Safety and Pharmacokinetics of the Respiratory Syncytial Virus Polymerase Inhibitor, ALS-8176, in Otherwise Healthy Infants Hospitalized with Acute RSV Infection

Abstract

Background. Determine safety of single/multiple ascending doses (SAD, MAD) of ALS‐8176 and PK of ALS‐8112 in RSV‐infected infants. Methods. Randomized, double‐blind, placebo‐controlled SAD, MAD study in otherwise healthy 1‐ to 12‐month‐old patients hospitalized with RSV infection. The cohort size and dose for the first SAD cohort was prespecified. The makeup of all other cohorts was determined by an Independent Data Monitoring Committee (IDMC), which regularly reviewed data. Safety and sparse PK were collected for 7 (SAD) and 28 (MAD) days post randomization. PK was analyzed by population PK methods. Results. A total of 112 (70 SAD:42 MAD) infants have been randomized into 7 SAD, MAD regimens (figure). Four unrelated serious adverse events (AEs) have been reported in the SAD (phlebitis, tachycardia, respiratory failure) and MAD (lymphadenitis). No study drug discontinuations have occurred and all treatmentemergent AEs (N = 114) were mild (N = 91) or moderate (N = 22) except respiratory failure, which was severe. Blinded AEs reported in ≥3 patients were as follows: No concerning trends in AEs, laboratories, vital signs, physical examinations, or electrocardiograms were identified in the blinded data or from IDMC reports. Available unblinded safety/efficacy data will be presented. ALS‐8176 was rapidly converted to ALS‐8112 and the PK was consistent with predictions from modeling and simulation in adults. ALS‐8112 plasma exposures increased in a less than dose proportional manner with increasing ALS‐8176 doses. No accumulation was noted. Body weight, renal function, and fed/fasted state were included as model covariates influencing PK. Conclusion. In hospitalized infants, ALS‐8176 was well‐tolerated and demonstrated predictable PK following single doses up to 25 mg/kg and multiple doses up to a 30 mg/kg loading dose followed by 6 mg/kg maintenance doses. Further evaluation of the efficacy, safety and PK of ALS‐8176 in pediatric patients is warranted.