A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season

Abstract

Background: Respiratory syncytial virus (RSV) is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In preclinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, this study evaluated their safety and tolerability when administered sequentially during the same RSV season.

Methods: Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intramuscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of antidrug antibody (ADA), and serum drug trough concentrations were assessed.

Results: Most children received all 5 doses (246/260 [94.6%]) and completed the study (241/260 [92.7%]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9% M/P, 8.4% P/M, 11.8% motavizumab only; level 3 AEs: 15.7% M/P, 6.0% P/M, 6.5% motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1% or less of any group).

Conclusions: The conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.

Trial registration: clinicaltrials.gov NCT00316264.

Figure 1

Subject disposition through the end of the study period. ^aIntent-to-treat population. ^bIncludes 1 subject with an SAE of visual disturbance who discontinued drug after 1 dose and did not complete the study; 2 additional subjects discontinued drug after receiving < 5 doses of study drug (1 with erythema multiforme after 2 doses and 1 with staphylococcal scalded skin syndrome after 3 doses, both in the M/P group), but since they were followed through the end of the study period are classified as having completed the study, thus they are not included in this total. ^cIncludes 1 subject for whom consent was withdrawn on day 13 and who died of a bowel obstruction on day 153. ^dCompleted the study through study days 270-300 (120-150 days after the final dose).

Figure 2

Antimotavizumab and antipalivizumab antibodies detected during the study. Antimotavizumab titers ranged from 1:40 to 1:1250 in the mixed motavizumab/palivizumab treatment group and from 1:10 to 1:250 in the mixed palivizumab/motavizumab treatment group. Final antibody assessments at days 270 to 300 correspond to 120-150 days after the final dose.

Figure 3

Serum trough concentrations for motavizumab and palivizumab. Data shown are mean (SD). The peak serum trough concentrations for each group reflect the sequence of dosing for that treatment group. Final serum concentrations (days 270-300) reflect those assessed 120-150 days after the final dose. Serum trough concentrations below the lower limit of quantification (motavizumab, 1.563 μg/mL; palivizumab, 10 μg/mL) were reported as 0.