Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006

Background: Brecanavir, a novel protease inhibitor (PI), has sub-nM in vitro antiviral activity against multi-PI-resistant HIV-1 and in vitro is >100-fold more potent than previously marketed PIs and approx. 10-fold more potent than the recently marketed PI, darunavir. Methods: HPR10006 is an open label, single-arm, descriptive 48 week study, with 8 and 24 week interim analyses. Thirty-one HIV-1-infected patients were enrolled and received brecanavir/ritonavir 300 mg/ 100 mg twice daily, with two nucleoside reverse transcriptase inhibitors, based on history and genotype. Results: At baseline, 25/31 had PI-sensitive virus and 6/31 had PI-resistant virus (median of two primary PI and five secondary PI mutations). Median baseline HIV-1 RNA was 5.0 and 4.2 log10 copies/mL, respectively. Four patients discontinued prior to Week 24. At Week 24, 77% (24/31) had HIV-1 RNA <50 copies/mL regardless of screening genotype, including 5/6 patients with PI-resistant virus (6/6 had HIV-1 RNA <400 copies/mL). Brecanavir/ritonavir was well tolerated with no serious adverse events or clinically concerning changes in laboratory parameters. Of 31 patients, 10 (32%) experienced drug-related Grade 2‐4 adverse events [most frequent events were fatigue (13%), dyspepsia (10%) and nausea (10%)]. Baseline isolate brecanavir IC50 values for all patients ranged from 0.1 to 0.2 nM. Median plasma trough concentration at Week 4 was 150 ng/mL. Correcting the IC50 (0.2 nM) value for protein binding (6-fold increase in vitro with 50% human serum) gives a corrected inhibitory quotient of 180. Conclusions: Brecanavir/ritonavir was well tolerated and showed potent antiviral activity in HIV-1infected patients harbouring both PI-sensitive and PI-resistant virus, following 24 weeks of dosing.