www.hivandhepatitis.com

ICAAC 2013: New Integrase Inhibitor GSK1265744 Safe and Well-tolerated in 8 Studies

The investigational HIV integrase inhibitor GSK1265744 was well tolerated with no notable safety concerns in a meta-analysis of 8 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 2013) 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 another well-tolerated once-daily integrase inhibitor would be a welcome addition to the antiretroviral armamentarium, a more ground-breaking application would be a once-monthly injection, which potentially could be used for simplified maintenance therapy or 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 GSK744plus 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 reported findings from a combined safety analysis of 8 Phase 1 or 2a clinical trials evaluating oral formulations or the long-acting parenteral (LAP) nanosuspension of GSK744.

Of these studies, 6 looked at oral tablet or suspension formulations administered to HIV negative healthy volunteers or HIV positive patients for up to 14 days. Participants received single or multiple doses ranging from 5 to 50 mg.

Another 2 studies looked at the LAP formulation in healthy volunteers receiving a single dose or repeat doses given as either 4 monthly injections or 2 quarterly injections (this includes people receiving the GSK744/TMC278 combination). Participants received intramuscular injections ranging from 100 to 800 mg or subcutaneous injections ranging from 100 to 400 mg.

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; 20 were people with HIV.

Results

• Across the studies there were no drug-related serious adverse events or deaths. 6 people (2%) withdrew early due to adverse events, including 2 events (dizziness and mild rash) judged to be drug-related.
• There were 3 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 3 people with grade 4 elevations in bilirubin (a possible indicator of liver toxicity), creatine kinase (which may indicate muscle damage), or triglycerides.
• There were 8 grade 3 elevations including 1 bilirubin, 3 creatine kinase, and 4 lipase (an enzyme that breaks down lipids).
• In addition, 8% had grade 2 or higher total cholesterol elevations.
• A total of 2540 electrocardiograms (ECGs) showed a small mean change in QT interval (time between 2 different waves in the heart rhythm), with a -2.9 msec difference between GSK744and placebo.
• No participants had intervals of more than 480 msec or increases of more than 60 msec from baseline.
• Most participants receiving parenteral GSK744reported some type of injection-site reaction such as pain, tenderness, erythema (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, lab test abnormalities, electrocardiogram changes, or injection site reactions.

"GSK744as single and repeat oral doses up to 50 mg and [subcutaneous or intramuscular] LAP injections up to 800 mg 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.

10/1/13

Reference

Y Lou, E Gould, D Chen, 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 (ICAAC 2013). Denver, September 10-13, 2013.Abstract H-672.