Transcript Document
RSV Features
• Single-stranded,
nonsegmented
RNA virus in the
paramyxoviridae
family
– Attachment (G)
proteins assist with
viral adherence to the
host cells
– Fusion (F) proteins
aid with viral
penetration
Randhawa J. www.template.bio.warwick.ac.uk/staff/easton/
MedImmune, Inc.
Top Causes of Infant
Hospitalization
Based on National Hospital Discharge Survey, 1997-1999
RSV Bronchiolitis
220,379
Bronchiolitis
(cause unspecified)
181,662
Pneumonia
(cause unspecified)
121,558
87,826
Jaundice
Dehydration
73,250
0
50,000
100,000
150,000
200,000
250,000
Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:629-32.
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•
RSV: A Leading Viral Cause of
Infant Death
CDC viral surveillance data and mortality data were analyzed from
1990-1999
RSV was found to be a leading viral cause of infant death*, with
nearly 9 times the mortality of influenza
Mortality Rate per
100,000 person-years
•
6
5
RSV
Influenza
4
3
2
1
0
<1
1-4
Age Bracket
5-49
Thompson WW, et al. JAMA. 2003;289:179-86.
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Annual Bronchiolitis
Hospitalizations
Among U.S. Children Less Than 1-Year Old, 1980-1996
140,000
130,000
Hospitalizations
120,000
110,000
100,000
90,000
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
Shay DK, et al. JAMA. 1999;282:1440-6.
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Palivizumab (Synagis®):
Mechanism of Action
• Palivizumab is a monoclonal
antibody that binds the F
(fusion) protein of RSV
Palivizumab
• Palivizumab prevents
infection of the host cell
• Palivizumab reduces viral
replication and spread of
RSV to other susceptible
cells
RSV
• Protective levels need to be
achieved prior to exposure
to RSV
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Respiratory Syncytial Virus
• Major viral respiratory pathogen in children
worldwide
– ~ 50% of infants infected in the first year of life
– >95% infected by 2 years of age
• Most common lower respiratory tract
pathogen of infants and young children
– 25-40% of first infections have signs or symptoms
of LRI, bronchiolitis or pneumonia
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Respiratory Syncytial Virus
• Leading cause of hospitalization in first year
of life
– Overall RSV hospitalization rates are 1-2%
• Annual mortality due to RSV in hospitalized
infants and children is 0.1 - 5%
– Dependent on risk factors
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Risk for Serious RSV Disease
• Primary populations at high risk
– Premature infants (< 35 weeks gestation)
– Chronic lung disease of prematurity
– Complicated congenital heart disease
• Hospitalization rates ~8-10x full-term infants
• Increased intensive care support
– 30% require ICU care
– 17% require mechanical ventilation
• Mortality rates ~2-6x full-term infants
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Respiratory Syncytial Virus
Envelope Spikes
G [298]
F [574]
Inner Envelope
M [256]
M2 [194]
Nucleocapsid
N [391]
P [241]
L [nd]
Surface of
Infected Cell
SH [64]
Electron photomicrograph of budding virion (Peter Collins, 1989; Fields Virology 2nd Edition, 1990.)
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Synagis® (palivizumab)
•
Humanized Mab specifc to conserved F
protein epitope
•
Broad neutralization vs A and B isolates
•
Active in cotton rat model of RSV
–
50-100x more active than RSV-IGIV
–
Serum levels of 30 ug/mL produce a 99%
reduction of RSV in cotton rat lung
–
Increased potency translated to a dose
reduction (15 mg/kg) compared to RespiGam
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Numax
13 aa differences compared to Synagis
2 framework aa changes made
Heavy Chain CDRs
T AGMS VG
CDR1
CDR2
D I WW D D K K H Y N P S L K D
CDR3
DM I F N F Y F D V
Light Chain CDRs
S AS S R VG YMH
CDR1
CDR2
D T S K L AS
CDR3
F QG S G Y P F T
kon
koff
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RSV titer reduction in lungs and upper
respiratory tract is enhanced
Cotton Rat Challenge Studies
RSV Lung Replication
6
8
Virus Titre (pfu/gm, log10)
Virus Titre (pfu/gm, log10)
3 mg/kg MAb Doses
7
6
5
4
3
ND*
105 Virus Challenge Dose
5
4
3
2
2
105
RSV Nasal Replication
107
2
Virus Challenge Dose
*ND: none detected
Control
MAb Dose (mg/kg)
Synagis
Numax
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Numax Enhanced Potency
Summary
• Numax has ~40-fold increased binding affinity
• Numax is 20-fold more potent than Synagis in
neutralizing RSV in tissue culture
• At the same serum concentration level of ~30
ug/Ml Numax can:
– Reduce RSV in the lungs of cotton rats better than
Synagis by 100-fold
– Reduce RSV in the upper respiratory tract of cotton
rats better than Synagis by 100-fold
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Clinical Potential of the
Enhanced Potency of Numax
• At same dose as Synagis®, should observe
further reductions in RSV hospitalizations
• Inhibition of nasal RSV replication may also:
– Decrease incidence of medically attended LRIs
Via RSV specific LRI reductions
– Decrease incidence/frequency of medically
