent in vitro antiviral activity, human pharmacokinetics (PK) supporting once daily dosing, and a favorable clinical safety profile. This study evaluated the short-term anti-HIV activity, PK, safety and tolerability of S/GSK1349572 in HIV-1 infected subjects who were INI-naïve.
Methods: This was a multicenter, randomized, parallel, double-blind, dose ranging, placebo-controlled study of S/GSK1349572 monotherapy over 10 days in INI-naïve HIV-1 infected adults who were not currently receiving antiretroviral therapy. Subjects with HIV RNA ≥5000 copies/ml and CD4 ≥100 cells/mm3 were randomized to doses of 2mg, 10mg, 50mg or placebo once daily. HIV-1 RNA, genotypes/phenotypes, safety labs, vital signs, ECGs and PK sampling were performed at regular intervals.
Results: Thirty-five subjects completed all study visits. Demographics were similar across treatment groups. No deaths or SAEs were reported; no subject withdrew from the study due to an adverse event (AE). The most common AEs were diarrhea, fatigue and headache; except for headache, similar AE rates were observed in S/GSK1349572 and placebo groups. The majority of AEs were mild to moderate in severity. No clinically significant trends in post-dose laboratory abnormalities, vital signs or ECG values were noted. A mean decrease from baseline on Day 11 in plasma HIV-1 RNA of 1.51 to 2.46 log10copies/mL was observed across the S/GSK1349572 doses tested (2mg - 50mg) compared with placebo (+0.05 log10 copies/mL). At the 50mg dose, the majority of subjects (70%) achieved undetectable plasma HIV-1 RNA levels (< 50 copies/mL). No S/GSK1349572 phenotypic resistance was observed; no signature substitutions associated with in vivo raltegravir or elvitegravir clinical resistance or with S/GSK1349572 in vitro passage were detected.
Conclusions: S/GSK1349572 was generally well-tolerated and demonstrated unprecedented anti-HIV activity following short-term, once-daily, unboosted dosing in INI-naïve patients. These data support progression into phase IIb clinical trials.
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