# Presentation: 533910

## Please Note: Due to technical difficulties the medical contrast images will not be in motion, the images will appear as still pictures.For medical images please refer to the transcript,  Part 2, beginning on page 101  for the description of the image that was provided by the presenter.

## OPTISONTM

- 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

- OPTISON

- June 24, 2008

## OPTISONTM CMC and Pre-clinical Data

- Morten Eriksen, MD, PhD
- Senior Scientist
- GE Healthcare

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- June 24, 2008

## Content

- Chemistry, Manufacturing and Control (CMC)
- Pre-Clinical data
- Animal Models

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## Optison constituents

- 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.

- _Optison contains:_
- Perflutren (octafluorpropane) gas (2.8% v/v)
- Human albumin as shell material
- Human albumin (1%) in vehicle

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## Optison size distribution and lung capillaries

- 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.

- Capillary size

- Optison size

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## Size stability in blood plasma

- 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.

- _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

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## Pre-Clinical

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## 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.

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## General toxicology (1)

|  | NOAEL | HED | Safety factor* |
| --- | --- | --- | --- |
| Single dose | 20 mL/kg (rats & dogs)
10 mL/kg  (monkeys) | 3.2 mL/kg (rats),       11.2 (dogs)
3.2 mL/kg  (monkeys) | 26x (rats), 89x (dogs)
26x (monkeys) |
| Repeat dose
29 - 31 days | 5 mL/kg/day (rats)
< 0.25 mL/kg (dog) ** | 0.8 mL/kg/day (rats)
- | 6x (rats)
- |
| Repeat dose, 3 times per week for 3 weeks | 5 mL/kg (rats)
20 mL/kg (dogs) | 0.8 mL/kg (rats)
11.1 mL/kg (dogs) | 6x (rats)
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*

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## 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.

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## 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):
- 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.

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## 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

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## Animal Models

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## 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.

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## 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.

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## Effect of indomethacine in pigs given Albunex.

- Source: Østensen et al. 1992

- 0.2 mL Albunex i.v.; 27 kg pig

- 3.2 mL Albunex i.v. to same pig after indomethacine.

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## Pulmonary macrophages in different species.

- Organ distribution of particles cleared from blood in different species.

- Source: The Pulmonary Intravascular Macrophage, ed. N.C. Staub, 1989

- Pulmonary artery pressure response to liposomes in different species.

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## 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.

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## 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!

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## 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

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**Notes:**
Thanks to FDA, to GE for sharing info....
Disclosures

## Clinical Outline

- Introduction to clinical applications
- Optison NDA Clinical Safety Data
- Optison Post-Marketing Surveillance
- Optison Clinical Literature
- Future uses of Contrast - Vascular

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## American Society of Echocardiography Guidelines for use of U/S contrast 2000

_**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 **

- At present, it is the position of this guideline committee that intravenous contrast agents demonstrate substantial value in the difficult-to-image 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.

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## Left ventricular endocardial border detection

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## Left ventricular endocardial border detection (6 apical segments as defined by the American Society of Echocardiography)

- Left ventricular endocardial border detection (6 apical segments as defined by the American Society of Echocardiography)

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## Left ventricular opacification (LVO) following intravenous injection of Optison 

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## NDA Clinical Safety Data

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## U/S contrast composition

| Product | Shell Material | Encapsulated Gas |
| --- | --- | --- |
| Albunex | 
Protein/Albumin | Air |
| Optison |  | Octafluoropropane/Perflutren |
| Definity | 
Phospholipids |  |
| SonoVue |  | Sulphur-hexafluoride |
| Sonazoid |  | Perfluorobutane |

- Air

- Albumin

- Perflutren

- Optison1 mil doses, 1998-2008

- Albunex~ 63,000 doses, 1994 - 1997

- Inert-Device/ISPAN -Intra-ocular use

-  vaccines, blood vol. replacement- PulmoliteR _ macroaggregated   albumin 150μ - 700 000 proc. p.a.

