Disclosures. Learning Objectives. Modification of RSV Prophylaxis Recommendations in the 2009 Red Book Why Was it Done, and What Does it Mean for You?

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1 Modification of RSV Prophylaxis Recommendations in the 2009 Red Book Why Was it Done, and What Does it Mean for You? David W. Kimberlin, M.D. Disclosures I have no actual or potential conflict of interest in relation to this program I am an of the American Academy of Pediatrics Report of the Committee on Infectious Diseases (Red Book) I am a member of the American Academy of Pediatrics Committee on Infectious Diseases (Red Book Committee) I participate as one of dozens of sites for clinical trials conducted by GSK, Cellex, and Cubist. All funds from these efforts go to my university and not to me. I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation Learning Objectives Discuss the AAP Committee on Infectious Diseases (COID) process for Red Book development and publication. Review the evidence for risk factors for severe RSV disease. Discuss the benefits of palivizumab administration relative to costs. Summarize new recommendations for use of palivizumab for the prevention of RSV. Author: Committee on Infectious Diseases Larry K. Pickering, MD, FAAP, Editor Carol J. Baker, MD, FAAP, David W. Kimberlin, MD, FAAP, Sarah S. Long, MD, FAAP, Pages Number Of Pages in Each Edition of the Red Book from 1938 to Year

2 Rationale for 2009 AAP Update of Additional data available on RSV seasonality Additional data on cost-benefit of palivizumab Limitations of available data on risk factors for identifying 32 week 0 days gestation through 34 weeks 6 days gestation children at increased risk of serious RSV lower respiratory tract disease Major Goals of New AAP Recommendations Target infants at highest risk for severe disease with risk factors that are most consistent and predictive Ensure optimal balance of benefit and cost Simplify approach for providers Unchanged: Recommendations for infants with gestational age of less than 32 weeks Unchanged: Recommendations for infants with chronic lung disease and congenital heart disease Changes for 2009 Infants between weeks gestation now only need 1 of 2 (rather than 2 of 5) of the risk factors most highly associated with hospitalization Infant attends child care One or more siblings or other children younger than 5 years live permanently in the child s household. Prophylaxis for these weekers for the first 3 months of life, only during RSV season Infant group Palivizumab Doses < 24 months old with chronic lung disease of prematurity who receive medical therapy within 6 months of start of RSV season GA of 28 weeks, 6 days or less and < 12 months old at start of season * GA of 29 weeks, 0 days through 31 weeks, 6 days and < 6 months old at start of season GA of 32 weeks, 0 days through 34 weeks, 6 days if born 3 months before or during RSV season and either attends childcare or has sibling or other children younger than 5 years old living in household Maximum of 3 doses (until infant reaches 90 days of age) * Erratum: 5 doses 2009 Red Book Table 3.61, pg 366

3 Since death from RSV is so rare in the era of pediatric critical care, the outcome on which we focus now is hospitalization For most infants between weeks gestation, hospitalization with RSV occurs during the first 3 months of life Some accumulation of palivizumab occurs with multiple monthly dosing (original FDA submission) There is reason to believe that some degree of significant protection exists beyond the 3 or 5 months of prophylaxis (clinical efficacy vs FDA antibody bar ) Rochester, New York Pediatrics 1999;104: Copenhagen, Denmark Acta Paediatr 2003;92: Corpus Christi, Texas Pediatr Infect Dis J 2004;23: The RSV season for palivizumab prophylaxis is now tied to CDC-published regional data on the calendar dates for RSV season across the United States For most areas of the US, monthly IM palivizumab prophylaxis injections will start on November 1, for a total of 3 or 5 monthly injections A maximum of 5 injections total (for all areas of the US) will likely prevent serious illness throughout RSV season Native Americans Pediatrics 2002;110:e20 Pediatrics 2004;114:e Pediatrics 2009;124:

