Shionogi-ViiV Healthcare LLC, a joint venture between Shionogi & Co., Ltd. and ViiV Healthcare Ltd., has announced that initial results have been received from the phase III SINGLE (ING114467) study of the investigational integrase inhibitor dolutegravir in treatment-naïve adults with HIV-1. The study demonstrated superiority of the dolutegravir-based regimen compared to the single tablet regimen Atripla.

At 48 weeks, 88% of study participants on the dolutegravir regimen were virologically suppressed (<50 copies/mL) vs. 81% of participants on the single tablet regimen Atripla [difference and 95% CI; 7.4% (+2.5% to +12.3%); difference in the primary endpoint was statistically significant, p=0.003].

Differences in efficacy were primarily driven by a higher rate of discontinuation due to adverse events on the Atripla arm. The SINGLE study was designed to demonstrate non-inferiority of the dolutegravir-based regimen versus Atripla, and the primary analysis met this criterion.  Statistical superiority was concluded as part of a subsequent, pre-specified testing procedure.

SINGLE is an ongoing double blind, double dummy study designed to compare the efficacy and safety of two antiretroviral regimens: dolutegravir 50mg plus abacavir/lamivudine (Kivexa/Epzicom) versus Atripla (tenofovir/emtricitabine/efavirenz). The primary endpoint was the proportion of study participants with undetectable HIV-1 RNA (<50c/mL) at 48 weeks; 414 treatment-naïve study participants were randomised and exposed to the dolutegravir-based regimen and 419 to the Atripla arm.  Overall, 2% of subjects on the dolutegravir-based regimen discontinued due to adverse events vs. 10% of those receiving the Atripla regimen. The most common drug related adverse events on Atripla were in the nervous system System Organ Class (reported by 41% of Atripla recipients, vs. 15% of participants receiving the dolutegravir-based regimen), while the most common drug related adverse events on the dolutegravir-based regimen were in the gastrointestinal system organ class (reported by 22% of subjects receiving the dolutegravir-based regimen and 22% of subjects receiving Atripla).

“Taken together with the results of the SPRING-2 trial, the SINGLE findings suggest that, if approved by regulators, a treatment regimen containing dolutegravir may offer people living with HIV an important additional first line option in the future” said Dr. Tsutae "Den" Nagata, chief medical officer, Shionogi & Co., Ltd.

“This study represents an important milestone in the development of dolutegravir-based regimens, including a single-tablet regimen, and also for the Shionogi-ViiV Healthcare joint venture. We look forward to receiving further safety and efficacy data from two Phase III studies in treatment experienced patients to continue to build a comprehensive picture of the role of dolutegravir in the treatment of HIV” said Dr John Pottage, Chief Medical Officer, ViiV Healthcare.

Full results of this study, including key secondary endpoints, will be presented at upcoming scientific meetings. SINGLE is the second of four phase III studies that are due to be reported in 2012. Data from the clinical trialSPRING-2 (ING113086) were announced in April 2012. Data from VIKING-3 (ING112574) and SAILING (ING111762 ) in treatment-experienced patients will be received later this year and will allow further characterization of the profile of dolutegravir. These studies are designed to support a future regulatory filing for dolutegravir.

SINGLE is an ongoing phase III, randomised, multi-centre, multinational, double-blind, double dummy study designed to compare the efficacy and safety of dolutegravir plus abacavir/lamivudine compared to Atripla in treatment-naïve patients. The primary objective for SINGLE is to demonstrate the antiviral activity of dolutegravir plus abacavir/lamivudine once-daily therapy compared to Atripla over 48 weeks. As per study design, trial participants will continue on blinded therapy in order to assess  the tolerability, long-term safety, and antiviral and immunologic activity of dolutegravir plus abacavir/lamivudine once-daily compared to Atripla over 96 weeks. Investigators will also evaluate viral resistance in patients experiencing virologic failure.

S/GSK1349572 (dolutegravir) is an investigational integrase inhibitor (INI) currently in development by Shionogi-ViiV Healthcare LLC for the treatment of HIV. Dolutegravir does not require an additional ‘booster’ drug be added to the regimen. 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. Given the stage of development of this investigational HIV therapy, the full picture of the efficacy and safety of dolutegravir has not been conclusively determined.