Transcript Document 7108068

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OPTISON™
GE Healthcare
FDA Cardiovascular and Renal
Drugs Advisory Committee
June 24, 2008
Optison Presentation Overview
Introductions
Larry Bell, MD
Global Head Regulatory Affairs GE Healthcare
Pre-Clinical
Morten Eriksen. M.D., Ph.D.
Senior Scientist, Physiologist
GE Healthcare
Clinical
Steven B. Feinstein, M.D., F.A.C.C.
Professor of Medicine
Director - Echocardiography Lab
Rush University Medical Center Chicago, IL
June 24, 2008
OPTISON
3
OPTISON™ CMC and Pre-clinical
Data
Morten Eriksen, MD, PhD
Senior Scientist
GE Healthcare
Content
Chemistry, Manufacturing and Control (CMC)
Pre-Clinical data
Animal Models
June 24, 2008
OPTISON
5
Optison constituents
Optison contains:
Perflutren (octafluorpropane) gas (2.8% v/v)
Human albumin as shell material
Human albumin (1%) in vehicle
Structure of the Optison
microsphere: Octafluoropropane
encapsulated by a 15 nm thick
shell of heat denatured human
albumin.
Except from the gas, Optison is
essentially identical to Albunex.
June 24, 2008
OPTISON
6
Optison size distribution and lung capillaries
18
150
Optison - as injected
16
Optison - post lung
Millions/ml
12
100
Capillary size
10
8
6
50
4
Percent smaller than given size
Capillary size (cumulative)
14
Optison size
2
0
0
0
5
10
15
Diameter (um)
Size Distribution of Optison microspheres as administered compared to size
distribution of lung capillaries (cumulative percentage smaller than stated
size) and theoretical distribution of Optison after passage through the lungs.
The number of particles from a clinical dose retained in the lungs is very small
compared to the number of lung capillaries.
June 24, 2008
OPTISON
7
Size stability in blood plasma
Theory: A bubble containing Perflutren (or any other heavy gas) suspended
in blood plasma might potentially increase in size by a net inward gas
diffusion of N2, O2, or CO2
Optison in blood plasma
Volume concentration (% v/v)
Volume concentration and size
distribution of Optison at various
time points during incubation in
plasma at 37°C with 85-95% gas
saturation. The data shows that
Optison bubbles decrease in size.
0.008
0.007
0.006
3 sec
6 sec
0.005
12 sec
0.004
60 s
0.003
0.002
0.001
0.000
1
10
100
Diameter (um)
June 24, 2008
OPTISON
8
Pre-Clinical
Absorption Distribution Metabolism
Excretion (ADME)
•
125I-Optison
microspheres are cleared from the
blood pool in rats during the first few minutes
following dosing.
• The liver is the major organ of uptake of albumin.
• Perflutren is cleared via exhaled air with an
elimination t1/2 of 40 seconds in dogs. Almost 100%
is recovered from exhaled air in 15 minutes.
June 24, 2008
OPTISON
10
General toxicology (1)
Single dose
NOAEL
HED
Safety factor*
20 mL/kg (rats & dogs)
3.2 mL/kg (rats),
11.2 (dogs)
26x (rats), 89x (dogs)
10 mL/kg (monkeys)
3.2 mL/kg (monkeys)
26x (monkeys)
Repeat dose
5 mL/kg/day (rats)
0.8 mL/kg/day (rats)
6x (rats)
29 - 31 days
< 0.25 mL/kg (dog) **
-
-
Repeat dose, 3
times per week for
3 weeks
5 mL/kg (rats)
0.8 mL/kg (rats)
6x (rats)
20 mL/kg (dogs)
11.1 mL/kg (dogs)
92x (dogs)
Teratology,
embryonic effects
> 10 mL/kg/day (rats)
-
-
0.25 mL/kg/day (rabbits)
NOAEL = No Observable Adverse Effect Level
HED = Human Equivalent Dose
* Relative to the highest approved human dose
**not established, effects were observed at the lowest dose
June 24, 2008
OPTISON
11
General toxicology (2)
• No toxicity or local irritation after intravascular,
perivascular, intramuscular, topical dermal and
ocular administration of Optison.
