ICAAC: Early trials involving new GSK protease inhibitor have encouraging results

GlaxoSmithKline’s investigational protease inhibitor 640385 (brecanavir) has potent anti-HIV activity against both resistant and sensitive virus, and is generally well tolerated when boosted by ritonavir and used in combination with Combivir, according to a 24 week interim analysis from a 48 week study presented to the 45^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC on Friday.

Laboratory studies have already shown that 640385 is a highly potent protease inhibitor with activity against HIV which has resistance to other drugs from this class. Early studies in HIV-negative volunteers have shown that the drug has a good pharmacokinetic profile and is well tolerated.

A 48 week open label study was designed to further examine the safety and efficacy of 640385, this time involving HIV-positive individuals. Patients were treated with 300mg of 640385, boosted by 100mg of ritonavir twice daily in combination with two nucleoside analogues (excluding tenofovir and abacavir). Pharmacokinetic profiles were taken on day one, and at weeks two and four. An interim analysis was performed after eight weeks.

Prior to entry to the study, patients had resistance tests performed. A total of 25 individuals had wild type HIV, the remaining six patients having resistant HIV with a median of two primary protease inhibitor mutations and five primary nucleoside analogue reverse transcriptase inhibitor (NRTI) mutations. In patients with wild type HIV the median baseline CD4 cell count was 264 cells/mm³, and median viral load was 5 log₁₀. Individuals with resistant HIV had a median baseline CD4 cell count of 389 cells/mm³, and a median viral load of 3.98 log₁₀.

No serious side-effects or laboratory abnormalities were reported. Two patients withdrew from the study before week eight for reasons unconnected with the study medication, one patient withdrew due to nausea and vomiting, and one due to grade 3 liver enzyme elevation. `Modest` increases in lipids were reported, although baseline measurements were not reported.

After 24 weeks of treatment a total of 81% of patients had a viral load below 400 copies/ml by intent to treat analysis (missing equals failure). 77% had viral load below 50 copies/ml at week 24. Median viral load had fallen by 3.3 log₁₀ in patients with wild type virus, and 2.2 log₁₀ in patients with resistance. This difference in viral load reduction was explained by lower HIV viral load in the PI-experienced group at baseline, said investigators.

CD4 cell count increased by a median of 122 cells/mm³ in patients with wild type HIV and by 79 cells/mm³ in patients with resistant virus.

Pharmacokinetic analysis is ongoing.

Phase IIb studies of brecanavir will begin in 2006.