Antiviral activity of S/GSK1349572, the only once-daily, unboosted integrase inhibitor in clinical development, evaluated in phase 2 study

Shionogi-GlaxoSmithKline Pharmaceuticals, LLC announced today results from a Phase 2a study evaluating antiviral activity of its investigational integrase inhibitor (INI), S/GSK1349572. The results of this study were presented at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention held this week in Cape Town, South Africa.

Issued: Tuesday, 21 July 2009, Cape Town, South Africa

Shionogi-GlaxoSmithKline Pharmaceuticals, LLC announced today results from a Phase 2a study evaluating antiviral activity of its investigational integrase inhibitor (INI), S/GSK1349572. The results of this study were presented at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention held this week in Cape Town, South Africa.

“We are excited about the study results presented on S/GSK1349572, which is the only once-daily, unboosted integrase inhibitor in clinical development,” said Garrett Nichols, MD, Project Leader, GlaxoSmithKline.  “These results strongly support the progression of S/GSK1349572 into Phase 2b trials, which start this month.  Integrase inhibitors are an important new class of compounds in HIV treatment, and we believe S/GSK1349572 holds the promise to offer a significant new treatment option for people living with HIV/AIDS.”

“There continues to be an urgent need for new HIV treatments that may help address issues of resistance and dosing convenience faced by many HIV patients today,” said Tamio Fujiwara, PhD, HIV Integrase Inhibitor Project Leader, Pharmaceutical Development Division, Shionogi & Co., Ltd.  “Shionogi is committed to the successful research and development of new treatments for HIV and looks forward to further progress with S/GSK1349572.”

Results

Thirty-five subjects completed this multi-center, randomized, parallel, double-blind, dose ranging, placebo-controlled study of S/GSK1349572 monotherapy over 10 days in INI-naïve HIV-1 infected adults.  On day 11, a mean decrease from baseline in plasma HIV-1 RNA levels of 1.5 to 2.5 log10 copies/mL was observed across the doses tested (2mg – 50mg).  All doses showed a significantly greater change from baseline in viral load when compared to the placebo group, which showed a mean increase in viral load (+0.05 log10 c/mL).  Seventy percent of patients achieved undetectable plasma HIV-1 RNA levels (<50 c/ml) at the="" 50mg dose, although they received no other antiretroviral="">

S/GSK1349572 was generally well-tolerated.  No deaths or serious adverse events were reported, and no subjects withdrew from the study due to an adverse event.  The most common drug-related adverse events were diarrhea and fatigue; however, the occurrence rates for both of these events were lower on the combined S/GSK1349572 arms when compared to the placebo arm (14 percent vs. 43 percent for diarrhea, and 7 percent vs. 29 percent for fatigue, respectively). 

Further studies are necessary to determine conclusively the safety and efficacy profile of this investigational compound in HIV-infected patients. 

Additional data at IAS

Shionogi-GlaxoSmithKline Pharmaceuticals, LLC also presented four posters at IAS highlighting pharmacokinetic and resistance data on S/GSK1349572.  Pharmacokinetic data from healthy subjects and integrase inhibitor (INI)-naïve HIV patients showed that S/GSK1349572 has a long plasma half-life, low inter-patient pharmacokinetic variability, and achieved therapeutic concentrations with once-daily dosing without the need for pharmacokinetic boosting agents.  S/GSK1349572 does not affect CYP3A, an enzyme responsible for metabolism of a number of drugs commonly used in HIV-infected patients.  Data were also presented showing that S/GSK1349572 can be given without regard to meals.   

In other data presented at the conference, S/GSK1349572 demonstrated activity in vitro against laboratory HIV strains that contain mutations associated with raltegravir (RAL) and elvitegravir (ELV) resistance (e.g., Q148R, N155H and Q148H/G140S).  S/GSK1349572 also demonstrated in vitro activity against known INI-resistant clinical isolates from patients experiencing virologic failure while on raltegravir.  Separate in vitro experiments showed that fewer mutations emerged in the test tube under S/GSK1349572 exposure than under raltegravir or elvitegravir exposure.  The mutations that emerged under raltegravir and elvitegravir exposure greatly increased the amount of drug required to inhibit viral replication (by greater than 100 fold in the case of some RAL and ELV mutants); in contrast, mutations that emerged under S/GSK1349572 exposure were associated with lower fold resistance to the compound (maximum 4.1-fold resistance).  These data suggest that S/GSK1349572 has the potential to provide an important treatment option for many patients. However, the clinical significance of resistance data continues to be evaluated, and these observations need to be confirmed in clinical studies.

About Integrase Inhibitors

Integrase inhibitors are a new class of anti-HIV drugs that block HIV replication by preventing viral DNA from integrating into the genetic material of human immune cells (T-cells).  This step is essential in the HIV-1 replication cycle.  Integrase is of great interest because it has a different mechanism of action and there is a need for new anti-HIV drugs that help address resistance issues and provide additional treatment options.  Patients need multiple, active antiretroviral drugs that can be administered in combination to attain viral suppression, as well as new drugs that offer different resistance profiles and simplified dosing.

About Shionogi-GlaxoSmithKline Pharmaceuticals, LLC

Shionogi-GlaxoSmithKline Pharmaceuticals, LLC is a long-standing joint venture between Shionogi & Co., Ltd. and GSK which has made considerable progress in developing next-generation integrase inhibitors for the treatment of HIV.  Launched in 2001, the joint venture was originally established for the development and commercialization of new agents to fight HIV and neurological disorders, including Alzheimer’s, stroke, and head injury.  More recently, the company has focused exclusively on several new integrase inhibitor candidates jointly discovered by Shionogi & Co., Ltd. and GSK.

GlaxoSmithKlineEnquiries

Robin Fastenau
Tel:       +1 919 522 5237 (mobile)
Director, Global Pipeline Communications                                   
- On site in Cape Town
Email: robin.e.fastenau@gsk.com


Shionogi & Co., Ltd. Enquiries

Corporate Communications Department
Osaka
Tel:       +81 6 6209 7885
Fax:      +81 6 6229 9596