Motavizumab

Abstract

Motavizumab (MEDI-524, Numax) is a second generation monoclonal antibody (mAb) derived from palivizumab (Synagis) using affinity maturation techniques. Motavizumab is currently undergoing US Food and Drug Administration review as a treatment for respiratory syncytial virus (RSV) prophylaxis. It has been evaluated in large-scale clinical studies, and has demonstrated efficacy in reducing the disease burden of RSV in high-risk infant populations.

Introduction

Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in children less than two years of age. RSV is a linear, non-segmented, negative sense, single stranded RNA virus. It belongs to the Paramyxoviridae family, which also includes measles, mumps and the parainfluenza viruses, commonly causing respiratory disease in children. Over 65% of infants are infected with RSV within their first year, and up to 2% of those infected are hospitalized.¹ Premature infants and immuno-compromised individuals are at the highest risk for severe RSV-related disease, which includes lower respiratory tract (LRT) infection, bronchiolitis and pneumonia.

Prior to 1996, the standard treatment option for RSV infections was ribavirin (Rebetol), a nucleoside analog that interferes with viral replication. Ribavirin has been used for over 20 years for treating RSV infections.² However, high morbidity and mortality in high-risk populations, conflicting results in the clinical effectiveness and the high cost of ribavirin underlined the need for a preventive strategy.

The need for RSV-specific immunoprophylaxis in infants led to the development of RSV-IGIV (RespiGam; MedImmune), a polyclonal IgG antibody preparation enriched in RSV-neutralizing antibodies from adults.³ The product was launched in the US in 1996. However, safety concerns associated with the product's origin (human plasma) and lack of efficacy in some patient populations directed the focus of research towards monoclonal antibodies (mAbs). The first such mAb to be developed was palivizumab (Synagis; MedImmune), which was found to have potent in vitro and in vivo anti-RSV activity.⁴ Palivizumab, launched in the US in 1998, is currently the only approved mAb for prophylactic treatment for RSV. The recommended dose of palivizumab is 15 mg/kg. However, the response to palivizumab is variable among individuals, and the product fails to prevent RSV infections effectively in some cases.⁵

Motavizumab (MEDI-524, Numax) is a humanized IgG1 mAb developed by MedImmune Inc., a subsidiary of AstraZeneca. Motavizumab was derived from palivizumab, and has proven to be more effective for treatment of RSV in infants, including those in higher risk groups. In January 2008, a biologic license application for motavizumab was submitted to the US Food and Drug Administration (FDA) by MedImmune. The agency issued a complete response letter (CRL) in November 2008 asking for additional information. At that time, MedImmune was expected to respond to the CRL within the first half of 2009; the company did not foresee a need to conduct any additional trials.

Origins and Preclinical Analysis

Motavizumab differs from palivizumab, its marketed predecessor, by 13 amino acid residues. Both mAbs target a highly conserved antigenic site A on the fusion (F) glycoprotein of RSV, but motavizumab has greater neutralizing activity compared to palivizumab.⁶ Variants of palivizumab were generated by a directed evolution approach that allowed researchers to modify the binding kinetics of the molecule. Among the candidates generated, the most potent palivizumab variant, A4b4, was shown to maintain its RSV neutralizing capability in vitro and in vivo in both fragment (Fab) and full IgG formats.⁷ While A4b4 demonstrated a 44-fold improvement in RSV neutralization over palivizumab in tissue culture,⁷ its potency in reducing the viral load in a cotton rat model remained only at two-fold.⁸ Subsequent studies demonstrated broad binding capacity of A4b4 to various tissues and cell types, leading to a rapid reduction of the molecule in circulation, thereby causing low bio-availability in the lung. The challenge then became to reduce or eliminate the tissue cross-reactivity of A4b4, while retaining its ability to neutralize RSV. This was achieved by mutating three residues in the A4b4 light chain that were responsible for extensive tissue binding, giving rise to motavizumab, which was studied further in tissue culture and cotton rat models. Motavizumab binds to RSV F protein with 70-fold higher affinity compared to palivizumab, which translates to an improvement of 18-fold in RSV neutralization in vitro⁸ and up to 100-fold in the cotton rat model.⁶

Clinical Studies Overview

Motavizumab has been investigated as a prophylactic treatment for RSV infection in a total of 12 clinical studies: three Phase 3, four Phase 2, two Phase 1/2 and three Phase 1 studies. An additional Phase 3 study [NCT00628303] for the potential reduction of serious early childhood wheezing by motavizumab has been suspended due to a study delay. Descriptions of the studies are available at www.clinicaltrials.gov and summarized in Table 1, but results have not yet been published for most of the studies.

Table 1.

