Respiratory Syncytial Virus (RSV) Just another virus or not? Doris Makari, MD Senior Director, Scientific Affairs Nov 16th, 2012

Transcription

1 Respiratory Syncytial Virus (RSV) Just another virus or not? Doris Makari, MD Senior Director, Scientific Affairs Nov 16th, 2012

2 Key Points RSV is not just another virus to infants RSV is the leading cause of hospitalization in infants High risk infants such as preterm infants are especially vulnerable Synagis can help prevent severe RSV disease in high risk infants Over time, AAP has continued to restrict access to Synagis by issuing more restrictive guidelines Please see Important Safety Information on slides 32 and 33.

3 RSV Structure

4 Leading Causes of Infant Hospitalization in the US Based on National Hospital Discharge Survey, * RSV bronchiolitis 220,379 Bronchiolitis** 181,662 Pneumonia** 121,558 Jaundice 87,826 Dehydration 73, , , , , ,000 * National Center for Health Statistics, Centers for Disease Control and Prevention, US Department of Health and Human Services. ** Cause unspecified Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:

5 Infectious Disease Hospitalizations in Infants in the US Kids Inpatient Database* was used to examine infectious disease hospitalizations and to estimate national rates. During 2003, an estimated 286,739 infectious disease (ID) hospitalizations occurred in infants <1 year of age. These infants accounted for 42.8% of all infant hospitalizations RSV bronchiolitis was the leading cause of infant hospitalization LRTIs accounted for 59% of the ID infant hospitalizations Among infants hospitalized with LRTI, the top discharge diagnoses were: RSV bronchiolitis, 23.5% Acute bronchiolitis, organism not specified, 19.0% Pneumonia, organism not specified, 13.2% Volume depletion, 11.6% *Kid s Inpatient Database (KID) was created by the Agency for Healthcare Research and Quality as a Healthcare Cost and Utilization Project. The KID for 2003 includes 3,438 hospitals from 36 states. The KID is the only all-payer inpatient care database, including the uninsured. Yorita KL et al Pediatrics. 2008;121:

6 RSV Disease Signs and Symptoms Upper respiratory infection 1 : Rhinorrhea and nasal congestion Lower respiratory infection 1 : Low-grade fever, coughing and wheezing followed by dyspnea; severe tachypnea In cases of extreme hypoxemia, respiratory failure occurs In high-risk infants, respiratory failure severe enough to require airway intubation can occur early in the course of illness Average duration of symptoms: 7-12 days 2 Average length of hospital stay: 4-8 days 2 1. Collins PL, et al. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields Virology. 5th ed. Philadelphia, PA: Lippincott-Raven Publishers; 2007: Horn SD, Smout RJ. J Pediatr :S133 S141.

7 Infants at High Risk for Severe RSV Illness Very young infants M Beem 1960 s Premature birth C Hall 1970 s Congenital heart disease N MacDonald 1980 s Chronic lung disease J Groothuis 1980 s

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9 Premature Birth Interrupts Lung Development Fetal Development Premature* Term* 8 weeks GA 16 weeks GA 24 to 35 weeks GA 36 weeks GA to 3 years Although alveoli are present in some infants as early as 32 weeks GA, they are not uniformly present until 36 weeks GA 1 *Pictures are artistic renditions of lung development and are designed to emphasize terminal acinus development and not the entire conducting airway system. Adapted from Moore Langston C, et al. Am Rev Respir Dis. 1984;129: Moore KL, Persaud TVN. In: The developing human: clinically oriented embryology. 7th ed. Philadelphia, PA: Saunders. 2003:

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11 History 1958 Agent caused URI in young chimpanzees: named Chimpanzee Coryza Agent (CCA) Accidental infection in Dr. Blount (one of the original investigators) found to cause human illness Described in children with bronchiolitis in early 1960 s and renamed Respiratory Syncytial virus (RSV) Infected humans developed increased complement fixation (CF) and neutralization (Nt) antibodies in response to infection Major pediatric viral respiratory pathogen worldwide *Proc Soc Exp Med and Biol 92: , 1956.

