Doris Makari, MD
Senior Director, Scientific Affairs
Nov 16th, 2012
Respiratory Syncytial Virus (RSV)
Just another virus… or not ?
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.
RSV Structure
Leading Causes of Infant Hospitalization
in the US
4
73,250
87,826
121,558
181,662
220,379
0 50,000 100,000 150,000 200,000 250,000
Dehydration
Jaundice
Pneumonia**
Bronchiolitis**
RSV bronchiolitis
Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:629-632.
Based on National Hospital Discharge Survey, 1997-1999*
* National Center for Health Statistics, Centers for Disease Control and Prevention, US Department of
Health and Human Services.
** Cause unspecified
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%
5 Yorita KL et al Pediatrics. 2008;121:244-252.
*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.
RSV Disease Signs and Symptoms
Upper respiratory infection1:
– Rhinorrhea and nasal congestion
Lower respiratory infection1:
– 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 days2
Average length of hospital stay: 4-8 days2
6
1. Collins PL, et al. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields Virology. 5th ed.
Philadelphia, PA: Lippincott-Raven Publishers; 2007:1601-1646.
2. Horn SD, Smout RJ. J Pediatr. 2003.143:S133–S141.
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
*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 2003.2
8 weeks GA 16 weeks GA 24 to 35 weeks GA 36 weeks GA
to 3 years
Premature* Term*
Although alveoli are present in some infants as early as 32 weeks GA,
they are not uniformly present until 36 weeks GA1
Premature Birth Interrupts Lung Development
9
1. Langston C, et al. Am Rev Respir Dis. 1984;129:607-613.
2. Moore KL, Persaud TVN. In: The developing human: clinically oriented embryology. 7th ed. Philadelphia, PA:
Saunders. 2003:241-253.
Fetal Development
*Proc Soc Exp Med and Biol 92:544-549, 1956.
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
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
RSV Nt Antibody inhibits RSV replication Prince et al 1986
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
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
-S-S- -S-S- -S-S-
Mouse
MAb 1129 Synagis®
Human
MAb
RSV-specific RSV-specific Non-RSV-specific
Synagis®
A humanized Monoclonal Antibody 5% of Mouse Sequences Transplanted
Please see Important Safety Information on slides 32 and 33.
Palivizumab:
Mechanism of Action
18
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-to-
cell fusion of RSV-infected cells.
Palivizumab prescribing information [package insert].
Please see Important Safety Information on slides 32 and 33.
IMpact-RSV Trial:
Prevention of RSV Hospitalizations
Randomized (2:1), double-blind, placebo-controlled trial
– 139 Centers in US, Canada and UK
– 1996-1997 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
19
The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.
Please see Important Safety Information on slides 32 and 33.
RSV-Related Hospitalization Rate
(IMpact Trial)
20
↓ 55% ↓ 47%
↓39%
↓ 78%
↓ 80%
All infants Infants
<32 wk
Infants
w/BPD Infants
w/o BPD
Infants
32-35 wk P<0.001 P=0.003 P=0.038 P<0.001 P=0.002
RS
V h
osp
italizati
on
rate
(%
)
10.6% 11.0%
12.8%
8.1%
9.8%
The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.
Placebo n=234 palivizumab
n=506
BPD = Bronchopulmonary dysplasia
Placebo n=500 Palivizumab
n=1002
Placebo n=123 palivizumab
n=250
Placebo n=372 palivizumab
n=739
Placebo n=266 palivizumab
n=496
Please see Important Safety Information on slides 32 and 33.
IMpact-RSV Study: Adverse Events
21
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
Most Frequently Reported Adverse Events Potentially Related
to Study Drug*
The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.
* 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.
Please see Important Safety Information on slides 32 and 33.
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 (1998-2002)
Primary Endpoint
– Hospitalization with confirmed RSV infection
22
Feltes TF et al. J Pediatr. 2003;143:532-540.
* CHD Requiring medication or supplemental oxygen
** IM = Intramuscular
Please see Important Safety Information on slides 32 and 33.
Cardiac Palivizumab Study:
Primary Endpoint
23
Feltes TF, et al. J Pediatr. 2003;143:532-540.
placebo (n=648)
palivizumab (n=639)
45% Relative Reduction (P=0.003)
All Patients
9.7%
5.3%
0.0
2.0
4.0
6.0
8.0
10.0
RS
V H
os
pit
ali
za
tio
n R
ate
(%
)
(63/648) (34/639)
Please see Important Safety Information on slides 32 and 33.
Cardiac Palivizumab Study:
Safety
24
Feltes TF, et al. J Pediatr. 2003;143:532-540.
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
Please see Important Safety Information on slides 32 and 33.
25
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
www.synagis.com.
Palivizumab Package Insert Indication and Select Safety Information
Please see Important Safety Information on slides 32 and 33.
RSV Hospitalizations in
Infants Receiving RSV Prophylaxis
26
Frogel M, et al. J Perinatol. 2008;28:511-517.
Palivizumab Outcomes Registry2
RSV-related Hospitalizations
2000–2001 (N=2116)
2001–2002 (N=5091)
2002–2003 (N=6291)
2003–2004 (N=6050)
0.2
2.9
1.5 1.1
0.7
4.5
1.7 1.6 1.1
1.6 1.3
0.7
0
2
4
6
All Infants <32 wk GA 32–35 wk GA
RS
V H
os
pit
ali
za
tio
n R
ate
(%
)
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 33.
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 33.
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 33.
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.
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
www.medimmune.com/about_us_products.aspx.
Top Related