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IAS 2013: Long-acting GSK1265744 and TMC278-LA Appear Safe and Practical in Early Study


A combination of antiretroviral drugs in long-acting nanosuspension formulations achieved adequate blood levels and appeared safe in HIV negative study volunteers, offering the potential for a maintenance or PrEP option that could be taken once monthly, researchers reported at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this week in Kuala Lumpur.

While modern antiretroviral therapy is highly safe and effective, agents that could be administered less frequently would improve convenience for people with HIV. A long-acting option could prove especially attractive for maintenance therapy once viral load is suppressed, or for pre-exposure prophylaxis (PrEP) in HIV negative people.

William Spreen from GlaxoSmithKline and colleagues evaluated the safety and pharmacokinetics of a nanosuspension formulation of GSK1265477 -- an investigational HIV integrase inhibitor similar to dolutegravir -- plus TMC278-LA, a long-acting formulation of Janssen's approved non-nucleoside reverse transcriptase inhibitor rilpivirine. GSK1265744 has shown good antiviral activity in a 10-day monotherapy study and is now in Phase 2b development.

A nanosuspension refers to tiny drug crystals suspended in a liquid, enabling it to remain active longer in the body. Decreasing particle size increases the total drug surface area, allowing for a manageable injection volume, Spreen explained.

This Phase 1 trial enrolled 47 healthy, HIV negative volunteers, 40 of whom received at least 1 injection. Just over half were women, most were white, and the mean age was 40 years.

Participants were randomly allocated to 4 treatment cohorts. Due to limited safety data, all participants received a 14-day lead-in of 30 mg/day oral GSK1265744to assess its safety and tolerability. Following a 7-day wash-out period, they then got a single 800 mg "loading dose" via intramuscular (IM) injection. After this they received:

  • Cohort 1: 3 doses of 200 mg GSK1265744 via subcutaneous (SC) injection at weeks 4, 8, and 12 (no TMC278-LA);
  • Cohort 2: 3 monthly doses of 200 mg GSK1265744 via IM injection at weeks 4, 8, and 12, plus 1200 mg TMC278-LA via IM injectionat week 8 and 900 mg at week 12
  • Cohort 3: 3 monthly doses of 400 mg GSK1265744 via IM injection at weeks 4, 8, and 12, plus 1200 mg TMC278-LA via IM injectionat week 8 and 600 mg at week 12
  • Cohort 4: a second 800 mg GSK1265744 dose via IM injection at week 12 (no TMC278-LA).

There were 7 participants who withdrew prematurely from the study for any reason during the oral lead-in phase, and 3 who did so during the injection phase.


  • In all dose cohorts, plasma drug concentrations reached levels expected to be therapeutic within 3 days.
  • Levels of both GSK1265744 and rilpivirine between doses remained well above the IC90, or 90% inhibitory concentration.
  • GSK1265744 reached concentrations that reduced viral load in a previous monotherapy study of people with HIV.
  • Both drugs had a long PK "tail," meaning concentrations remained high for a prolonged period and declined slowly -- in practice, this would allow for some "forgiveness" in case of missed or delayed doses, Spreen noted.
  • All regimens were generally safe and well-tolerated.
  • 1 participant discontinued the study during the oral lead-in phase due to dizziness, and 1 stopped during the injection phase due to transient skin rash.
  • Overall, headache was the most common non-injection-related side effect.
  • There were no reported severe (grade 4) drug-related adverse events or laboratory abnormalities, and no notable electrocardiogram changes.
  • Most participants reported injection site reactions such as pain, tenderness, redness, or nodules, but these were mostly mild andno one withdrew for this reason.
  • Moderate injection site pain was more common with IM compared with SC injections, but nodules were more common and somewhat larger with SC administration.

"Co-administration of injectable long-acting nanosuspensions of [GSK1265744] and TMC278 was safe and generally well tolerated in healthy adults," the researchers concluded.

"Monthly or quarterly dosing regimens achieved clinically relevant plasma concentrations" of GSK1265744and TMC278, they continued, adding that these data support evaluationin longer-term clinical studies.

Spreen noted that a dosing-ranging study is pending, and researchers plan to look at various strategies involving oral lead-in or induction therapy with both drugs for up to 6 months before proceeding to long-acting injections.



W Spreen, P Williams, D Margolis, et al. First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and tolerability in healthy adults.7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WEAB0103.