12 The Formalin Vaccine story 1960 s Studied in healthy infants and children <2 years Enhanced pulmonary disease occurred in very young (<12month) seronegative infants in subsequent RSV season after receiving FI-RSV vaccine i(1960 s) 15x greater hospitalization, several deaths Vaccinated Infants developed unusually high compliment fixation antibodies Neutralizing antibody responses were low, however-- For almost 2 decades neutralizing antibodies were blamed for this tragedy

13 RSV Nt Antibody inhibits RSV replication Prince et al 1986

14 Rationale for Immunoprophylaxis with RSV IgG Nt Antibody in Humans RSV illness occurs later and is milder in term newborns with high maternal IgG Nt antibody levels (1:300-1:400) Glezen et al 1973 Serum Nt antibody correlates inversely with rate of infection Henderson et al 1979, Fernald et al1983 The Baby Moose experience Hemming and Weisman

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16 RespiGam IV infusion over several hours Derived from pooled human donor RSV hyperimmune globulin (RSV-IGIV) Licensed 1995 Indicated in premature infants <35 wk GA and BPD babies Not Indicated in patients with CHD 16

17 Synagis A humanized Monoclonal Antibody 5% of Mouse Sequences Transplanted Mouse MAb 1129 Synagis Human MAb -S-S- -S-S- -S-S- RSV-specific RSV-specific Non-RSV-specific Please see Important Safety Information on slides 32 and 33.

18 Palivizumab: Mechanism of Action Palivizumab acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking a critical step in the membrane fusion process. Palivizumab also prevents cell-tocell fusion of RSV-infected cells. Please see Important Safety Information on slides 32 and 33. Palivizumab prescribing information [package insert].

19 IMpact-RSV Trial: Prevention of RSV Hospitalizations Randomized (2:1), double-blind, placebo-controlled trial 139 Centers in US, Canada and UK RSV season Infants 35 weeks GA and 6 months of age or younger, or infants 24 mo with bronchopulmonary dysplasia (BPD) 15mg/kg IM every 30 days for 5 injections N = 1502 Primary endpoint: hospitalization with confirmed RSV infection Intent-to-treat Analysis of all patients as randomized The IMpact-RSV Study Group. Pediatrics. 1998;102: Please see Important Safety Information on slides 32 and 33.

20 RSV hospitalization rate (%) RSV-Related Hospitalization Rate (IMpact Trial) 39% 55% 80% 47% 12.8% 10.6% Placebo n=500 Palivizumab n= % 8.1% 9.8% 11.0% Placebo n=372 palivizumab n=739 Placebo n=266 palivizumab n=496 Placebo n=234 palivizumab n=506 Placebo n=123 palivizumab n=250 All infants P<0.001 Infants w/o BPD P<0.001 Infants wk P=0.002 Infants <32 wk P=0.003 Infants w/bpd P=0.038 BPD = Bronchopulmonary dysplasia The IMpact-RSV Study Group. Pediatrics. 1998;102: Please see Important Safety Information on slides 32 and 33.

21 IMpact-RSV Study: Adverse Events Most Frequently Reported Adverse Events Potentially Related to Study Drug* Placebo Palivizumab P Fever 3.0% 2.8%.870 Nervousness 2.6% 2.5%.865 Injection site reaction 1.6% 2.3%.444 Diarrhea 0.4% 1.0%.357 * Reported events in at least 1% of children in the palivizumab group are provided along with the corresponding incidence in the placebo group. These represent adverse events reported by the investigator and include those identified by protocol mandated testing and other clinically indicated evaluations. The IMpact-RSV Study Group. Pediatrics. 1998;102: Please see Important Safety Information on slides 32 and 33.

22 The Cardiac Palivizumab Study: Overview Study Objective To evaluate safety, tolerance, and efficacy of palivizumab in children 24 months with hemodynamically significant congenital heart disease (CHD)* Design Randomized, double-blind, placebo-controlled trial 1,287 children 24 months of age with hemodynamically significant CHD Randomly assigned 1:1 to receive 5 monthly IM** injections of 15 mg/kg palivizumab or placebo 4 consecutive RSV seasons ( ) Primary Endpoint Hospitalization with confirmed RSV infection * CHD Requiring medication or supplemental oxygen ** IM = Intramuscular Feltes TF et al. J Pediatr. 2003;143: Please see Important Safety Information on slides 32 and 33.

23 RSV Hospitalization Rate (%) Cardiac Palivizumab Study: Primary Endpoint 45% Relative Reduction (P=0.003) % placebo (n=648) palivizumab (n=639) All Patients 5.3% (63/648) (34/639) Feltes TF, et al. J Pediatr. 2003;143: Please see Important Safety Information on slides 32 and 33.

24 Cardiac Palivizumab Study: Safety Placebo Palivizumab Fever 23.9% 27.1% Infection 2.9% 5.6% Injection site reaction 2.2% 3.4% URI 46.1% 47.4% Conjunctivitis 9.3% 11.3% Arrhythmia* 1.7% 3.1% Cyanosis* 6.9% 9.1% *None of the events reported as arrhythmia and one reported as cyanosis (placebo recipient) were judged related to the study drug. Adverse events reported at an absolute incidence 1% higher in the palivizumab group compared with the placebo group. No child had study drug discontinued for a related adverse event. Palivizumab total number of adverse events: 639 Placebo total number of adverse events: 648 Feltes TF, et al. J Pediatr. 2003;143: Please see Important Safety Information on slides 32 and 33.