attended otitis media
• ? decrease in RSV associated wheezing and
asthma
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Pharmacokinetics
Phase II
• Healthy adults
– Mean half-life 15-18 days
– Consistent with an IgG1 and Synagis
– Dose proportionality
• Children
– Mean serum trough after first and second 15 mg/kg
doses 34.5- and 59.6, respectively
– Comparable to Synagis
Primary Study Objectives
• To compare the efficacy of Numax to Synagis
when administered monthly IM for reduction
in incidence of RSV hospitalization in high
risk children
Assumption is that the Numax treatment group will
have an additional 45% decrease in hospitalizations
compared to the Synagis treatment group
• To compare the safety of Numax to Synagis
in high risk children
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Phase III Design
• Randomized (1:1) double-blind Synagis
controlled trial
– Liquid formulation of Synagis and Numax
LIQ Synagis approved by FDA July 2004
• Sample size of 5750
• Northern and southern hemispheres
– 2 sequential N hemisphere RSV seasons
• Safety oversight by Data Monitoring Committee
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Phase III Schema
1st Injection
Last Injection
End of Follow-up
Injections q 30 days
Premature < 6 mos
BPD < 24 mos. with
recent Rx
CHD Excluded
R
A
N
D
O
M
I
Z
E
Synagis-LQ IM 15 mg/kg
30 days after
last scheduled
infusion visit
(Efficacy and Safety)
Study period = 150 days
Numax-LQ IM 15 mg/kg
Primary Endpoint – RSV Hospitalization
Secondary
Medically attended LRI (RSV subset)
OM
Antibiotic Use
PK, IM
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Eligibility
Who Do We Want In the Trial?
• 24 months of age or younger with a diagnosis
of chronic lung disease (CLD) of prematurity
– requiring medical intervention/management (e.g.,
supplemental oxygen, steroids, bronchodilators, or
diuretics) within the previous 6 months
• Key point
– CLD is diagnosed by a physician qualified to make
this diagnosis
– Document in records
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Eligibility
Who Do We Want In the Trial?
• 35 weeks gestation or less at birth and 6
months of age or younger
• Key point
– GA determined by review of birth record
– Hierarchy:
Qualified pediatric assessment
Ultrasound
Dates
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Primary Endpoint
RSV Hospitalizations
• There are three ways to meet endpoint:
– Primary RSV hospitalization
– “Nosocomial” RSV hospitalization
– Death proven to be RSV related
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Primary RSV Hospitalizations
(section 3.4.2)
• A Primary RSV hospitalization is defined as:
– A respiratory hospitalization with a positive RSV test
within 48 hours of hospitalization
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Primary RSV Hospitalizations
(section 3.4.2)
• Key points
– A respiratory hospitalization is an admission for a
respiratory cause as determined by the admitting
physician
Actively follow child
– A nasal secretion specimen must be obtained for
central lab testing for RSV for all such events within
48 hours of hospitalization
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Nosocomial RSV Hospitalizations
(section 3.4.2)
• A nosocomial RSV hospitalization is defined
as:
–
New onset of LRI in an already hospitalized child,
–
with an objective measure of worsening
respiratory status AND
–
a positive RSV test within 48 hours of the
deterioration
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Nosocomial RSV Hospitalizations
• “New LRI”
– Child must have resolved or be clearly resolving any
previous respiratory illness
– Must have illness thought to be an infection of the
lower respiratory tract
includes symptoms such as cough, retractions,
rhonchi, wheezing, crackles or rales and
associated symptoms of fever, coryza, apnea
• “Objective Worsening”
– New or increase in supplemental oxygen
– New or increase in mechanical ventilation
Additional support is not transient
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RSV Related Deaths
(section 3.4.2)
• Deaths which can be demonstrated to be
caused by RSV
– by autopsy or clinical history
– AND virologic evidence
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Secondary Objectives
• To compare the incidence of medically-attended (MA)
lower respiratory tract infections (LRIs)
– To compare the incidence of RSV-specific MA LRI in a
subset of patients
• To compare the frequency and incidence of MA OM
infections
• To compare the frequency of prescribed antibiotics for
MA LRI and MA OM infections
• To determine serum trough drug levels and
immunogenicity
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MA-LRI Events
(section 3.5.3.1)
• A qualified investigator determines the LRI event
– By record review or by direct patient assessment
• LRI definition
– Bronchiolitis
– Pneumonia, or
– LRI
wheezing, rhonchi/crackles/rales, respiratory
distress/retractions
associated symptoms of fever, coryza, or apnea
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RSV Specific MA-LRI Events