4 Palivizumab Correlate of Protection Just how much palivizumab do you need in the bloodstream to modify disease? MedImmune looked at an animal model to answer this question for the FDA, to determine human dose for clinical studies Decreased viral titers with RSV challenge in cotton rats who had been given a dose-ranging series of palivizumab injections (and compared with Respigam, RSV IVIg) Palivizumab Correlate of Protection IM Prophylaxis, in Cotton Rats Cotton rats (4/group) were IM dosed with MEDI-493 at 0.56, 1.67, or 5 mg/kg, followed by challenge 24 hours later with 10 5 pfu of RSV-Long strain and kill 4 days later. RSV-IGIV doses were 16.7, 27.8, 50, 83.3, or 250 mg/kg. Findings: A 50-fold increase in potency for MEDI-493 compared to RSV-IGIV was noted and a >2-log reduction in RSV titer was present at 1.67 mg/kg, with MEDI-493 serum levels of mcg/ml dapproved/approvalapplications/therapeuticbiologicapplications/ucm htm Serum Palivizumab Concentrations from Registration Trials, mg/kg Nadir after dose 1 (mcg/ml, SE) 37.4 (1.2) Nadir after dose (2.4) Nadir after dose (2.9) Nadir after dose (1.7) FDA Clinical Review of Palivizumab, Preclinical models of RSV: The sponsor has performed several experiments utilizing the cotton rat model of RSV disease. In general, RSV is inoculated into the nares of the animals and the resulting viral load and pathology noted in the lungs and upper airways. Infected animals develop bronchiolitis and focal pneumonia. These studies showed that MEDI-493 was effective in both prophylaxis and treatment of RSV pulmonary infection. The sponsor felt that the prophylactic MEDI-493 blood level which resulted in a pulmonary viral titer reduction of at least 100 fold compared to placebo was probably an effective blood level--this level was found to be > 30 to 40 mcg/ml at the time of viral challenge. Additional studies showed the MEDI-493 did not induce enhancement of infection or subsequent pathology upon primary or secondary infection with RSV, and that MEDI- 493 administration did not preclude the development of innate immunity to RSV. FDA Comment: It would have been useful to know the blood level that protected against bronchiolitis rather than just the blood level that produced a 100 fold decrease in lung RSV viral titer. However, in these experiments no quantitative correlation of pathology to blood level was performed. One month after your last dose, you are not suddenly unprotected Protection from serious infection may last several weeks or months after multiple doses (data not analyzed or presented that way) Even if RSV persists in a community after the RSV season, it is likely that there is still some degree of protection against RSV for infants who have received even a single dose of palivizumab 2009 Red Book Table 3.59, pg 365

5 Pali/Motavizumab Recommendations Working Group for RSV immunoprophylaxis has been formed by the CDC as part of the ACIP (Advisory Committee on Immunization Practices) AAP representation CDC epidemiologists CDC statisticians CDC financial analysts Motavizumab Recombinant humanized IgG1 monoclonal antibody derived from palivizumab Binds to conserved epitope of F glycoprotein Binding affinity 70 fold > palivizumab Neutralizing activity 18 fold > palivizumab RCT, non-inferiority trial (palivizumab: motavizumab) has been completed Summary of Palivizumab Clinical Efficacy (IMpact-RSV Trial Results) Incidence of RSV Hospitalization Palivizumab:Motavizumab Trial Placebo n=500 Palivizumab n=1,002 Reduction P value Palivizumab Motavizumab Reduction Relat. Risk 95% CI All RSV hospitalizations 10.6% 4.8% 55% <0.001 All premature infants With CLD (n=762) Without CLD (n=740) Infants wk gestation All (n=373) Without CLD (n=335) 12.8% 8.1% 9.8% 10.0% 7.9% 1.8% 2.0% 1.8% 39% 78% 80% 82% < Infants <32 wk (n=1111) 11.0% 5.5% 47% Pediatrics 1998;102:531 All RSV hospitalizat. ITT n=6, % (62/3306) 1.4% (46/3329) 26% ( ) All CLD 3.9% (28/723) 3.0% (22/722) 23% ( ) Premature, no CLD 32 wk gest. >32 to 36 wk gest. 1.3% (34/2583) 1.5% (19/1265) 1.1% (15/1318) 0.9% (24/2607) 1.0% (13/1306) 0.8% (11/1301) 31% 33% 27% ( ) ( ) ( ) All >32 to 36 wk gest. 1.1% (15/1382) 1.1% (15/1371) ( ) All North America Participants 1.7% (21/1264) 1.7% (22/1299) ( ) Pediatrics 2010;125:e35 Other Endpoints Palivizumab:Motavizumab Trial Palivizumab Motavizumab P value Incidence of RSV Outpatient MALRI (ITT) CLD Premature, no CLD >32 to 36 wk gest Incidence of All Cause Outpatient MALRI Skin adverse events Severe skin AE Discontinuation due to AE 3.9% (46/1183) 4.9% 3.6% 3.0% 2.0% (24/1227) 2.3% 1.9% 1.5% % 19.5% % 0.1% 0% (0/3298) 7.2% 0.4% 0.3% (9/3315) < Mortality rates 0.1% (4/3306) 0.2% (8/3329).387 Pediatrics 2010;125:e35