25 Palivizumab Package Insert Indication and Select Safety Information Palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. Palivizumab is contraindicated in children who have had a previous significant hypersensitivity reaction to palivizumab. Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to palivizumab. However, the relationship to palivizumab is unknown. The most frequently occurring adverse reactions are fever and rash. The first dose of palivizumab should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. The efficacy of palivizumab dosing less frequently than monthly throughout the RSV season, has not been established. Please see accompanying full prescribing information, including patient information or visit Please see Important Safety Information on slides 32 and

26 RSV Hospitalization Rate (%) RSV Hospitalizations in Infants Receiving RSV Prophylaxis 6 Palivizumab Outcomes Registry 2 RSV-related Hospitalizations (N=2116) (N=5091) (N=6291) (N=6050) All Infants <32 wk GA wk GA Frogel M, et al. J Perinatol. 2008;28: Please see Important Safety Information on slides 32 and 33.

27 Synagis Approval 1998 First AAP Guidelines Issued AAP Policy Statement (Pediatrics Nov. 1998) Recommendations: Infants <2 yo with CLD who have required medical therapy within the past 6 months Severe CLD patients may require 2 seasons Premature infants <28 wk GA and <12 mo old Premature infants 29 to 32 wk GA and <6 mo old Premature infants 32 to 35 wk GA and <6 mo old with additional risk factors (6 listed including tobacco exposure and distance from local hospital) Please see Important Safety Information on slides 32 and

28 2003 AAP Redbook Guidelines 2003 AAP Redbook RSV Prophylaxis Guidelines Recommendations: CLD patients no change 28 wk GA or less no change 29 to 32 wk GA no change 32 to 35 wk GA 35 wk GA now defined as 32 wk 1 day and 35 wk 0 days GA, effectively eliminating the 35 wk GA group. Risk factors now defined as 2 of 5 with Tobacco Exposure and Daycare listed as controllable risk factor (reduce exposure). 5 monthly doses Season defined as November to March with local virology as guidance. Now indicated for hemodynamically significant and cyanotic CHD 24 months of age or younger. Please see Important Safety Information on slides 32 and

29 2009 AAP Redbook Guidelines 2009 AAP Redbook RSV Prophylaxis Guidelines Choice of Palivizumab or RSV-IGIV Recommendations: CLD Patients no change 28 wk GA or less no change 29 to 32 wk GA no change 5 dose maximum recommended 32 to 34 wk GA ( defined as 32 wks 0 days and 34 wks 6 days) 3 dose maximum 3 mo CA or less at onset of season AND 1 of 2 risk factors (Child Care/Preschool Aged Siblings) Season defined as November to March with local virology as guidance. South and Midwest acknowledged as different seasons. CHD no change Please see Important Safety Information on slides 32 and

30 Summary RSV is not just another virus to infants RSV is the leading cause of hospitalization in infants High risk infants such as preterm infants are especially vulnerable Synagis (palivizumab) can help prevent serious RSV disease in high risk infants Over time, AAP has continued to restrict access to Synagis Please see Important Safety Information on slides 32 and 33.

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32 Palivizumab Indication & Important Safety Information Palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. Safety and efficacy were established in children with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (<35 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD). The recommended dose of palivizumab is 15 mg/kg of body weight given monthly by intramuscular injection. The first dose of palivizumab should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. Children, including those who develop an RSV infection, should continue to receive monthly doses throughout the season. The efficacy of palivizumab at doses less than 15 mg/kg, or of dosing less frequently than monthly throughout the RSV season, has not been established. Continued on next slide.

33 Palivizumab Indication & Important Safety Information Palivizumab is contraindicated in children who have had a previous significant hypersensitivity reaction to palivizumab. Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to palivizumab. Other acute hypersensitivity reactions, which may be severe, have also been reported on initial exposure or re-exposure to palivizumab. The relationship between these reactions and the development of antibodies to palivizumab is unknown. If a significant hypersensitivity reaction occurs with palivizumab, its use should be permanently discontinued. If anaphylaxis or other significant hypersensitivity reaction occurs, administer appropriate medications (e.g., epinephrine) and provide supportive care as required. If a mild hypersensitivity reaction occurs, clinical judgment should be used regarding cautious readministration of palivizumab. Palivizumab should be given with caution to children with thrombocytopenia or any coagulation disorder. Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. Adverse reactions occurring greater than or equal to 10% and at least l% more frequently than placebo are fever and rash. Please see accompanying full prescribing information, including patient information at