First results of new integrase compound: GSK1349572

Simon Collins, HIV i-Base

Three posters at the meeting provided insight into a new compound in development from Shionogi and GSK.

Lalezari and colleagues presented first virological efficacy data from a 10-day Phase IIa dose-finding study (2, 10 and 50mg monotherapy or placebo, all once-daily) of GSK1349572 (GSK572) in 35 treatment-naive patients. [1]

Patients in the 50mg arm showed a mean viral load drop of almost 2.5 logs and 7/10 patients in this arm had viral load reductions to <50 copies/mL.

The 10 mg and 2mg doses reached mean viral load declines of approximately -2.0 and -1.5 logs respectively. No serious side effects were observed and reported events were generally similar to the placebo group.

Two pharmacology studies showed the advantages of limited interpatient variability and an indication that the 50mg dose left a significant safety buffer before activity dropped, and that higher doses were unlikely to increase activity. Median half-life was 15 hours. Steady state geometric mean (CV%) AUC (0-24) and Cmax ranged from 16.7 (15) ug.h/mL and 1.5 (24) ug/mL at 10 mg once daily to 76.8 (19) ug.h/mL and 6.2 (15) ug/mL at 50mg once daily. The geometric mean steady-state C24 at 50mg was 1.5 ug/mL which is ~23-fold higher than the in vitro protein-adjusted IC90. [2, 3]

In vitro results with a broad panel of resistant isolates, suggested minimal cross-resistance to elvitegravir and raltegravir. with high level resistance only developing after serial passaging for 56 and 84 days respectively. [4]

A second resistance poster looking at GSK572 susceptibility to a range of common integrase mutation patterns seen in raltegravir and elvitegravir studies (based on limited in vivo data), suggested that cross-resistance with other integrase inhibitors might be sufficiently likely for GSK572 not to be able to rescue people with previous integrase resistance. For example, although G140S/Q148H resulted in a median fold-change in susceptibility of less than 4-fold (n=7), G140S/Q148R lead to a range of around 8-19-fold changes (n=2). By comparison both these dual mutations confer high-level phenotypic resistance to raltegravir (>87-fold). [5]

Of note, in addition to greater virological impact during a short monotherapy than other currently used drugs, this compound is being developed as a once-daily drug, does not require boosting and PK is unaffected by food.


  1. Lalezari J et al. Potent antiviral activity of S/GSK1349572: a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients: ING111521 protocol. 5th IAS 2009, Cape Town. Abstract TUAB105.
  2. Song I et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients. 5th IAS 2009, Cape Town. Abstract WEPEB250.
  3. Min S et al. Pharmacokinetics (PK) and safety in healthy subjects of S/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI). 5th IAS 2009, Cape Town. Abstract WEPEA099.
  4. Sato A et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor. 5th IAS 2009, Cape Town. Abstract WEPEA097.
  5. Underwood M et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. 5th IAS 2009, Cape Town. Abstract WEPEA098.

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