• No genotoxicity.
• In-vitro human blood compatibility of Optison
without ultrasound exposure: No hemolysis.
June 24, 2008
OPTISON
12
Ultrasound related studies
• In-vivo rabbit blood compatibility of Optison with US exposure:
− No hemolysis
− Reductions in WBCs comparable to latex particle controls
• Cardiovascular effects in dogs, 0.25 mL/kg (groups of 3 animals dosed
with vehicle, Optison and Optison + dipyramidole):
−
No effects related to Optison at 5 min. interval measurements
• Endothelial damage studied in dogs, 0.72 mL/kg Optison and local
high power ultrasound (MI = 0.8 and 1.8):
−
June 24, 2008
No endothelial damage (HE staining and albumin in tissue by
immunohistochemical staining) in jugular vein wall, aortic wall,
myocardium and kidney compared to non-exposed control
tissue.
OPTISON
13
Optison in the microcirculation
Muscle capillary intravital fluorescence microscopy studies in rat and
mouse muscle with i.v. and i.a. injections of Optison:
• Optison particles move with same speed as RBCs, but adhere to
inflamed endothelium without causing blockage of blood flow.
[Yasu et al.]
• No alterations in arterial pressure and microvascular blood flow were
observed. Large microparticles or aggregates were not seen in vessels.
[Dittrich et al. 1995]
• Rat spinotrapezius muscle with arterial injections of Optison showed
occasional blockage of capillaries caused by large bubbles. This was
consistent with finding of prolonged contrast in dog myocardium
observed after direct intracoronary injections.
[Skyba et al. 1996]
Optison does not block systemic capillaries after i.v. injection
June 24, 2008
OPTISON
14
Animal Models
Dog models
Hemodynamic effects of particles
Anaesthetized dogs can be instrumented for simultaneous
measurements of hemodynamic variables. Pressure can be measured in:
−systemic arteries
−left ventricle of the heart
−central veins
−pulmonary artery
Blood flow in arteries and cardiac output can be measured by implanted
flowmeters, ultrasound Doppler or thermodilution, and the ECG can be
recorded and analyzed.
The preparations can be combined with acute disease, such as
myocardial ischemia, infarction or reperfusion injury.
Direct effects of mechanical blockage of the pulmonary circulation
cannot be studied in the intact animal, since the number of lung
capillaries (≈ 1011) is much larger than the number of particles (≈ 108)
dosed.
June 24, 2008
OPTISON
16
Pigs as experimental animals for
evaluation of particle-based drugs
• Animals from the Artiodactyla order (pig, goat, sheep and
cow) have intravascular pulmonary macrophages.
• These macrophages react to particles in the bloodstream by
activation, phagocytosis and thromboxane A2 release.
• The resulting pulmonary vasoconstriction can be severe.
• Release of thromboxane and the pulmonary hypertension
response can be abolished by indomethacine.
• Phagocytosis persists after treatment with indomethacine,
causing substantial first-pass extraction of particles which
adversely impacts ability to study ADME, general toxicity and
efficacy.
June 24, 2008
OPTISON
17
Effect of indomethacine in pigs given Albunex.
0.2 mL Albunex i.v.; 27 kg pig
3.2 mL Albunex i.v. to same
pig after indomethacine.
Source: Østensen et al. 1992
June 24, 2008
OPTISON
18
Pulmonary Arterial Pressure Change (cmH2O)
Pulmonary macrophages in different species.
Cat
Calf
Sheep
Goat
Pig
Newborn Pig
Pulmonary Arterial Pressure Change (cmH2O)
Rabbit
Dog
Guinea Pig
Rat
Mouse
0
20
40
60
80
100
Clearance of
Blood - Borne Particles
(in % of Recovered Dose)
Liver/
Lung
Spleen
Organ distribution of particles cleared
from blood in different species.
70
60
50
40
30
sheep
goat
cow
20
10
0
10-2
10-1
1
102
10
60
50
40
dog
cat
rat
30
20
10
0
10-2
10-1
1
10
102
Doses of liposomes
(mol of total lipids/kg)
Pulmonary artery pressure response to
liposomes in different species.
