Once-daily dolutegravir is non-inferior to twice-daily raltegravir in treatment-naïve adults with HIV-1

Shionogi-ViiV Healthcare LLC today announced 48-week data from the SPRING-2 Phase III study, which is evaluating the investigational integrase inhibitor dolutegravir in treatment-naïve adults with HIV-1 infection. In this double-blind, double-dummy study, the proportion of study participants who were virologically suppressed (HIV-1 RNA100,000 c/mL), the response rates were 82% for DTG vs. 75% for RAL. These data were presented at the XIX International AIDS Conference in Washington, DC.

Prespecified secondary analyses also supported non-inferiority of dolutegravir to raltegravir; the proportion of subjects without treatment-related discontinuations was 93% on dolutegravir and 92% on raltegravir. Median CD4 increases were also similar in both groups (+230 cells/mm3). Virologic failure occurred in 5% of DTG subjects and 7% of RAL subjects; neither genotypic integrase resistance mutations nor NRTI resistance mutations were detected in the DTG group vs. 1 subject and 4 subjects, respectively, who failed RAL.

The tolerability of dolutegravir was similar to that of raltegravir, with adverse events (AEs) leading to withdrawal at 2% in both arms. Commonly occurring AEs (10-15% of subjects on both arms) comprised nausea, headache, nasopharyngitis and diarrhoea. Grade 3 or higher liver enzymes (ALT) occurred in 2% of subjects in each group; no Grade 3 or higher elevation in serum creatinine (a measure of kidney function) occurred on either arm.

“These data offer compelling evidence for once-daily dolutegravir as an option that does not require a booster for first-line HIV treatment. Furthermore, the efficacy was similar regardless of which dual NRTI therapy was used with the core dolutegravir regimen,” said John Pottage, MD, Chief Scientific and Medical Officer, ViiV Healthcare. “There have been many recent incremental advances in the treatment of HIV, but we believe dolutegravir could be a significant step forward in how we approach the management of the disease.”

“These data from treatment-naïve subjects come from the first of four studies within our dolutegravir clinical programme. We are very pleased that in SPRING-2, we did not observe any genotypic resistance in treatment- naïve subjects treated with dolutegravir, which supports preclinical evidence that DTG has a high barrier to resistance . We continue to look forward to data from further studies in a variety of clinical settings—including treatment-experienced people living with HIV—to support regulatory submission later in 2012,” said Dr. Tsutae “Den” Nagata, Chief Medical Officer, Shionogi & Co., Ltd.

SPRING-2 is the first of four Phase III studies that are due to be reported in 2012. Topline data from the clinical trial SINGLE (ING114467) were reported earlier this month and will be presented at an upcoming scientific meeting; results from VIKING-3 (ING112574) and SAILING (ING111762) will be received later this year and will allow further determination of the profile of dolutegravir. These studies are designed to support a future regulatory submission for dolutegravir.

SPRING-2 Study Design

SPRING-2 (ING113086) is a Phase III, randomised, double-blind, double-dummy, multicentre, parallel group, non-inferiority study. The study included 822 HIV-1 infected treatment-naïve participants. The ongoing study compares the efficacy and safety of unboosted dolutegravir to raltegravir as part of an overall treatment regimen; both treatment arms are administered with investigator-selected dual nucleoside reverse transcriptase inhibitor therapy (either abacavir + lamivudine or tenofovir + emtricitabine).

The primary objective for SPRING-2 is to demonstrate the antiviral activity of dolutegravir 50mg administered once-daily compared to raltegravir 400mg administered twice-daily over 48 weeks. Secondary objectives include the assessment of antiviral activity of dolutegravir compared to raltegravir at 96 weeks, to compare the tolerability, long-term safety and antiviral and immunologic activity of dolutegravir to raltegravir, and to evaluate viral resistance in study participants experiencing virological failure.

About Dolutegravir

S/GSK1349572 (dolutegravir) is an investigational integrase inhibitor (INI) currently in development by Shionogi-ViiV Healthcare LLC for the treatment of HIV. DTG, which is in phase III clinical development, is currently the only once-daily INI that does not require a pharmacologic booster. Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.