Investigational protease inhibitor TMC310911 highly potent in phase 2 study

Michael Carter
Published: 04 May 2014

The investigational ritonavir-boosted protease inhibitor TMC310911 has a potent antiviral effect, favourable pharmacokinetic profile and is safe and well-tolerated, according to results of a phase 2a clinical trial published in the March 1 edition of the Journal of Acquired Immune Deficiency Syndromes.

Four different doses of the drug were evaluated, each showing a similar antiviral effect. The study population consisted of 33 people who had not taken HIV treatment before (treatment-naive) and treatment lasted for 14 days.

“TMC310911 has shown potent antiviral activity in treatment-naive HIV-1 infected individuals,” write the authors.

The findings build on earlier research. Initial laboratory work showed that TMC310911 has activity against both wild-type and drug-resistant strains of HIV. Evaluation of the compound in a phase 1 study involving HIV-negative individuals suggested the drug had good pharmacokinetics and was safe.

The latest research was an open-label study involving people living with HIV who had never taken antiretroviral treatment before. All the participants had fully drug-sensitive virus.

The participants had a median age of 32 years and 31 were white men. Almost two-thirds (64%) had a baseline viral load between 10,000 and 100,000 copies/ml; the remaining participants had a viral load above this level. The median duration of diagnosed HIV infection was 2.7 years.

Participants were randomised to receive one of four doses of TMC310911:

  • 75mg twice daily.
  • 150mg twice daily.
  • 300mg twice daily.
  • 300mg once daily.

All these doses were taken with a 100mg ritonavir booster.

Treatment lasted 14 days.

A decrease in viral load was observed after four days of therapy. On day eight, the mean declines in viral load from baseline ranged between -1.30 log10 (75mg twice daily) and -1.06 log10 (300mg once daily). By day 15, falls in viral load from baseline were broadly similar for all four doses and were between -1.79 log10 (150mg twice daily) and -1.69 log10 (300mg twice daily).

All but one individual had at least a 1 log10 fall in viral load. No participants developed drug-resistant virus.

CD4 counts among people taking the once-daily 300mg dose increased by an average of 93 cells/mm3 between baseline and day 14. Modest falls in CD4 count were observed in the other treatment arms.

Concentrations of TMC310911 increased with dose. Daily exposure of the drug was comparable between the 300mg once-daily dose and the 150mg twice-daily doses.

A total of 19 people experienced at least one treatment-associated side-effect. The most common were mild tiredness (27%) and nausea (12%). No serious treatment-associated adverse events were observed.

“The results of this study further underline the antiviral potency of TMC310911 and provide the first evidence of clinical efficacy of TMC310911,” comment the authors. “Efficacy, safety, and PK [pharmacokinetic] findings from this study provide a strong basis for further evaluation of TMC310911 in larger clinical trials of longer duration that may include treatment-naive and treatment-experienced HIV-infected patients carrying resistant virus.” The investigators recommend these studies should include women and people with viral hepatitis and end-stage organ disease.

Reference

Stellbrink H-J et al. Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naïve HIV-1-infected patients. J Acquir Immune Defic Syndr, 65: 283-89, 2014.