Good safety profile with long-acting integrase inhibitor GSK744

Analysis of eight studies involving 245 people taking oral or injected GSK1265744 confirmed that the long-acting integrase inhibitor is well tolerated and results in few serious lab abnormalities.

Injection site reactions, the most frequent adverse events, were usually grade 1.

Both oral and long-acting parenteral (LAP) formulations of GSK744 are in development. The once-daily oral agent has a half-life of about 40 hours, while half-life of the intramuscular or subcutaneous LAP formulation stretches from 30 to 40 days.

This analysis involved six short-term oral dosing studies in healthy volunteers or people with HIV and two LAP studies in volunteers. LAP injections were tested as single, monthly, or quarterly doses at 100 to 800 mg intramuscularly or 100 to 400 mg subcutaneously. There were 245 study participants, 65 of them (26.5%) women, with a median age of 32 (range 18 to 64). Twenty-nine people with a median age of 31 years (range 18 to 54) received placebo.

Six people (2.4% of 245) withdrew because of adverse events, two of them judged drug related (dizziness and a grade 1 rash). Four people (1.6%) had grade 3 or 4 adverse events, and 3 (1.2%) had serious adverse events (foot osteomyelitis, uterine fibroids, and appendicitis). No one had drug-related grade 3 or 4 adverse events or serious adverse events.

Two noninjection-related adverse events affected more than 5 study participants. Headache troubled 7% of participants, with similar rates in the GSK744 oral (7%), LAP (6%), and placebo groups (10%). Abdominal pain arose in 2% of study participants, including 2% taking oral GSK744, 2% taking the LAP formulation, and no one taking placebo.

Most people getting an intramuscular injection of GSK744 (74%) or a subcutaneous injection (96%) had an injection site reaction (ISR), compared with 25% getting intramuscular placebo and 50% getting subcutaneous placebo. ISRs affecting the highest proportions of participants were pain (73% and 86% with intramuscular and subcutaneous GSK744), erythema (19% and 79%), nodules (14% and 79%), injection site warmth (8% and 29%), induration (6% and 25%), and itching (5% and 18%). Researchers detected no consistent relationships between GSK744 dose and occurrence of any individual ISR.

Of the top three ISRs, pain lasted for medians of 5 and 6 days with intramuscular and subcutaneous injection, erythema lasted medians of 5 and 7 days, and nodules lasted medians of 22 and 47 days. No one dropped out of a study because of ISRs, all ISRs resolved, and there were no grade 3 or 4 ISRs. In a 40-person substudy, most participants rated injections “very tolerable,” which was the highest rating on the scale used.

Among grade 4 lab abnormalities, 1 person each with bilirubin, creatine kinase, or triglyceride elevations. Grade 3 abnormalities included 1 bilirubin elevation, 3 creatine kinase elevations, and 4 lipase elevations. Overall, the most frequent grade 2 or worse lab abnormalities involved total cholesterol (5%), lipase (4%), bilirubin (2%), glucose (2%), and creatine kinase (2%).

Evaluation of 2540 postdose electrocardiograms (ECGs) showed that the difference in average QTcF change from baseline between the GSK744 group and the placebo group was -2.9 msec (95% confidence interval -4.96 to -0.81 msec). No one had a QTcF of 480 msec or longer or a change from baseline of 60 msec or greater. GSK744 dose was not related to change from baseline QTcF.