Long-Acting, Investigational Integrase Inhibitor Cabotegravir Shows Promise

Pharmacokinetic data for cabotegravir (CAB, GSK1265744), an integrase inhibitor in development, were presented by Susan L. Ford et al of GlaxoSmithKline at the recent 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014) in Washington, D.C. The drug is currently in phase 2 trials. Two versions of cabotegravir are being studied: an oral version that would be taken once a day and a long-acting version to be injected every four to 12 weeks. The 12-week injectable version is under development for pre-exposure prophylaxis (PrEP) in HIV-negative patients, while the oral version and injections every four or eight weeks are intended to keep HIV-positive patients virally suppressed (defined as < 50 copies/mL). The versions meant for maintenance therapy for HIV-positive people are supplemented by the non-nucleoside reverse transcriptase inhibitor rilpivirine (Edurant) or by TMC278 LA, a long-acting injectable version of rilpivirine currently under development.

An earlier trial, reported by William Spreen of GlaxoSmithKline at the 7th International AIDS Society Conference in Kuala Lumpur, Malaysia, in 2013 had shown that 5 mg or 30 mg of oral cabotegravir taken daily produced a 2-log10 decrease in HIV viral load, even as monotherapy. Both doses appeared to be equally efficacious and led to drug concentrations of > 90% inhibitory concentration (IC90) for both cabotegravir and rilpivirine. As TheBodyPRO.com's Warren Tong reported, "the hope is that [long-acting cabotegravir and rilpivirine] can act as long-lasting PrEP … or effective treatment for HIV-infected patients that could replace daily pills."

An interim proof-of-concept study named LATTE enrolled 207 virally suppressed HIV-positive participants in one of four arms: 10, 30 or 60 mg of daily oral cabotegravir boosted by 25 mg of rilpivirine or 600 mg of efavirenz (Sustiva, Stocrin). Week 48 results reported at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in Boston seem promising, with 91%-96% of study participants in the cabotegravir arms remaining virally suppressed after 48 weeks, compared to 94% for those in the efavirenz arm.

Ford reported now at ICAAC 2014 that the early development target for cabotegravir was a pharmacokinetic concentration of about four times protein-adjusted IC90 (PA-IC90) between doses. A population pharmacokinetic analysis of eight studies involving 346 HIV-positive and HIV-negative volunteers estimates an oral absorption rate constant of 2.16 and a long-acting absorption rate constant (KA LA) of 0.000454. Participants in these studies were overwhelmingly male (80%) and white (69%), with a median body mass index (BMI) of 25.5 kg/m2 (considered slightly overweight, according to the U.S. Centers for Disease Control and Prevention).

The analysis showed that KA LA was greater in men than women (0.000845 versus 0.000285) and decreased with increased BMI: KA LA was 35%-43% higher in those with a BMI in the 10th quantile and 20%-24% lower in those in the 90th quantile compared to the median BMI.

This pharmacokinetic population model predicts the following steady-state long-acting cabotegravir dosing regimens for intramuscular injections in the phase 2 trial:

  • 800-mg initial injection plus 400 mg injected every four weeks thereafter as maintenance therapy should yield a drug concentration of 3.35 µg/mL as maintenance therapy.
  • 800-mg initial injection plus 600 mg injected every eight weeks thereafter as maintenance therapy should yield a drug concentration of 2.02 µg/mL.
  • 800 mg injected every 12 weeks for PrEP should yield a drug concentration of 1.57 to 2.02 µg/mL.

All of these are higher than the 1.35-µg/mL drug concentration measured in the 10-mg daily oral cabotegravir regimen studied in the LATTE trial, in which more than 90% of participants remained virally suppressed.

The phase 2b clinical trials currently underway will show whether these predictions bear out.