Phase 2 study of Gileads integrase inhibitor elvitegravir (GS-9137)
4 April 2007. Related: Conference reports, Antiretrovirals, CROI 14 (Retrovirus) 2007.
Simon Collins, HIV i-Base
Andrew Zolopa from Stanford University presented results from a Phase 2 study of Gileads integrase inhibitor elvitegravir (GS-9137) in treatment experienced patients.
This was a partially blinded, active-controlled, 48-week dose-finding study that randomised 278 patients to 20mg, 50 mg or 125mg doses of GS-9137 (given once-daily with 100mg boosting dose of ritonavir) or to boosted comparator protease inhibitors (CPI/r) in treatment-experienced subjects (>/=1 PI mutation). Background regimens included investigator choice of NRTI with or without T-20. Choice of CPI included darunavir and tipranavir for 49% and 27% patients respectively in the CPI/r arm.
After week 8, the 20mg arm was closed because of a high rate of virologic failure. However, although the primary endpoint is change in viral load at week 24 (DAVG24), the 16 week analyses reported here, will be less complicated by later use darunavir or tipranavir to GS-9137 arms, which was allowed (mainly after week 16 for most patients) when new data showed a lack of drug-drug interactions.
Baseline mean CD4 and viral load was 185 cells/mm3 and 4.59 log copies/mL. Mean age was 45 years, 90% were male, and 73% were Caucasian. T-20 was used by 19% of patients in the CPI/r arm compared to around 25% patients in the 50 and 125 mg arms. 50% of patients across all arms had no sensitive RTIs (GSS=0), and patients had a median of 10-11 IAS-defined PI mutations.
Prior to week 16, the majority of GS-9137 patients received only 2 NRTI as background therapy; 26% of the GS-9137 50 mg and 125 mg patients added a PI by week 24, mainly after week 16.
The mean changes in viral load at week 16 were -1.5 and -1.7log in the 50mg and 125 mg arms respectively compared to -1.2 log in the CPI/r arm, and are detailed in Table 1.
Table 1: Viral load responses (ITT analysis)
|CPI/r||9137 – 50mg||9137 – 125mg|
|Wk 16 change in VL||-1.2 log||-1.5 log||-1.7 log|
|Mean difference vs CPI/r (p value vs CPI/r)||-0.3 log (p=0.09)||-0.5 log (p=0.01)|
|% <50 copies/mL||30%||38%||40%|
|CD4 change (c/mm3) (+/-SD)||28 (+/-69)||52 (+/-90)||61(+/-97)|
|Wk 24 change in VL||-1.2 log||-1.4 log||-1.7 log|
|Mean difference vs CPI/r (p value vs CPI/r)||-0.2 log (p=0.09)||-0.5 log (p=0.01)|
|% ever achieved -1 log reduction||51%||69%||76%|
|Grade 1/3 side effects||14%||13%||14%|
|Grade 1/3 lab abnormalities||32%||21%||21%|
|D/c due to study drug||3%||3%||1%|
Inclusion of at least one other active drug in the OBT was essential for durability of virological response. Patients in the 125mg arm averaged viral load reductions of -2.0 to -2.4 logs by week 8 but this was only sustained to weeks 16 and 24 in patients (n=47) with either >/= one active RTI, or new use of T-20. In people with no active drugs (n=26) viral load rebounded to approximately -0.7 log below baseline by week 16.
GS-9137 was well tolerated. No dose relationship was observed in treatment-emergent grade 3 or 4 adverse events or laboratory abnormalities, and fewer patients in the GS-9137 treatment arms discontinued study drug because of adverse events than in the CPI/r arm.
Zolopa AR, Mullen M, Burger D et al. The HIV Integrase Inhibitor GS-9137 Demonstrates Potent Antiretroviral Activity in Treatment-experienced Patients. Oral Abstract 143LB.
The oral presentation can be viewed online from the CROI website (see Wednesday, 10.00-12.00am Clinical Trials).