Antiviral Activity of Oral JNJ-53718678 in Healthy Adult Volunteers Challenged With Respiratory Syncytial Virus: A Placebo-Controlled Study

Abstract

ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.

A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein

“…No significant differences in RT-qPCR AUC were observed between the 200-mg and 350-mg dose groups, although it should be noted that the study was not designed to assess differences in treatment effect between the two doses. The terminal half-life of RV521 (8.54 to 9.35 h) is shorter than or comparable to that reported for other studied anti-RSV compounds (33 to 35 h for GS-5806 [12], 63 h for ALS-008176 [19], and 6.5 to 10.5 h for JNJ-53718678 [20]), which may offer advantages, especially in relation to pediatric dosing, in avoiding accumulation and potential toxicity. The safety and PK of RV521 will be assessed in infants hospitalized with RSV infection in a planned phase 2a study.…”

“…Although cross-study comparisons of data are inherently limited, the observed safety profile of RV521 seems to compare favorably with that of other anti-RSV agents (19,20). PK data from the current study suggest that RV521 200 mg and 350 mg are effective therapeutic doses in adult subjects, both resulting in significant improvements compared with placebo in primary and secondary viral load and disease severity endpoints.…”

“…RV521 treatment also led to statistically significant improvements in multiple secondary viral load endpoints. Other compounds that have been tested using this RSV challenge model include the oral nucleoside analogue prodrug ALS-008176 (19) and two inhibitors of the RSV-F protein, GS-5806 (12) and JNJ-53718678 (20). Observed reductions in RT-qPCR-assessed AUC viral load relative to that with placebo in these studies were 73 to 88% with ALS-008176 (19), 38 to 67% with GS-5806 (22 to 77% as assessed by quantitative culture) (12), and 41 to 53% with JNJ-53718678 (9 to 47% as assessed by quantitative culture) (20).…”

“…Other compounds that have been tested using this RSV challenge model include the oral nucleoside analogue prodrug ALS-008176 (19) and two inhibitors of the RSV-F protein, GS-5806 (12) and JNJ-53718678 (20). Observed reductions in RT-qPCR-assessed AUC viral load relative to that with placebo in these studies were 73 to 88% with ALS-008176 (19), 38 to 67% with GS-5806 (22 to 77% as assessed by quantitative culture) (12), and 41 to 53% with JNJ-53718678 (9 to 47% as assessed by quantitative culture) (20). Although not directly comparable, the results arising from these different studies, which used the same or very similar RSV challenge study designs, show that the magnitude of viral load reduction by RV521 treatment compares favorably with ALS-008176 and suggests an improvement over JNJ-53718678 and the majority of the GS-5806 dosing regimens tested.…”

Respiratory syncytial virus entry and how to block it

“…Fusion inhibitors GS-5806 (presatovir) and JNJ-53718678, developed by Gilead Sciences and Janssen Pharmaceuticals, respectively, have both performed well in phase II double-blind, placebo-controlled, human-challenge studies. Oral administration of either compound led to a reduction in viral load and disease severity among healthy adults experimentally infected intranasally with a clinical isolate of RSV 143,144 . The participants were administered the fusion inhibitors either 5 days after inoculation or at the time of a positive test for RSV, demonstrating that these compounds could be used for treatment of an upper respiratory tract infection if administered soon after infection.…”