Source: The Pulmonary Intravascular Macrophage, ed. N.C. Staub, 1989
June 24, 2008
OPTISON
19
The pig is an inappropriate model for
screening of ultrasound contrast agents
• It has abundant intravascular lung macrophages, not
detected in humans, and the acute hemodynamic response
to i.v. injected particles is atypical of human response.
• The response might mask other acute effects with relevance
for human safety.
• The biodistribution of ultrasound contrast agents is
predominantly to the lungs and the first-pass arterial
concentration is reduced, this impacts the ability to study
ADME, general toxicity and efficacy.
June 24, 2008
OPTISON
20
Optison / Albunex In Other Species
• Albunex has been injected in dog preparations at single
doses up to 20 ml without any effects on pulmonary arterial
pressure [Walker et al 1992]
• The effects of Optison on pulmonary arterial pressure in
dogs is none or minimal.
• Optison does not affect pulmonary arterial pressure in man
measured during CABG surgery [Erb et al 2001]
• Optison has been injected in ≈1 million doses without
serious events that can be attributed to pulmonary vascular
effects.
Data from the pig is not a good predictor of clinical side effects.
dog models are better!
June 24, 2008
OPTISON
21
Clinical Overview
Steven B. Feinstein, M.D., F.A.C.C.
Professor of Medicine
Director of the Echocardiography Lab
Rush University Medical Center, Chicago, IL
June 24, 2008
OPTISON
22
Clinical Outline
Introduction to clinical applications
Optison NDA Clinical Safety Data
Optison Post-Marketing Surveillance
Optison Clinical Literature
Future uses of Contrast - Vascular
June 24, 2008
OPTISON
23
American Society of Echocardiography
Guidelines for use of U/S contrast 2000
At present, it is the position of this guideline
committee that intravenous contrast agents
demonstrate substantial value in the difficult-toimage patient with comorbid conditions limiting
an ultrasound evaluation of the heart. For such
patients, the use of intravenous contrast agents
should be encouraged as a means to provide
added diagnostic information and to streamline
early detection and treatment of underlying
cardiac pathophysiology.
ASE Position Paper
Task Force on Standards and Guidelines for the Use of Ultrasonic Contrast in
Echocardiography: S. L. Mulvagh, MD Chair, A. N. DeMaria MD, Co chair, S. B.
Feinstein MD, P. N. Burns, PhD et al., Contrast Echocardiography: Current
and Future Applications, J Am Soc Echocardiogr, 2000 13(4):331-342
June 24, 2008
OPTISON
24
Left ventricular endocardial border detection
June 24, 2008
OPTISON
25
Left ventricular endocardial border detection
(6 apical segments as defined by the American
Society of Echocardiography)
3
?
2
1
June 24, 2008
3
4?
2
5?
1
6
OPTISON
4
5
6
26
Left ventricular opacification (LVO)
following intravenous injection of Optison
June 24, 2008
OPTISON
27
NDA Clinical Safety Data
U/S contrast composition
Product
Shell Material
Encapsulated Gas
Albunex
Air
Optison
Protein/Albumin
Octafluoropropane/Perflutren
Phospholipids
Sulphur-hexafluoride
Definity
SonoVue
Sonazoid
Perfluorobutane
Perflutren
-Inert
-Device/ISPAN
-Intra-ocular use
Albumin
- vaccines, blood vol. replacement
- PulmoliteR _ macroaggregated
albumin 150µ - 700 000 proc. p.a.
Albunex
Optison
~ 63,000 doses, 1994 - 1997
1 mil doses, 1998-2008
June 24, 2008
Air
OPTISON
29
Overview of Clinical Investigations (1995-1996)
Study No.
