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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: 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.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.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).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.clinicaltrials.gov NCT00316264.

SUBMITTER: Fernandez P

PROVIDER: S-EPMC2898783 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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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.

Fernández Pilar P Trenholme Adrian A Abarca Katia K Griffin M Pamela MP Hultquist Micki M Harris Brian B Losonsky Genevieve A GA

BMC pediatrics 20100603

<h4>Background</h4>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 M ...[more]

PMID: 20525274

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Project description:Respiratory syncytial virus (RSV) is a public health concern that causes acute lower respiratory tract infection. So far, no vaccine candidate under development has reached the market and the only licensed product to prevent RSV infection in at-risk infants and young children is a monoclonal antibody (Synagis®). Polyclonal human anti-RSV hyper-immune immunoglobulins (Igs) have also been used but were superseded by Synagis® owing to their low titer and large infused volume. Here we report a new drug class of immunoglobulins, derived from human non hyper-immune plasma that was generated by an innovative bioprocess, called Ig cracking, combining expertises in plasma-derived products and affinity chromatography. By using the RSV fusion protein (F protein) as ligand, the Ig cracking process provided a purified and concentrated product, designated hyper-enriched anti-RSV IgG, composed of at least 15-20% target-specific-antibodies from normal plasma. These anti-RSV Ig displayed a strong in vitro neutralization effect on RSV replication. Moreover, we described a novel prophylactic strategy based on local nasal administration of this unique hyper-enriched anti-RSV IgG solution using a mouse model of infection with bioluminescent RSV. Our results demonstrated that very low doses of hyper-enriched anti-RSV IgG can be administered locally to ensure rapid and efficient inhibition of virus infection. Thus, the general hyper-enriched Ig concept appeared a promising approach and might provide solutions to prevent and treat other infectious diseases.ImportanceRespiratory Syncytial Virus (RSV) is the major cause of acute lower respiratory infections in children, and is also recognized as a cause of morbidity in the elderly. There are still no vaccines and no efficient antiviral therapy against this virus. Here, we described an approach of passive immunization with a new class of hyper-enriched anti-RSV immunoglobulins (Ig) manufactured from human normal plasma. This new class of immunoglobulin plasma derived product is generated by an innovative bioprocess, called Ig cracking, which requires a combination of expertise in both plasma derived products and affinity chromatography. The strong efficacy in a small volume of these hyper-enriched anti-RSV IgG to inhibit the viral infection was demonstrated using a mouse model. This new class of immunoglobulin plasma-derived products could be applied to other pathogens to address specific therapeutic needs in the field of infectious diseases or even pandemics, such as COVID-19.

Project description:IntroductionPalivizumab is indicated for the prevention of respiratory syncytial virus (RSV) infection in high-risk children. Previous palivizumab utilization studies examined prior authorization claims but did not examine utilization within insured populations as a whole. This study describes outpatient palivizumab utilization trends and characterizes high-risk infants receiving palivizumab within Medicaid- and commercially insured populations.MethodsInfants born July 1, 2003 through June 30, 2013 were identified in the MarketScan® Multistate Medicaid and Commercial claims databases. Infants with ≥ 18 months of continuous medical insurance enrollment with pharmacy benefits after birth and evidence of chronic lung disease of prematurity (CLDP), congenital heart disease (CHD), or preterm birth without CLDP or CHD were studied. Palivizumab use and demographic and clinical characteristics were measured in infant subgroups. Outpatient palivizumab utilization rates were calculated for each seasonal year (July-June) and for each infant subgroup.ResultsIn total, 29,350 (2.1%) Medicaid-insured and 9589 (2.5%) commercially insured infants received palivizumab and had CLDP, CHD, or were born at < 37 weeks gestational age (wGA). Infants with CLDP (82%) and those < 29 wGA (78%) had the highest utilization. Decreases in utilization rates between the 2003-2004 and 2012-2013 seasons were seen among Medicaid-insured infants born at 29-36 wGA (all P < .0001), and commercially insured infants born at 31-32 wGA (P < .0001), 33-34 wGA (P = .055), 35-36 wGA (P < .0001), and with CHD (P = .003). Utilization by month was consistent across subgroups among Medicaid- and commercially insured infants, with most doses administered from November to March.ConclusionPalivizumab use is targeted to a small percentage of infants who are at highest risk of hospitalization for RSV disease. Utilization declined in recent years in both Medicaid- and commercially insured infant groups. Most palivizumab doses were administered from November to March, with most infants receiving ≤ 5 doses.FundingAstraZeneca.

Dataset Information

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.

Publications

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.

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