respiratory syncytial virus (rsv) - csg knowledge...

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


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].


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.


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%


Placebo n=234 palivizumab

n=506

BPD = Bronchopulmonary dysplasia

Placebo n=500 Palivizumab

n=1002


n=250


n=739


n=496


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*


* 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 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


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)


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


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


http://www.synagis.com/

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

(%

)


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)


28

2003 AAP Redbook Guidelines

2003 AAP Redbook RSV Prophylaxis Guidelines


• 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.


29

2009 AAP Redbook Guidelines

2009 AAP Redbook RSV Prophylaxis Guidelines

– Choice of Palivizumab or RSV-IGIV


• 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


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®


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.

respiratory syncytial virus (rsv) - csg knowledge...

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