Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants

Abstract

Background:MEDI8897 is a recombinant human monoclonal antibody being developed for prophylaxis of serious respiratory syncytial virus (RSV) disease in all infants.Methods:In this phase 1b/2a dose-escalation study, healthy preterm infants with a gestational age of 32–35 weeks were randomized to receive a single intramuscular injection of MEDI8897 (10, 25 or 50 mg) or placebo. Safety, pharmacokinetics, RSV-neutralizing antibody and antidrug antibody (ADA) assessments were performed during the 360-day follow-up period. Infants who experienced medically attended lower respiratory tract infections (LRTIs) were tested for RSV.Results:MEDI8897 serum half-life ranged from 62.5–72.9 days. On day 151, 87% of infants in the 50 mg group had serum concentrations above the 90% effective concentration target level of 6.8 µg/mL, and 90% showed a ≥4-fold rise from baseline in serum RSV-neutralizing antibody levels. Adverse events (AEs) were reported in 17 of 18 (94.4%) placebo and 66 of 71 (93.0%) MEDI8897 recipients. Three MEDI8897 recipients experienced 5 serious AEs (3 LRTIs, 2 febrile seizures). ADA was detected at any time postbaseline in 28.2% of MEDI8897 recipients and at day 361 only in 26.5% of subjects. ADA response was not associated with AEs. Five (7%) MEDI8897 recipients experienced medically attended LRTIs through day 150; 1 tested positive for RSV (10 mg group).Conclusions:MEDI8897 had a favorable safety profile in healthy preterm infants. The extended half-life of MEDI8897 and demonstrated RSV-neutralizing activity support protection from RSV for the duration of a typical 5-month season after a single 50 mg intramuscular (IM) dose.

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

“…59 However, it is the trough concentrations and the half-life that drive FIP dose selection for mAbs, especially those targeted against infectious antigens. 3,19,21 For these products, clinicians seek a dosing regimen that sustains a trough concentration above a target value. In doing so, the patient achieves stronger immunity against the infectious antigen (respiratory syncytial virus, HIV, bacterial antigens, etc).…”

“…Adult and pediatric concentration-time profiles featuring intravenous and intramuscular administrations were extracted from the literature for pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin (IVIG). 3,[18][19][20][21][22][23][24][25] No adult PK data were available for palivizumab.…”

Community-Acquired Respiratory Viruses in Transplant Patients: Diversity, Impact, Unmet Clinical Needs

“…Similarly, individuals with very severe immunodeficiency (right, 2 to 7 criteria; red line) had a higher risk for mortality than those with moderate immunodeficiency (right, 1 criterion, green line) or moderate risk (right, 0 criteria; blue line) (OR, 11.1; 95% CI, 2. Community-Acquired Respiratory Viruses Posttransplant Clinical Microbiology Reviews pharmacokinetics in adults and infants (144,145). Currently, no studies are planned with this compound in immunocompromised patients, but initial studies in otherwise healthy patients are ongoing.…”

Alternative conformations of a major antigenic site on RSV F

“…Comparison of the neutralization potency of two site Ø antibodies, D25 [34] and 5C4 [35], with palivizumab, a site II-directed conformation-independent antibody [36], demonstrated that the prefusionspecific antibodies are 10-100 times more potent [8]. Other potent prefusion-specific human antibodies that bind to the apex of the trimer, such as AM22 and RSD5, have also been isolated in recent years [8,37,38], and one of them (MEDI8897) is now in advanced stages of clinical development [39].…”