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## Overview of Clinical Investigations (1995-1996)

| Study No. | Study Description | Dose
Individual/accumulated | No. subjects  |
| --- | --- | --- | --- |
| FS-1000 | Safety, dose-ranging, preliminary efficacy | 0.5  40.0 mL
44.0 mL | 40 |
| FS-1250 | Safety: Evaluate immunologic response to re-challenge – 1 year later (Patients from FS-1000) | 20.0 mL
0.02 mL * | 5 |
| 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
8.7 mL | 101 |
| FS-3500 | 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
8.7 mL | 102 |

- * Intra-dermal injection

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**Notes:**
Table 3 at page 36 ,  added dose information

## 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 |  | X |  |  |
| Vital Signs | X | X | X | X | X |
| O2 Saturation | X | X | X | X | X |
| Chemistry Panel | X | X | X | X | X |

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**Notes:**
Table 6 - Page 43

## Clinical SafetyThere were no safety concerns based on physical & neurological exams, spirometry & chemistry   

| Criteria |
| --- |
| Physical examination |
| Neurological examination |
| Spirometry |
| Chemistry Panel |

- No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA

- Demo

- PFP

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**Notes:**
P – 46  59
Check if “no statistically” is correct

## 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 |

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**Notes:**
Page 44-45

## Clinical Vital Signs

- Based on b*ody 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

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**Notes:**
Page 48-49

## Clinical Oxygen Saturation for Optison

| Protocol  | Results |
| --- | --- |
| FS- 1000 | Statistically, but no clinically significant 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) |
| FS- 1500 | No changes |
| FS- 6000 | No changes –vol 20mL - 1 liver (HPS) subj. remained stable at 76% |
| FS- 1250 | No changes
One lung patient declined 8.25% after 1% HSA at 10 min. |
| FS- 3000 | 3,636 oxygen measurements, 13 measurements changed (0.4%) in 5 patients. |
| FS- 3500 | 3,672 oxygen measurements, 7 measurements changed (0.2%) in 4 patients                     .  |

- No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA

**1000**
**&**
**6000**

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**Notes:**
Page 45
 Of note, in four (4) FS069 subjects out of 199 (97 in FS3000 and 102 in FS3500), O2 saturation dropped transiently and similarly in four (4) of 199 FS069 subjects, O2 saturation increased. Two of the four FS069 subjects with a transient drop in O2  saturations were obese

The FS3000 and FS3500 clinical studies required the subjects to rest in the supine position for over 2 hours. It is now known that the prevalence of obstructive sleep apnea (OSA) is increased in obese subjects and estimated to be 38-50%. Overall in the US, the prevalence of OSA in the US is 6% with an additional 2% undiagnosed.   

Int J Obes Relat Metab Disord. 1994 Mar;18(3):173-7. (references: 1. The prevalence of obstructive sleep apnea in an obese female population; 2. Kripke DF et al., Sleep 20(1):65-76, 1997}.

## Transient changes (    ) in Oxygen Saturation 

| Protocol | Agent | Patient # with decreased Oxygen Saturation | Patient # with increased Oxygen Saturation | Comments |
| --- | --- | --- | --- | --- |
| FS- 3000 | 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 |

**3000**
**&**
**3500**

-  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.

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**Notes:**
Table 12 P - 54

## Clinical Immunological Responses:  None

| Protocol | # Subjects Optison | # Subjects1% HSA | Intra-dermal & i.V. inj. | Blood samples | Blood analysis - ELISA | Cytokines & complement activation |
| --- | --- | --- | --- | --- | --- | --- |
| FS- 1000  | 16 |  | X | -24 h, -1h 
2h
1,2,3 wk | IgG, IgA, IgM, IgD & IgE | - |
| FS- 1250  | 5* (from FS-1000) |  | X |  |  | Interleukin-1 alpha, interleukin-2, TNF-α. iC3b & SC56-9 |
| FS- 6000 | 25 | 25 | X |  |  |  |

| FS- 1000 | FS- 1250 | FS- 6000 |
| --- | --- | --- |
| No immunological response
 | 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.  | 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.

