Fostemsavir (FTR) is an investigational first-in-class attachment inhibitor prodrug of temsavir (TMR). TMR binds to HIV-1, locking gp120 in a conformational state that prevents initial attachment to and infection of host immune cells. Study 205889 (AI438011, NCT01384734) is a recently completed Phase 2b dose-ranging trial in treatment-experienced (TE) HIV-1-infected participants. Herein, we present efficacy results through Week 192 (latest visit achievable by all participants prior to study conclusion) and cumulative safety data.
TE adults (≥1-week of prior ART and naïve to integrase inhibitors) were randomized to 1 of 4 FTR arms (400 or 800mg BID; 600 or 1200mg QD) or reference (REF; atazanavir/ritonavir [ATV/r] 300/100mg QD), each with raltegravir (RAL, 400mg BID) and tenofovir (TDF, 300mg QD). After the Week 48 interim analysis, those randomized to FTR switched to open-label FTR at 1200mg QD with RAL+TDF. REF participants remained on ATV/r+RAL+TDF.
251 adults were treated: 200 FTR, 51 REF. Median time on FTR was 4.5 years (max 5.6); 2.9 years for REF. Rates of virologic suppression (HIV-1 RNA <50 c/mL, Table 1) and mean improvement in baseline CD4 count (+279.9 and +263.7 cells/µl) were comparable between FTR and REF through Week 192. Most adverse events (AEs) were low-grade (Grade 1-2) in intensity. A greater percentage of REF than FTR participants experienced Grade 2-4 AEs related to study drug or Grade 3-4 AEs (39% vs. 12%; 33% vs. 18% respectively). Fewer participants in the FTR arm had an AE leading to discontinuation (4% vs. 12% for REF). No participant discontinued due to a FTR-related AE. There were 3 drug-related SAEs (overdose in FTR arm, and overdose and influenza on REF). The most common drug-related AEs for FTR were headache (6%) and nausea (5%), and for REF were nausea, dizziness (8% each), and AEs related to bilirubin elevation (e.g., jaundice, scleral icterus; 8-18%).
Among HIV-1-infected TE participants, FTR with RAL+TDF demonstrated favorable safety compared to ATV/r with RAL+TDF with lower cumulative rates of Grade 2-4 related AEs, Grade 3 4 AEs, and AEs leading to discontinuation despite longer median exposure (4.5 vs. 2.9 years). FTR had comparable rates of virologic suppression to ATV/r throughout 192 weeks.These results support the ongoing Phase 3 evaluation of FTR in heavily TE adults with limited therapeutic options (≤2 classes of ARVs remaining) due to resistance, tolerability issues or contraindications (NCT02362503).