Study Description
Dose
Individual/
accumulated
FS-1000
Safety, dose-ranging, preliminary efficacy
No.
subjects
0.5  40.0 mL
40
44.0 mL
FS-1250
Safety: Evaluate immunologic response to re-challenge –
1 year later (Patients from FS-1000)
20.0 mL
5
0.02 mL *
FS-1500
Mass Balance: Measure PFP in blood and expired air as a
measure of clearance; half-life; recovery in expired air
20.0 mL
10
FS-6000
Single Blind Safety and immunological response in
healthy volunteers and in subjects with cardiac, hepatic
and respiratory diseases. Comparison to 1% HSA
20.0 mL
50
FS-3000
Comparative: Evaluate safety and efficacy for
endocardial border delineation and left ventricular
chamber opacification vs. Albunex and enhancement of
Doppler signals vs. baseline, non-contrast signal
0.2  5.0 mL
101
Comparative: Evaluate safety and efficacy for
endocardial border delineation and left ventricular
chamber opacification vs. Albunex and enhancement of
Doppler signals vs. baseline, non-contrast signal
0.2  5.0 mL
FS-3500
8.7 mL
102
8.7 mL
* Intra-dermal injection
June 24, 2008
OPTISON
30
Clinical Safety Parameters – all studies
Criteria
FS-1000*
(n=40)
F5-1500*
(n=10)
FS-6000**
(n=50)
FS-1250*
(n=5)
FS-3000/
FS-3500 ***
(n=203)
12-lead ECG
X
X
X
X
X
Physical examination
X
X
X
X
X
Neurological
examination
X
Spirometry
X
Vital Signs
X
X
X
X
X
O2 Saturation
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
*Baseline, 2h, 24h
** Baseline, 2h, 48h
*** Baseline, 30 min, 48h (up to 10 days)
Vital signs 5 to 20 min intervals. Min 48h and max 10 days between each test agents
O2 sat at -2, 2, 4, 6, 8, 10, 20 and 40 min
June 24, 2008
OPTISON
31
Clinical Safety
There were no safety concerns based on
physical & neurological exams, spirometry & chemistry
No clinically
significant
changes after
Optison, or
between Optison
and Albunex or
1% HSA
Criteria
Physical examination
Neurological examination
Spirometry
Chemistry Panel
PFP
June 24, 2008
OPTISON
32 Demo
Clinical ECGs
There were no changes in 12 lead ECG
Protocol
Results
FS- 1000
No changes
FS- 1500
3 subjects with minor rhythm
changes
FS- 6000
No changes
FS- 1250
1 subject had irregularities at
baseline which reverted to NSR
FS- 3000
No changes
FS- 3500
No changes
June 24, 2008
OPTISON
No clinically
significant
changes after
Optison, or
between
Optison and
Albunex or 1%
HSA
33
Clinical Vital Signs
Based on body temperature, heart rate, respiratory rate & BP
• No changes for FS-1000, FS-1250, FS-6000, FS- 3000 and
FS-3500
• FS-1500 (PK study, N=10) Individual changes:
– One patient elevated respiration rate of 22 breaths/min
– One patient had increase in HR and multiple AEs –
uncertain relationship
June 24, 2008
OPTISON
34
Clinical Oxygen Saturation for Optison
Protocol
Results
FS- 1000 Statistically, but no clinically significant
FS- 1500
FS- 6000
FS- 1250
FS- 3000
FS- 3500
June 24, 2008
changes
(at 6 min one patient tried to minimize
breathing & coughed: O2 Sat. changed
from 96 to 87% but recovered to 96% at
8 min)
No changes
No changes –vol 20mL - 1 liver (HPS)
subj. remained stable at 76%
No changes
One lung patient declined 8.25% after
1% HSA at 10 min.
3,636 oxygen measurements, 13
measurements changed (0.4%) in 5
patients.
3,672 oxygen measurements, 7
measurements changed (0.2%) in 4
patients
.
