The investigational HIV integrase inhibitor GSK1265744 was well tolerated, with no notable safety concerns, in a meta-analysis of eight studies testing the drug as either a pill or a long-acting injection, researchers reported at the recent 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Denver.
GSK1265744 (or GSK744 for short), being developed by GlaxoSmithKline, has shown robust antiviral activity in clinical trials to date. It is now in phase 2b trials. While a new well-tolerated once-daily integrase inhibitor would be a welcome addition to the antiretroviral armamentarium, a more groundbreaking application would be a once-monthly injection, which potentially could be used for simplified maintenance therapy or for pre-exposure prophylaxis (PrEP).
At the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this past summer, William Spreen from GlaxoSmithKline reported that an injected nanosuspension formulation of GSK744 plus TMC278-LA, a long-acting formulation of Janssen's NNRTI rilpivirine (Edurant), was safe and generally well tolerated in healthy, HIV-negative volunteers.
At ICAAC, GlaxoSmithKline researchers reported findings from a combined safety analysis of eight phase 1 or 2a clinical trials evaluating oral formulations or the long-acting parenteral (LAP) nanosuspension of GSK744.
Six of the studies looked at oral tablet or suspension formulations administered to HIV-negative healthy volunteers or HIV-positive participants for up to 14 days. Participants received single or multiple doses ranging from 5 to 50mg.
Two studies looked at the LAP formulation in healthy volunteers receiving a single dose or repeat doses given as either four monthly injections or two quarterly injections (this includes people receiving the GSK744/TMC278 combination). Participants received intramuscular injections ranging from 100 to 800mg or subcutaneous injections ranging from 100 to 400mg.
The analysis included a total of 245 participants (180 men and 65 women) treated with GSK744 and 29 placebo recipients, with a median age of about 32 years. Twenty were HIV positive.
Across the studies there were no drug-related serious adverse events or deaths. Six people (2%) withdrew early due to adverse events, including two side-effects (dizziness and mild rash) judged to be drug-related. There were three serious events not considered related to GSK744 (osteomyelitis or bone marrow inflammation, uterine fibroids and appendicitis).
Overall, 18% of participants reported any drug-related adverse events other than injection-site reactions. The most common were headache (7%) and abdominal pain (2%).
Several participants experienced treatment-emergent laboratory abnormalities of at least moderate (grade 2) severity. These included three people with grade 4 elevations in bilirubin (a possible indicator of liver toxicity), creatine kinase (which may indicate muscle damage) or triglycerides. There were eight grade 3 elevations, including one bilirubin, three creatine kinase and four lipase (an enzyme that breaks down lipids). In addition, 8% had grade 2 or higher total cholesterol elevations.
A total of 2540 electrocardiograms showed a small mean change in QT interval (time between two different waves in the heart rhythm), with a -2.9 msec difference between GSK744 and placebo. No participants had intervals of more than 480 msec or increases of more than 60 msec from baseline.
Most participants receiving parenteral GSK744 reported some type of injection-site reaction such as pain, tenderness, redness, itching or nodules (hard lumps). Reactions were more common with GSK744 than with inactive placebo injections. Most injection-site symptoms (93%) were reported as mild. There were no severe injection-site reactions, no one withdrew for this reason and all reactions resolved.
Injection-site reactions were more common with subcutaneous injection than with intramuscular administration, including pain (86 vs 73%), redness (79 vs 19%) and nodules (79 vs 14%). Pain and redness after intramuscular injection lasted a median of five days, while nodules after subcutaneous administration lasted a median of 47 days.
No relationship was observed between drug dose and any non-injection-site adverse events, laboratory test abnormalities, electrocardiogram changes or injection-site reactions.
"GSK744 as single and repeat oral doses up to 50mg and [subcutaneous or intramuscular] LAP injections up to 800mg were well tolerated," the researchers summarised. "All [injection-site reactions] were self-limited and predominantly grade 1."
"This meta-analysis supports the continued clinical development of GSK744 as both oral and LAP formulations," they recommended.
Lou Y et al. Meta-analysis of safety data from eight clinical studies with GSK1265744, an HIV integrase inhibitor, dosed orally or as injection of long-acting parenteral nanosuspension. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, abstract H-672, 2013. View the abstract on the ICAAC website.