A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus (RSV) Infection of the Lower Respiratory Tract

Marty, Francisco M; Chemaly, Roy F; Mullane, Kathleen M; Lee, Dong-Gun; Hirsch, Hans H; Small, Catherine B; Bergeron, Anne; Shoham, Shmuel; Ljungman, Per; Waghmare, Alpana; Blanchard, Elodie; Kim, Yae-Jean; McKevitt, Matt; Porter, Danielle P; Jordan, Robert; Guo, Ying; German, Polina; Boeckh, Michael; Watkins, Timothy R; Chien, Jason W; Dadwal, Sanjeet S

In the past 5 years, treatment with a fusion inhibitor or nucleoside polymerase inhibitor significantly reduced RSV viral load, signs, and symptoms in 3 challenge studies in healthy human volunteers [16, 22, 23] . However, clinical trials of presatovir conducted in multiple different patient populations, including this study and a companion URTI study (Chemaly et al [24] , this issue), indicate difficulties remain in translating challenge study results to successful clinical trials in patients with natural infection [25, 26] . One partial explanation is the challenge model's inconsistent representation of the natural infection setting. Challenge study volunteers were inoculated intranasally with RSV, then monitored for nasal RSV replication with twice-daily nasal washes that were immediately evaluated with molecular assays for RSV [16, 22, 23] . Antiviral treatment was initiated 6-24 hours after RSV detection, generally several days before peak viral load and prior to manifestation of significant clinical signs and symptoms [16, 22, 23] . In the present study, patients with naturally acquired RSV LRTI received presatovir later in the disease course compared with challenge study subjects (median [range], 5 days after symptom onset); delay was also observed in the URTI trial (median [range], 4 [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] days) and other studies of presatovir in natural RSV infection [25, 26] . Because clinical signs and symptoms tend to correlate with nasal viral load [16, 22] , these patients presumably presented near or more likely after peak nasal viral load, potentially beyond the therapeutic window for presatovir even in immunocompromised patients. Host immune-mediated clearance of the virus at this stage may also mask treatment-induced reduction in viral load. Thus, treatment delay may explain lack of presatovir efficacy in the current study.