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
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,
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
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.
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.
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
No relationship was observed between drug dose and any non-injection-site adverse events, laboratory test abnormalities, electrocardiogram changes or
"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.