Download 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.
MedImmune, Inc.
•
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.
MedImmune, Inc.
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.
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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.)
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
Primary Endpoint
RSV Hospitalizations
• There are three ways to meet endpoint:
– Primary RSV hospitalization
– “Nosocomial” RSV hospitalization
– Death proven to be RSV related
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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)
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
Secondary Endpoints
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.
Pharmacokinetics & Immunogenicity
• Blood will be collected to describe:
– Trough serum concentrations of MEDI-524
– Immunogenicity of MEDI-524
MedImmune, Inc.
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
MedImmune, Inc.
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
MedImmune, Inc.