OPTISON
No clinically
significant
changes after
Optison, or
between
Optison and
Albunex or 1%
HSA
35
1000
&
6000
Transient changes ( ) in Oxygen Saturation
Protocol Agent
FS- 3000
Patient # with
Patient # with
Comments
decreased Oxygen increased Oxygen
Saturation
Saturation
Optison 3117
COPD, MI, HTN, smoker
3121
275 lbs, DM, MI, nicotine and alcohol use
3416
Nicotine and alcohol use, valve dx, HTN,
MI
3113
228 lbs, pleural effusion
Albunex 3118
FS- 3500
Optison 5319
COPD, pneumonia
5111
221 lbs, sleep apnea, DM
5305
83 years of age
5410
Chronic bronchitis, pneumonia, CAD
• None of the changes were symptomatic
• Change defined as > 7.5% from baseline
• All changes were transient in nature
• Changes are considered random fluctuations, or related to undiagnosed OSA or variability
of oxygen saturation measurements in subjects required to rest in supine position for over
2 hours.
June 24, 2008
OPTISON
36
3000
&
3500
Clinical Immunological Responses: None
Protocol
# Subjects
Optison
FS- 1000
FS- 1250
# Subjects
1% HSA
Intra-dermal
& i.V. inj.
Blood
samples
Blood
analysis ELISA
Cytokines &
complement
activation
16
X
-24 h, -1h
-
5*
X
2h
IgG, IgA,
IgM, IgD &
IgE
(from FS-1000)
FS- 6000
25
FS- 1000
No immunological
response
25
X
1,2,3 wk
FS- 1250
1 subject: mild skin reaction after intra-dermal
inj., and did not receive i.v. inj. None of the
subjects developed antibodies to Optison or had
any cytokine release or complement activation.
Interleukin-1
alpha,
interleukin-2,
TNF-α. iC3b &
SC56-9
FS- 6000
1 subject had total CPK at 2h of
157 U/L (Normals 26-140 U/L).
Returned to normal within 24h.
Subject had several AEs – all
resolved. No other responses.
No specific antibodies to Optison. No significant increases above normal
ranges of cytokine release or complement activation
* Intra-dermal approx 1 year after first i.v. inj.
June 24, 2008
OPTISON
37
Optison NDA includes adverse events only
Adverse Events:
Any event happening within the study period,- temporally
related but not necessarily casual related
Adverse Reactions:
Reactions (events) within the study period with a causal or
unknown relationships to the product
June 24, 2008
OPTISON
38
All AEs were mild/moderate, transient and
frequently unrelated to Optison
Adverse Events in All Participants Exposed to Optison
Body System
Phase III Trials
All Trials (Ph. I, II & III)
N= 199
N= 279
No.
%
No.
%
Body as a whole
13/199
6.5
47/279
16.8
Cardiovascular System
8/173
4.6
11/182
6.0
Digestive System
6/70
8.6
14/85
16.5
Endocrine System
3/73
4.1
3/77
3.9
Hemic and Lymphatic System
1/17
5.9
2/20
10.0
Musculoskeletal System
5/55
7.3
15/78
19.2
Nervous System
4/34
11.8
6/39
15.4
Respiratory System
8/79
10.1
14/92
15.2
Skin and Appendages
3/30
10.0
7/36
19.4
Special Senses
4/50
8.0
19/72
26.4
Urogenital System
2/56
3.6
9/74
12.2
One patient can have multiple events and are recorded as such
June 24, 2008
OPTISON
39
AEs in patient with impaired cardiac function
is lower than for not impaired patients
Adverse Events in Patients with Impaired Functions Exposed to Optison
Phase III Trials
Body System
Impaired
All Trials (Ph. I, II & III)
Not Impaired
Impaired
Not Impaired
No.
%
No.
%
No.
%
No.
