Preliminary Antiviral Activity and Safety of Experimental PI Brecanavir/ritonavir (BCV/r)

Brecanavir (BCV), a novel protease inhibitor (PI), has sub-nanomolar in vitro antiviral activity against multi-PI resistant HIV-1. BCV is >100-fold more potent than currently marketed PIs in-vitro, and displays promising safety and pharmacokinetics in healthy subjects.

Presented at the Toronto AIDS conference last week, this was an open label, single-arm, descriptive 48-week study with 24 week interim analysis.

31 HIV-1 infected subjects received BCV/r 300 mg/100mg BID with NRTIs, based on history and genotype.

Entry criteria: CD4+ cell count ³200 cells/mm3, HIV-1 RNA ³1000 c/mL, ability to use a dual NRTI backbone (27/31 subjects received Combivir). Full pharmacokinetic profiles were taken on Day 1 and at Weeks 2 and 4.

Results

At baseline (BL), 25/31 had PI-sensitive virus and 6/31 had PI-resistant virus (median of 2 primary PI and 5 NRTI mutations).

Median BL HIV-1 RNA was 5.0 and 4.2 log10 c/mL, respectively.
" Four subjects discontinued prior to Week 24. At Week 24, 77% (24/31) had HIV-1 RNA <50 c/mL regardless of screening genotype, including 5/6 subjects with PI-resistant virus (6/6 had HIV-1 RNA <400 c/mL).

Overall median increase in CD4+ cell count was 84 cells/mm3.

BL isolate BCV IC50 values for all subjects ranged from 0.1-0.2 nM. Median Ct at Week 4 was 150 ng/mL.

BCV/r was well-tolerated with no SAEs or clinically concerning changes in laboratory parameters.

Of 31 subjects, 10 (32%) experienced drug-related Grade 2-4 adverse events (most frequent events were fatigue (13%), dyspepsia (10%) and nausea (10%)), and 4 (13%) reported any Grade 3-4 AE.

In conclusion, the authors write, "Following 24 weeks of dosing, BCV/r was well tolerated and showed potent antiviral activity in PI-sensitive and PI-resistant HIV-1 infected subjects."

"IC50 values were nearly identical for PI-sensitive and PI-resistant viruses. Median trough plasma levels exceeded corrected IC50 values by "180-fold."

Dupont Circle Physicians Group, Washington DC, United States, Quest Clinical Research, San Francisco CA, United States, AIDS Research Consortium of Atlanta, Inc, Atlanta GA, United States, Orlando Immunology Center, Orlando FL, United States, Therafirst Medical Center, Ft. Lauderdale FL, United States, Southwest CARE and Wellness Center, Santa Fe NM, United States, Hampton Roads Medical Specialists, Hampton VA, United States, Phoenix Body Positive, Phoenix AZ, United States, GlaxoSmithKline, Research Triangle Park, United States.

08/25/06

Reference
D Ward, J Lazezari, M Thompson, and others. Preliminary Antiviral Activity and Safety of Brecanavir/ritonavir (BCV/r) in HIV-infected Patients (Study HPR10006); A 24 Week Interim Analysis. 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract CDB0376.

Additional Brecanavir Article on HIV and Hepatitis.com

Cross-resistance Profile of Experimental PI Brecanavir