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**Notes:**
Page 59 - 60
All analyses done by external expert: 
Calvin Saravis, Ph:D. Harvard medical school

## 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

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## 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

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**Notes:**
Table 17 page 63

## AEs in patient with impaired cardiac function is lower than for not impaired patients

| Adverse Events in Patients with Impaired Functions Exposed to Optison |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 
Body System
 | Phase III Trials |  |  |  | All Trials (Ph. I, II & III) |  |  |  |
|  | Impaired |  | Not Impaired |  | Impaired |  | Not Impaired |  |
|  | No. | % | No. | % | No. | % | No. | % |
| CARDIAC IMPAIRMENT |  |  |  |  |  |  |  |  |
| 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 |

**Significant cardiac disease as documented by medical history; EF< 40%:**

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**Notes:**
Table 18 page 64

## 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 |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 
Body System
 | Phase III Trials |  |  |  | All Trials (Ph. I, II & III) |  |  |  |
|  | Impaired |  | Not Impaired |  | Impaired |  | Not Impaired |  |
|  | No. | % | No. | % | No. | % | No. | % |
| PULMONARY IMPAIRMENT |  |  |  |  |  |  |  |  |
| 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 |

**Respiratory diseases – COPD, emphysema, pulmonary hypertension, bronchiectasis**

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**Notes:**
Table 18 page 64

## Optison Post-Marketing Surveillance

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## 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

- OPTISON

- June 24, 2008

**Notes:**
Journal of the American College of CardiologyVolume 29, Issue 5, April 1997, Pages 994-999  Font Size:     

## 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 anti-histamins 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)
Heparin used and patient recovered | Unknown  |
| 0402s-000325 Feb’04 | Hypoxia | Hypoventilation prior to Optison and 1 day post-op CABG | Unrelated |
| 0508s-0006
31 Aug’05 | Dyspnea exacerbation | Multiple co-morbidities and multiple drug sensitivities. Underwent dobutamine stress echo resulted in increased shortness of breath | Unknown |

- *Defined by the reporter of event

- OPTISON

- June 24, 2008

## 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

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- June 24, 2008

## “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.”

- “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

- OPTISON

- June 24, 2008

## Optison Literature

- OPTISON

- June 24, 2008

## Review of clinical literature 1998-2008

-  975 ICU patients: chest pain & no ST-elevation
-  3 ml Optison
-  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

| Variable | Pre-Optison | Post-Optison | P-value |
| --- | --- | --- | --- |
| 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 |

- 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

- * Report on safety data not previously published

- OPTISON

- June 24, 2008

## 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.

- OPTISON

- June 24, 2008

**Notes:**
ASA IV
Patients have severe systemic disease that limits activity and is a constant threat to life.  Patients are unable to walk up one flight of stairs or two level city blocks.  Distress is present even at rest. Patients pose significant risk since patients in this category have a severe medical problem of greater importance to the patient than the planned dental treatment.  Whenever possible, elective dental care should be postponed until such time as the patient's medical condition has improved to at least an ASA III classification.  This classification represents a "red flag" ‐ a warning flag indicating that the risk involved in treating the patient is too great to allow elective care to proceed.  Examples: History of unstable angina pectoris, myocardial infarction or cerebrovascular accident within the last six months, severe congestive heart failure, moderate to severe chronic obstructive pulmonary disease, and uncontrolled diabetes, hypertension, epilepsy, or thyroid condition. If emergency treatment is needed, medical consultation is indicated.