Clinical studies of motavizumab

Study design	Doses	Results	Reference	Clinical trial
Phase 3	Infants (1–6 month-old) received 15 mg/kg/month motavizumab (IM), for a maximum of 5 injections during their first RSV season.	Motavizumab reduced RSV hospitalizations by 83% compared to placebo (8.3 vs 1.4%). There was also a 71% reduction in outpatient acute LRT infections (9.5 vs 2.8%).	9	NCT00121108
Phase 3	Preterm infants (6–24 month-old) with or without CLD were given 15 mg/kg/month motavizumab (IM) and followed up for 5 months.	Motavizumab is non-inferior to palivizumab: RSV hospitalizations reduced by 26% (1.4 vs 1.9%), RSV-specific outpatient medically-attended LRT infections reduced by 50% (2.0 vs 3.9%).	10	NCT00129766
Phase 3	Children (<2 years-old) with hemodynamically significant CHD were given 15 mg/kg/month motavizumab (IM) for 5 months.	Completed in September 2008. No data available.	N/A	NCT00538785
Phase 3	Preterm infants less than 6 months old will be given 15 mg/kg/month motavizumab (IM) for a total of 5–6 injections and followed up for signs of early childhood wheezing between their 2nd and 3rd birthdays.	Suspended. (Study is being delayed)	N/A	NCT00628303
Phase 2	Children less than 24 months with hemodynamically significant CHD were given monthly doses of motavizumab. No specific dosing information was reported.	Expected to be completed in October 2006. No data available.	N/A	NCT00240890
Phase 2	Children less than 24 months were given 15 mg/kg/month motavizumab (IM) for 5 months. Subjects were divided into three groups: Group 1 received two doses of motavizumab followed by three doses of palivizumab (2×M, 3×P); Group 2 received 2×P, 3×M; Group 3 received five doses of motavizumab.	Completed in February 2007. No data available.	N/A	NCT00316264
Phase 2	Children less than 12 months with RSV illness who did not require hospitalization were given a single 30 mg/kg IM dose of motavizumab or placebo.	Completed in July 2008. No data available.	N/A	NCT00435227
Phase 2	Previously healthy infants less than 12-months old, who are hospitalized with LRT illness will receive a single IV dose of motavizumab (30 or 100 mg/kg) or placebo.	Currently ongoing.	N/A	NCT00421304
Phase 1/2	Preterm infants less than six months of age were given motavizumab at 3 and 15 mg/kg (IM), infants less than 2 years-old with (CLD) received only 15 mg/kg of motavizumab.	Motavizumab is well-tolerated in high-risk children. Its safety, immunogenicity, and pharmacokinetic profile is similar to that of palivizumab.	11	NCT00113490
Phase 1/2	Children less than 24 months, previously treated with motavizumab, received 15 mg/kg/month motavizumab or palivizumab (IM) for a total of 4–5 injections.	Repeated dosing is well-tolerated, pharmacokinetics of motavizumab resembles that of other IgGs, adverse events of immunogenicity not increased.	12	NCT00192478

Notes: CHD, congenital heart disease; CLD, chronic lung disease; IV, intravenous; IM, intramuscular; LRT, lower respiratory tract; N/A, not available; RSV, respiratory syncytial virus.

Phase 3 Studies

Native American Indian infants are considered to be at high risk for RSV infection. A Phase 3, randomized, double-blind, placebo-controlled trial [NCT00121108, MI-CP117] evaluated the safety, efficacy and tolerability of motavizumab in healthy Native American Indian infants in the southwestern region of the US. The estimated enrollment was 2,100 subjects between one to six months of age. Infants received monthly intramuscular (IM) injections of motavizumab (15 mg/kg) or placebo, for a maximum of five injections during their first RSV season. The primary endpoint was the incidence of RSV hospitalizations through the first five months of the study. Motavizumab demonstrated an 83% reduction in RSV hospitalizations compared to placebo (8.3 vs 1.4%).⁹ There was also a 71% reduction in outpatient acute LRT infections (9.5 vs 2.8%). Subjects continue to be monitored; the study is scheduled for completion in December 2012.

The safety and efficacy of motavizumab was compared with palivizumab in prophylactic treatment of RSV in high-risk infants in a multinational clinical trial [NCT00129766] with over 300 study locations. In this randomized, double-blind, active control Phase 3 study, an estimated 6,600 preterm infants (six to 24 months old) with or without chronic lung disease were administered 15 mg/kg motavizumab via monthly IM injections, and followed for 5 months. Motavizumab was found to be non-inferior to palivizumab, reducing RSV hospitalizations by 26% (1.4 vs 1.9%).¹⁰ Motavizumab also reduced RSV-specific outpatient, medically-attended lower respiratory tract infections by 50% (2.0 vs 3.9%). The incidence of adverse events was similar in both groups.

The safety, tolerability, pharmacokinetics and immunogenicity of motavizumab and palivizumab were compared in a study of children with congenital heart disease (CHD). In this double-blind, Phase 3 trial [NCT00538785, MI-CP124-S2] children up to 2 years of age with hemodynamically significant CHD were given monthly IM injections of either 15 mg/kg motavizumab or palivizumab for 5 months. The estimated enrollment was 800 subjects. Outcomes assessed include the number of adverse events, and the incidence of RSV hospitalization and incidence of RSV-specific, medically-attended outpatient LRT infections. The study was completed in September 2008; as of June 2009, results have not been published.