%
Body as a whole
1/34
2.9
12/165
7.3
1/34
2.9
46/245
18.8
Cardiovascular System
1/32
3.1
7/141
5.0
1/32
3.1
10/150
6.7
Digestive System
0/15
0.0
6/55
10.9
0/15
0.0
14/70
20.0
Endocrine System
1/16
6.3
2/57
3.5
1/16
6.3
2/61
3.3
Hemic and Lymphatic System
0/6
0.0
1/11
9.1
0/6
0.0
2/14
14.3
Musculoskeletal System
0/13
0.0
4/42
9.5
0/13
0.0
15/65
23.1
Nervous System
0/8
0.0
4/26
15.4
0/8
0.0
6/31
19.4
Respiratory System
1/30
3.3
7/49
14.3
1/30
3.3
13/62
21.0
Skin and Appendages
0/5
0.0
3/25
12.0
0/5
0.0
7/31
22.6
Special Senses
1/11
0.0
4/39
10.3
0/11
0.0
19/61
31.1
Urogenital System
0/10
0.0
2/46
4.3
0/10
0.0
9/64
14.1
CARDIAC IMPAIRMENT
Significant cardiac disease as documented by medical history; EF< 40%:
June 24, 2008
OPTISON
40
AEs in patient with impaired pulmonary function
are lower or same level as for not impaired patients
Adverse Events in Patients with Impaired Functions Exposed to Optison
Phase III Trials
Body System
Impaired
All Trials (Ph. I, II & III)
Not Impaired
Impaired
Not Impaired
No.
%
No.
%
No.
%
No.
%
Body as a whole
2/47
4.3
11/152
7.2
5/53
9.4
42/226
18.6
Cardiovascular System
2/47
4.3
6/126
4.8
2/49
4.1
9/133
6.8
Digestive System
1/17
5.9
5/53
9.4
3/19
15.8
11/66
16.7
Endocrine System
2/22
9.1
1/51
2.0
2/24
8.3
1/53
1.9
Hemic and Lymphatic System
N/A
N/A
1/17
5.9
0/1
0.0
2/19
10.5
Musculoskeletal System
0/10
0.0
4/45
8.9
3/15
20.0
12/63
19.0
Nervous System
1/9
11.1
3/25
12.0
1/10
10.0
5/29
17.2
Respiratory System
2/21
9.5
6/58
10.3
5/27
18.5
9/65
13.8
Skin and Appendages
0/8
0.0
3/22
13.6
0/10
0.0
7/26
26.9
Special Senses
0/10
0.0
4/40
10.0
3/13
23.1
16/59
27.1
Urogenital System
0/13
0.0
2/43
4.7
2/18
11.1
7/56
12.5
PULMONARY IMPAIRMENT
Respiratory diseases – COPD, emphysema, pulmonary hypertension, bronchiectasis
June 24, 2008
OPTISON
41
Optison Post-Marketing
Surveillance
Spontaneously Serious Adverse Reports 1998 – 2008
12 reports in 10 years with ~1million doses administered < 0.001%
Patient no.
Event
Comments
Cause*
0206s-0002
25 Jan’ 01
Chest pain with abnormal ECG
1h post Optison
Unknown
0206s-0003
8 Feb’01
Decreased HR 175 71 bpm.
Chest pain. Abnormal ECG
Dobutamine peak dose 40 mg/kg. Possible paradoxical
response to dobutamine? (8% occurrence –JACC
1997,29(5):994. Responded to atropine.
Unknown
0207s-0009
12 Aug’98
Convulsion.
ER visit for chest pain and ventricular tachycardia;
status post cardioversion. Recovered.
Unknown
0207s-0010
24 Feb’00
Bradycardia
Treated with fluids, 1mg atropine. Continued stress test
without symptoms.
Unknown
0207s-0011
13 Apr’00
ECG change
Reporting physician felt the recorded EKG changes
were not symptomatic or caused by Optison
Unrelated
0507s 005
26 July ‘05
Pericardial rupture post MI, death
Angina x 1 week. Admitted with acute inferior MI. Two
days later Dobuamine stress echo.
Unrelated
*Defined by the reporter of event
Optison 1998-2005, 2007 to present
June 24, 2008
OPTISON
43
Spontaneously Serious Adverse Reports 1998 – 2008
12 reports in 10 years total administered doses~1 mill 
~0.001%
Patient
no.
Event
Comments
Cause*
0206s-0001
19 June’02
Anaphylactic shock. Hypoxia.
Chest pain
Hypotension, nausea began within 5 min
Related
0402s-0002
17 Fed’04
Anaphylactic reaction
Multiple allergies. Previous blood transfusion without
reactions. Possibly related?
