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Novel HIV Integrase Inhibitor Dolutegravir Matches Raltegravir in Phase 3 Study

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ViiV Healthcare and Japan's Shionogi announced this week that its experimental integrase inhibitor dolutegravir (formerly S/GSK1349572) worked as well as the sole approved integrase inhibitor, raltegravir (Isentress), for people with HIV starting antiretroviral treatment for the first time.

In SPRING-2, the first Phase 3 study to report results, 88% of participants who took 50 mg dolutegravir with 2 nucleoside/nucleotide reverse transcriptase inhibitors(NRTIs) achieved undetectable HIV RNA at 48 weeks, compared with 85% of those using a raltegravir triple combination regimen. Both drugs were well tolerated, with 2% in each arm stopping treatment due to side effects.

At the recent Conference on Retroviruses and Opportunistic Infections (CROI 2012) in Seattle researchers reported findings from the Phase 2b SPRING-1 study, which showed that 88% of people taking 50 mg dolutegravir in a triple regimen maintained undetectable viral load at 96 weeks, compared with 72% of those taking efavirenz (Sustiva).

Below is an edited excerpt from the recent ViiV/Shionogi press release describing the SPRING-2 trial and its findings.

Shionogi-ViiV Healthcare Announces Initial Data from Pivotal Phase III Study of Dolutegravir in HIV

SPRING-2 study meets primary endpoint of non-inferiority of dolutegravir compared to raltegravir over 48 weeks in treatment-naive HIV patients

London, UK -- April 2, 2012 -- ViiV Healthcare and Shionogi & Co., Ltd. today announced that initial results have been received from the SPRING-2 (ING113086) Phase III study of the investigational integrase inhibitor dolutegravir in treatment-naive adults with HIV-1. The study met its primary objective, demonstrating non-inferiority of dolutegravir to raltegravir. Through 48 weeks, 88% of study participants on dolutegravir were virologically suppressed (<50 copies/mL) vs. 85% of participants on raltegravir (with a 95% confidence interval [CI] for the difference, -2.2% to + 7.1%; the lower end of the CI [-2.2%] was above the prespecified -10% non-inferiority limit).

SPRING-2 is an ongoing non-inferiority study designed to compare the efficacy and safety of dolutegravir 50 mg administered once-daily versus raltegravir 400 mg administered twice daily, both with two nucleoside reverse transcriptase inhibitors(NRTIs); 411 treatment-naive study participants were randomized in each arm. The primary endpoint of the study was the proportion of study participants with undetectable HIV-1 RNA (<50 copies/mL) through 48 weeks. The tolerability of dolutegravir was similar to that of raltegravir, with rates of adverse events leading to withdrawal at 2% in both arms. Drug-related nausea was reported by 10% of patients in each arm; no other adverse events related to study medication were reported by more than 5% of participants in either arm.

"The SPRING-2 findings indicate that once daily unboosted dolutegravir may offer people living with HIV an additional treatment option in the future. These are the first large-scale safety and efficacy data in naive patients, and we look forward to seeing further data in 2012 to build a more comprehensive picture of the role of dolutegravir," said Dr John Pottage, Chief Medical Officer, ViiV Healthcare.

"At ViiV Healthcare we have a total focus on the needs of people living with HIV, and as a result we see the continued need for new, effective and convenient therapies. We are committed to building connections and collaborations, like the Shionogi-ViiV Healthcare dolutegravir program, to meet these needs," said Dr. Dominique Limet, Chief Executive Officer, ViiV Healthcare. 

"The SPRING-2 study has met its primary endpoint for dolutegravir in treatment-naive patients. This marks an important milestone for the development of dolutegravir and the Shionogi-ViiV Healthcare joint venture. We look forward to completing further Phase III studies in a variety of clinical settings in order to fully understand the potential clinical benefit for a range of HIV patient populations," said Dr. Tsutae "Den" Nagata, Chief Medical Officer, Shionogi & Co., Ltd.

Full results of this study, including the full results of the secondary endpoints, will be presented at an upcoming scientific meeting. SPRING-2 is the first of four Phase III studies that are due to be reported in 2012. Data from the clinical trials SINGLE (ING114467), VIKING-3 (ING112574) and SAILING (ING111762), will be received throughout the year and will allow further determination of the profile of dolutegravir. These studies are designed to support a future regulatory file for dolutegravir.

About SPRING-2

SPRING-2 (ING113086) is a Phase III, randomized, double-blind, multicenter, parallel group, non-inferiority study. The study included 822 HIV-1 infected treatment-naive participants. The study compares the efficacy and safety of dolutegravir and 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 [Epzicom] or tenofovir + emtricitabine [Truvada]).

The primary objective for SPRING-2 is to demonstrate the antiviral activity of dolutegravir 50 mg administered once-daily compared to raltegravir 400 mg 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. It is currently the only once-daily, unboosted INI in Phase III clinical development. 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.

About Shionogi-ViiV Healthcare LLC

The Shionogi-ViiV Healthcare LLC is a joint venture between Shionogi & Co., Ltd. and ViiV Healthcare Ltd., a global company with a sole focus on HIV established in 2009 by GlaxoSmithKline and Pfizer, Inc. Dolutegravir is the lead compound in the Shionogi-ViiV Healthcare LLC partnership. Shionogi-ViiVHealthcare LLC is also developing another integrase inhibitor which is at an earlier stage of development.

About Shionogi & Co., Ltd

Headquartered in Osaka, Japan, Shionogi & Co., Ltd. is a major research-driven pharmaceutical company dedicated to placing the highest value on patients. Shionogi's Research and Development currently targets three therapeutic areas: Infectious Diseases, Pain, and Metabolic Syndrome. The Company is the originator of innovative medicines which have been successfully delivered to millions of patients worldwide. In addition, Shionogi is engaged in new research areas such as allergy and cancer. Contributing to the health of patients around the world through development in these therapeutic areas is Shionogi's primary goal. For more details, pleasevisit www.shionogi.co.jp. For more information on Shionogi Inc. headquartered in Florham Park, NJ, please visit www.shionogi.com.

About ViiV Healthcare 

ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV. The company’s aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and new HIV medicines as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.

4/3/12

Source

ViiV Healthcare and Shionogi. Shionogi-ViiV Healthcare Announces Initial Data from Pivotal Phase III Study of Dolutegravir in HIV. Press release. April 2, 2012.