• Extremely important efficacy endpoint
• May be more likely to succeed than
effectiveness endpoint
• Based on assumption that Numax is superior
to Synagis
– Synagis will reduce RSV MA LRI by 50% and Numax
will reduce RSV MA LRI by 75%
– Requires large subject numbers (~2600)
– Requires capturing all events and testing all events
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RSV Specific MA-LRI Events
• ALL MA LRI events must have nasal secretions
collected for RSV testing within 48 hours of
medical diagnosis
• If a visit for a respiratory illness can not be
assessed by the site PI within that time frame,
a nasal secretion sample should be collected
within 48 hours of that visit
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Medically-Attended Otitis Media
(OM) section 3.5.3.2
• A qualified investigator will determine OM event
– Either by record review or by direct patient assessment
• OM definition
– Acute otitis media, acute tympanic membrane (TM)
perforation, bulging TM, red TM with fever, otitis media
with effusion, or middle ear effusion
– Record as “otitis media”
• A diagnosis of persistent middle ear effusion will
not be recorded as a new OM event
•
If another event occurs 21 days
– Should have documentation of resolution of previous
episode (defined by normal ear exam)
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Overall Participation
• Approximately 5750 children at risk for
serious RSV disease will be randomized
– Northern hemisphere 2004
~2500 patients
– Southern hemisphere 2005
~750 patients
– Northern hemisphere 2005
~2500 patients
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North America MI-CP110 Sites
2
2
1
1
1 PEI
3
3
1
1
2
1
1
1
10
1
4
1
6
1
1
3
2
1
7
5
2
15
3
1
8
1
2
2
1 NS
9
2
2
5
3
2
3 MA
1 RI
1 DE 2 CT
2 NJ
1 MD
2 DC
5
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Protocol Procedure
Compliance Goals
• All patients to receive 5 doses of study drug
• All patients to be followed through Day 150 per
protocol (all visits/procedures conducted)
– If a patient “misses” a visit/declines a procedure/etc.,
study drug injections and subsequent follow-up should
continue according to the protocol
• Assessment of endpoints obtained for all patients
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Schedule of Routine Patient
Evaluations
Study Day
Screen
0
Informed Consent
X
History & PE
X
30
60
90
120
150
X
Labs – chemistries
X
Study Drug
X
X
X
X
X
IM & PK
X
(x)
(x)
(x)
X
Safety Assessment
X
X
X
X
X
X
Med-Attended Events
X
X
X
X
X
X
X
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Respiratory Hospitalization –
Now what do I do?
• Nasal secretions for RSV testing must be obtained
within 48 hours (before or after admission)
– RT-PCR testing will be performed by a Central Lab
• Document Respiratory Status
– Physical findings – respiratory signs & symptoms
– Supplemental oxygen / Mechanical ventilation /
Medications
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Secondary Endpoints
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Medically-attended LRI
• All medically-attended LRI events in all patients
must be captured
– Sites should encourage parents to contact them in the
case of an illness
• If a patient is seen at a doctor’s office, clinic, ER,
etc., other than the investigational site, then visit
records must be obtained by the site
• The site Investigator will verify LRI by review of the
visit records or by direct patient assessment
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Medically-attended LRI –
Subset Study
• For all respiratory illness events, a nasal specimen
for RSV testing must be obtained within 48 hours
of the visit
• If the patient is assessed by another medical
provider, and a LRI is suspected, a nasal specimen
MUST be obtained
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Medically-attended Otitis Media
• All medically-attended OM events in all patients
must be captured
– Sites should encourage parents to contact them in the
case of an illness
• If a patient is seen at a doctor’s office, clinic, ER,
etc., other than the investigational site, then visit
records must be obtained by the site
• The site Investigator will verify OM by review of the
visit records or by direct patient assessment
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Pharmacokinetics & Immunogenicity
• Blood will be collected to describe:
– Trough serum concentrations of MEDI-524
– Immunogenicity of MEDI-524
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Endpoint Goals
• Nasal secretions collected within 48 hours in order
to determine endpoints for
– All primary respiratory hospitalizations
– All nosocomial respiratory deteriorations
– All medically-attended LRIs (Participants in Subset Study)
• When in doubt, collect nasal secretions
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Specimens Collected for RSV
Diagnostic Testing
• RT PCR (Hexaplex) will be performed for
RSV detection
• Acceptable specimens include:
– Nasal wash aspirate
– Nasal aspirate
– Nasal swab
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