Unknown
0207s-0027
6 Aug’99
Urticaria, facial edema
Patient on ACE-inhibitor (Lisinopril). Treated with antihistamins and steroids
Unknown
0206s-0006
8 Feb’01
Shortness of breath. Baseline
hypoxia with Ox sat ~70% post 10
days C-section.
30 y old, 388lbs (176 kg)
Unknown
0402s-0003
25 Feb’04
Hypoxia
Hypoventilation prior to Optison and 1 day post-op
CABG
Unrelated
0508s-0006
Dyspnea exacerbation
Multiple co-morbidities and multiple drug sensitivities.
Underwent dobutamine stress echo resulted in
increased shortness of breath
Unknown
31 Aug’05
Heparin used and patient recovered
*Defined by the reporter of event
June 24, 2008
OPTISON
44
One reported death unrelated to Optison *
 July 18, 2005, Acute inferior MI (1 week of
angina)
 July 21, 2005, low dose dobutamine stress echo
(10mcg/kg/min)
 Approximately 1 h later, found unresponsive in
electromechanical dissociation (EMD)
 CPR unsuccessful, urgent 2-D echo, new
pericardial effusion noted
 Diagnosis: Post MI myocardial rupture
* Occurred in the United Kingdom
June 24, 2008
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“In conclusion, it appears from the report
of Dr. Hillis that is highly likely that the
death of this unfortunate patient occurred
as a result of spontaneous cardiac rupture
and is not likely to be related to the
procedures that were carried out prior to
the incident.”
Dr. Roxy Senior
Consultant Cardiologist
June 24, 2008
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Optison Literature
Review of clinical literature 1998-2008
56 clinical studies: ~9250 patients received Optison
Patient population:
8670 cardiac ( incl. 2159 ICU patients) & 578 non-cardiac
No concerns about Optison AEs or changes in any safety parameters
Tong 2005/Wei 2008*: ICU patients with chest pain and non-diagnostic ECG
• 975 ICU patients: chest pain & no ST-elevation
Variable
Pre-Optison
Post-Optison
P-value
• 3 ml Optison
Heart rate
72±14
72±14
0.62
sDB
135±27
133±28
0.35
dBP
72±15
76±16
0.66
O2 Sat
97±2
98±2
0.3
PR Interval
165±26
167±25
0.41
QRS interval
98±22
99±23
0.56
QT interval
403±53
407±43
0.20
QTc interval
434±64
437±33
0.79
• No AEs related to Optison. No serious
cardiopulmonary reactions or deaths
• 105 patients with continuous ECG, O2 Sat. &
hemodynamic measurements
• No significant changes after Optison
* Report on safety data not previously published
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Erb et al, JASE 2001, vol 14: 595-600
Intraoperative Contrast Echocardiography with IV Optison
Does Not Cause Hemodynamic Changes During Cardiac Surgery
• 35 heart surgery patients (CABG, ASA class IV), received 97 total injections of 0.3ml
bolus doses of Optison delivered via a central venous catheter
•No statistically significant differences in ST-segment changes, HR, arterial and
central venous pressure, peripheral O2 saturation, cardiac index, LVEF and regional
wall motion were seen 5 and 10 min after Optison in all patients undergoing
concurrent use of anesthetics, high oxygen content and positive end expiratory
pressure (PEEP).
Sub-groups
Time of measurements
PAs mmHg
PAd mmHg
CO2
comments
97 injections
(n=35 patients,
ASA class IV**)
