Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviralexperienced subjects: Week 48 analysis of AI438011, a Phase IIb, randomized controlled trial

Background: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds directly to HIV-1 gp120, blocking initial viral attachment and entry into host CD4+ T-cells. Efficacy, safety and dose-response data of fostemsavir in treatment-experienced, HIV-1-infected subjects, through week 48, are reported. Methods: AI438011 is an ongoing Phase IIb, randomized, active-controlled trial (NCT01384734). Subjects were randomized 1:1:1:1:1 into five arms: Fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily or 1,200 mg once daily) and a reference arm (ritonavirboosted atazanavir [ATV/r] 300/100 mg once daily), each with a backbone of raltegravir 400 mg twice daily plus tenofovir disoproxil fumarate 300 mg once daily. Results: In total, 251 subjects were treated. Through week 48, the proportion of fostemsavir subjects with HIV-1 RNA <50 copies/ml was 61-82% and 77-95% (modified intent-to-treat [mITT] and observed analysis, respectively); 71% and 88% for ATV/r subjects (mITT and observed). Observed virological response rates were 74-100% versus 96% (fostemsavir versus ATV/r) in subjects with baseline viral load <100,000 copies/ml and 60-91% versus 71% when baseline viral load was ≥100,000 copies/ml. Across fostemsavir arms, median CD4+ T-cell count increases from baseline were 145-186 cells/μl and 142 cells/μl for the ATV/r arm. Fostemsavir doses were generally well tolerated and no fostemsavir-related adverse events led to discontinuation. Conclusions: Through week 48, fostemsavir continued to be well tolerated and showed similar efficacy to ATV/r. These results support the ongoing Phase III trial in heavily treatment-experienced adults with limited therapeutic options (≤2 classes of active antiretrovirals remaining).