S/GSK744 and long-acting formulation indicate broadly similar resistance profile to dolutegravir
25 July 2013. Related: Conference reports, Antiretrovirals, Drug resistance, Intl Drug Resistance Workshop Toronto 2013.
Simon Collins, HIV i-Base
The first resistance data on the follow-on integrase inhibitor to dolutegravir, a Long Acting Parenteral (LAP) formulation of S/GSK1265744, was included as an oral presentation at the workshop. [1]
Although GSK744 is being developed in an oral formulation, most attention has been focused on a long acting injection with potential indication for both treatment and prevention with rilpivirine, which also has both oral and long acting formulations.
Pharmacokinetic results last year reported that plasma concentrations of GSK744-LAP remained above the IC90 for at least three months following a single intramuscular or subcutaneous injection at doses of 200 mg or higher. [2] The potential for use as PrEP was shown by impressive results earlier this year that generated full protection in a macaque study following multiple rectal exposure. [3]
Previous in vitro studies also supported a resistance profile that retains sensitivity to raltegravir and elvitegravir associated mutations. [4]
At the workshop new data were presented showing that, as with raltegravir, GSK744 effectively inhibits HIV integration and reduces LTR-circles without impacting levels of viral DNA. No further mutations emerged when GSK744 was passaged for 56 days with raltegravir-associated single site directed mutations E92Q or N155H. However, further mutations developed with the Q148H/K/R pathway although the associated reduced fold change (FC) sensitivity (FC 5.6 with Q148R and FC 5.1 with Q148R) could be overcome by higher dosing.
comment
The resistance profile for GSK-744 appears similar to dolutegravir, rather than being a compound that could salvage dolutegravir resistance. This should inform the approach both to future studies and to proposed integrase sequencing.
Current studies with GSK-744 include an ongoing safety study with rilpivirine LA in HIV negative volunteers and an induction/maintenance study (starting with GSK-744 plus two RTIs and switching to GSK-744 plus rilpivirine maintenance) in treatment naive patients. [5, 6]
References:
- Yoshinaga T et al. Advanced mechanistic studies of GSK1265744, a new HIV integrase inhibitor (INI) dosed by oral administration or long-acting parenteral injection. International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, 4-8 June 2013, Toronto. Oral abstract O22.
http://www.intmedpress.com/journals/avt/abstract.cfm?id=2658&pid=88 (abstract book)
http://www.informedhorizons.com/resistance2013/pdf/Presentations/Yoshinaga.pdf (PDF slides) - Spreen W et al. Pharmacokinetics, safety and tolerability of the HIV integrase inibitor SGSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. 19th International AIDS Conference, 22-27 July 2012, Washington. Abstract TUPE040.
http://pag.aids2012.org/abstracts.aspx?aid=10191 - Andrews C et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th CROI, 3-6 March 2013, Atlanta. Oral late breaker abstract 24LB.
http://www.retroconference.org/2013b/Abstracts/48044.htm - Yoshinaga T et al. Antiviral characteristics of S/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral Injection. 52nd ICAAC, San Francisco, 9-12 September 2012. Oral abstract H-550.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=e1c18d5b-830f-4b4e-8671-35bcfb20eed5&cKey=3ecd6397-c9eb-4793-94f5-fde7784fe6ab&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d - ClinicalTrials.gov. A study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 intramuscular and subcutaneous injections in healthy adult subjects.
http://clinicaltrials.gov/ct2/show/NCT01593046 - ClinicalTrials.gov. Dose ranging study of GSK1265744 plus nucleoside reverse transcriptase inhibitors for induction of HIV-1 virologic suppression followed by virologic suppression maintenance by GSK1265744 plus rilpivirine.
http://clinicaltrials.gov/ct2/show/NCT01641809