Phase 2 Studies

A Phase 2 study [NCT00240890] evaluated the safety and tolerability of motavizumab as prophylaxis against RSV infections in children with hemodynamically significant CHD. In this randomized, double-blind, active control study, children under 24 months were given monthly doses of motavizumab, and followed up for 5 months. The study was initiated in November of 2005; the enrollment estimate was 600 subjects.

In a randomized, double-blind Phase 2 study [NCT00316264, MI-CP127] motavizumab was compared with palivizumab in terms of safety, tolerability and immunogenicity of the mAbs. High-risk children less than 24 months were given 15 mg/kg of motavizumab or palivizumab by IM injection every 30 days, for a total of 5 injections during the same RSV season. Subjects were divided into three groups of approximately 80 subjects: Group 1 received two doses of motavizumab followed by three doses of palivizumab; Group 2 received two doses of palivizumab followed by three doses of motavizumab; and Group 3 received 5 doses of motavizumab only. The immunogenicity of motavizumab and palivizumab were evaluated by summarizing serum ELISA-binding activity at each time point and overall; the pharmacokinetics of the mAbs were evaluated by serum concentrations. The study was completed in early 2007.

A Phase 2, randomized, double-blind, placebo-controlled, multicenter study [NCT00435227, MI-CP146] was conducted to assess the safety and efficacy of a single dose of motavizumab in children with RSV illness who did not require hospitalization. Children less than 12 months of age were administered 30 mg/kg IM dose of motavizumab or placebo. The estimated enrollment was 12 subjects. The study was completed in July 2008.

A randomized, double-blind, placebo controlled, Phase 2 study [NCT00421304, MI-CP141] will evaluate the efficacy and safety of motavizumab in previously healthy infants (less than 12-months old) hospitalized with LRT illness. An estimated 150 subjects will receive a single intravenous (IV) dose of motavizumab (30 or 100 mg/kg) or placebo. The study is ongoing but not recruiting participants, and has an estimated completion date of September 2009.

Phase 1/2 Studies

The safety, immunogenicity and pharmacokinetics of motavizumab were assessed in 217 high-risk children in a Phase 1/2 trial [NCT00192478]. In this randomized, open-label, repeat dose, dose-escalation study, preterm infants less than six months of age were given up to 5 IM doses of motavizumab at 3 and 15 mg/kg, while infants less than 2 years-old with chronic lung disease (CLD) of prematurity received the 15 mg/kg dose of motavizumab only. Subjects were followed up for 150 days after the last dose. Motavizumab appeared to be well-tolerated in high-risk children, and its safety, immunogenicity and pharmacokinetic profile was similar to that of palivizumab.¹¹

A randomized, double-blind study evaluated the safety, tolerability, and immunogenicity of motavizumab after dosing for a second season of RSV. In this Phase 1/2 study [NCT00113490], children less than 2 years of age, who had previously received at least 3 doses of motavizumab in the previous RSV season (as part of NCT00192478) were given 15 mg/kg motavizumab or palivizumab every 30 days for a total of 4–5 IM injections. A total of 136 children received either motavizumab (n = 66) or palivizumab (n = 70). Repeated dosing for a second season seemed to be well tolerated for both mAbs and the incidence of adverse events or immunogenicity were not increased.¹²

Phase 1 Studies

An initial Phase 1 study [NCT00192465] evaluated the safety, tolerability and pharmacokinetics (PK) of motavizumab in healthy adults. Single doses of 3, 15 or 30 mg/kg were administered IV to adults (18–49 years). In addition, one or two 3 mg/kg doses were administered IM. The safety, tolerability, PK and immunogenicity of single IV doses of palivizumab were then assessed in healthy children (1–24 months) in a Phase 1 study [NCT00192504]. In an on-going Phase 1 study [NCT00578682] scheduled for completion in December 2010, a single dose, dose escalation study will evaluate the safety, tolerability, PK of palivizumab administered IV at doses of 0.3–30 mg/kg in healthy adults (18–45 years).

Future Prospects

Data from clinical trials of motavizumab are promising. It displays better efficacy and a lower dose requirement compared to palivizumab, which makes it an attractive candidate for prophylaxis against RSV. Large-scale Phase 3 studies of motavizumab have been performed, in some cases at over 300 study locations. However, the results from these trials remain, for the most part, unpublished.

Better pharmacokinetics, broader neutralizing capacity and longer half-life are desirable features for such immunoprophylactic molecules, so the search continues for next generation mAbs. One such product currently under development by MedImmune is MEDI-557 (MEDI-524-YTE), a third generation humanized mAb with an extended half-life, derived from motavizumab. A randomized, double-blind, single-dose, dose-escalation Phase 1 study [NCT00578682] to evaluate the safety, tolerability and pharmacokinetics of this mAb in healthy adult participants was on-going as of June 2009. Motavizumab and similar next generation antibodies will likely comprise one of the few available means in the fight against such a common respiratory infection in high-risk patients.