5 min vs baseline
1.3 ± 2.4
0.6 ± 2.4
0.2 ± 2.3
NS
10 min vs baseline
0.7 ± 5.0
0.9 ± 3.0
-0.5 ± 2.0
NS
** Patients have severe systemic disease that limits activity and is a constant threat to life.
June 24, 2008
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Herzog, JAMA 2008, vol 299; 2023-2025
Incidence of adverse events associated with use of perflutren contrast
agents for echocardiography
• 112 776 Echo studies from Hennepin County
Medical Center, Minneapolis, Minnesota
• 16 025 received ultrasound contrast
Optison: 3051 patients (Feb1998 – Feb 2002)
Definity: 12 974 patients (Feb 2002 – Oct 2007)
Patient population
Definity
n=12974
81%
Optison
n=3051
19%
• All patients receiving contrast were routinely
observed for at least 30 min
Indication for resting echo:
LV function
10764
2447
• Patient groups were similar
WM abnormalities
2522
558
• Methods of identifying adverse events were
comparable
Right heart function/
pulmonary hypertension
1768
377
• No adverse events after Optison
Valvular disease
1304
334
• 20 Adverse events after Definity of which 4
were serious:
- 65% had history of allergy
- 65% were women
- Causal relationship uncertain
ICU patients
2431
520
Estimated Pulmonary artery
pressure > 35 mmHg
1882
440
Overall rate of Adverse Events was low
June 24, 2008
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Future Use of Contrast
Vascular
Need for improved management and noninvasive diagnosis of cardiovascular disease
• More than 79 million American adults have CVD
• 1.2 million Heart Attacks
• 700,000 strokes
• 240,000 TIAs
Anterior difficult
w/o contrast
• CVD is no 1 reason in hospital discharges
Anterior walls
w/ contrast
*Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007
June 24, 2008
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Nearly 1/3 of Americans (73 Million) have
diabetes or are at risk
• 58 million people die each year from CV disease
• DM and HTN are the primary predisposing factors
• Over 90% of type II DM is linked with excessive weight
• 147 million people have impaired glucose tolerance and will
increase to 420 million by year 2025; most notably in developing
countries 84M to 228M
• > 65 years of age = 15.8% with diabetes
• USA Prevalence of diabetes = 9.3% (6.5% diagnosed and 2.8
undiagnosed)
• USA = 26% of the population have impaired fasting glucose
N Engl J Med. 2007 Jan 18;356(3):213-5
June 24, 2008
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Future use of vascular U/S contrast could
play a significant role in CVD management
1.
Enhancement of the carotid
artery luminal morphology
in patients with known or suspected
carotid artery stenosis
2.
Improved resolution of c-IMT for CV
risk assessment in patients with risk
factors…monitoring of treatment
3.
Anterior difficult
w/o contrast
Anterior walls
w/ contrast
Identification of arterial wall
neo-vascularization (vasa vasorum) in patients
with known stenosis
June 24, 2008
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Enhancement of the carotid artery
luminal morphology
June 24, 2008
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Identification of arterial wall
neo-vascularization (vasa vasorum)
June 24, 2008
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Identification of arterial wall
neo-vascularization (vasa vasorum)
Courtesy:Hans-Peter Weskott, Hannover, Germany
June 24, 2008
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U/S contrast expected to be safe and effective
in subjects at risk of vascular disease
Dose of U/S contrast:
Same range as approved indication
MI carotid imaging:
0.06 – 0.40
Safety parameters:
Vitals, O2 saturation, 12-lead ECG, AEs
Study population:
Phase 2:
Subjects with known or suspected carotid artery disease
Stable cerebrovascular and cardiovascular disease
Phase 3/clin.practice:
Include more unstable patients representing
patients in clinical practice (dependent on phase 2)
June 24, 2008
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Summary: Optison has an excellent safety profile
Based on pre-clinical, clinical and post-marketing experience
• Pre-clinical studies indicate Optison is safe
- The pig is an inappropriate model for safety of ultrasound contrast agents and
the canine may be a more appropriate model
•Clinical NDA studies show no serious safety concerns
-Extensive safety monitoring (ECG, vital signs, O2 saturations, immunological,
cytokine, complement) revealed no significant findings
• Post-marketing experience in ~1 million patients: excellent safety profile
- 45 post marketing non-serious reports
- 12 SAE’s
- One reported death; follow up information revealed death by cardiac rupture
unrelated to Optison usage (adjudicated by Dr. Roxy Senior, external reviewer)
• Literature survey patients no safety concerns
- ~60 studies and > 9200 Optison patients including > 2100 ICU patients
- Erb et al 2001: No pulmonary artery pressure changes in critically ill ventilated
patents with catheters in place receiving Optison bolus injection
- Herzog 2008 (N=16,025): No Optison adverse events in 3051 patients
June 24, 2008
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