## 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)
-   All patients receiving contrast were routinely     observed for at least 30 min
-  Patient groups were similar
-  Methods of identifying adverse events were        comparable
-  No adverse events after Optison
-  20 Adverse events after Definity of which 4    were serious:	- 65% had history of allergy	- 65% were women	- Causal relationship uncertain

| Patient population | Definityn=1297481% | Optisonn=305119% |
| --- | --- | --- |
| Indication for resting echo:
LV function
WM abnormalities
Right heart function/ pulmonary hypertension
Valvular disease | 
10764 
2522
1768
1304 | 
2447
558
377
334 |
| ICU patients | 2431 | 520 |
| Estimated Pulmonary artery pressure > 35 mmHg | 1882 | 440 |

- Overall rate of Adverse Events was low

- OPTISON

- June 24, 2008

**Notes:**
ASA IV
Patients have severe systemic disease that limits activity and is a constant threat to life.  Patients are unable to walk up one flight of stairs or two level city blocks.  Distress is present even at rest. Patients pose significant risk since patients in this category have a severe medical problem of greater importance to the patient than the planned dental treatment.  Whenever possible, elective dental care should be postponed until such time as the patient's medical condition has improved to at least an ASA III classification.  This classification represents a "red flag" ‐ a warning flag indicating that the risk involved in treating the patient is too great to allow elective care to proceed.  Examples: History of unstable angina pectoris, myocardial infarction or cerebrovascular accident within the last six months, severe congestive heart failure, moderate to severe chronic obstructive pulmonary disease, and uncontrolled diabetes, hypertension, epilepsy, or thyroid condition. If emergency treatment is needed, medical consultation is indicated.

## Future Use of ContrastVascular

- OPTISON

- June 24, 2008

## Need for improved management and non-invasive diagnosis of cardiovascular disease

-  1.2 million Heart Attacks
-  700,000 strokes
-  240,000 TIAs
-  CVD is no 1 reason in hospital discharges

*Anterior difficult **w/o contrast*

*Anterior walls **w/ contrast*

- *Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007

- OPTISON

- June 24, 2008

**Notes:**
Shape: 
est 875 000 first AMI and 500 000 recurrent attacks. In 2002 657k deaths due to heart attacks and stroke  657 – 164 = 400 000 deaths due to AMI
ACCF/SCAI/SVMB/SIR/ASITN 2007 clinical expert on stenting:
500 000 new strokes and 200 000 recurrent strokes

## 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

- OPTISON

- June 24, 2008

## Future use of vascular U/S contrast could play a significant  role in CVD management

- Enhancement of the carotid artery luminal morphologyin patients with known or suspected carotid artery stenosis
- 2. 	Improved resolution of c-IMT for CV risk assessment in patients with riskfactors...monitoring of treatment
- 3. 	Identification of arterial wall neo-vascularization (vasa vasorum) in patientswith known stenosis

*Anterior difficult **w/o contrast*

*Anterior walls **w/ contrast*

- OPTISON

- June 24, 2008

**Notes:**
Facts about CV disease
est 875 000 first AMI and 500 000 recurrent attacks. In 2002: 164k deaths due to stroke,  400 000 deaths due to AMI
500 000 new strokes and 200 000 recurrent strokes

CAE: carotid endarterectomy
CAS: carotid arterial stenting

Costs
We have only got input on costs from clinical. There may be additional costs for project management, regulatory work, technical work: I have not asked about that specifically. To be sure about no negative surprises I/we should bring this up with MD Management/Finance. My best guess is that we may end up with 50% of another man-year. 

Upstream marketing costs:
2007: animal work 7k + IMT Feinstein study 25k
2008: TPP and market forecasting validation: Advisory meeting
2009/2010: Reimbursement, health economic work, positioning and segmentation market research

## Enhancement of the carotid artery luminal morphology

- OPTISON

- June 24, 2008

## Identification of arterial wall neo-vascularization (vasa vasorum)

- OPTISON

- June 24, 2008

## Identification of arterial wall neo-vascularization (vasa vasorum)

- Courtesy:Hans-Peter Weskott, Hannover, Germany

- OPTISON

- June 24, 2008

## 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)

- OPTISON

- June 24, 2008

## 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

- OPTISON

- June 24, 2008