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FDA Advisory Committee Meeting “Safety Considerations in the Development of Ultrasound Contrast Agents” June 24, 2008

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FDA Advisory Committee Meeting “Safety Considerations in the Development of Ultrasound Contrast Agents” June 24, 2008. Nonclinical Development Program: SonoVue ® Patricia D. Williams, PhD Chief Operating Officer Summit Drug Development, LLC Rockville, MD. Pharmacology studies

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FDA Advisory Committee Meeting“Safety Considerations in the Development of Ultrasound Contrast Agents”June 24, 2008

Nonclinical Development Program: SonoVue®

Patricia D. Williams, PhD

Chief Operating Officer

Summit Drug Development, LLC

Rockville, MD

nonclinical development program sonovue
Pharmacology studies

Toxicology studies

Studies on concurrent SonoVue administration and ultrasound exposure at high acoustic pressure

Retrospectively (after anaphylactoid reactions were observed in humans) potential mechanisms of these reactions were studied in vitro and in vivo

Nonclinical Development Program: SonoVue
pharmacology studies sonovue
Imaging Studies to define the expected human dose of SonoVue (pig, dog)

Safety pharmacology studies at multiples of human imaging doses (MHDbsa) 3 (mouse), 5 (rat), 10 (rabbit), 18 (dog), 200 (monkey):

- Cardiovascular (dog, monkey)

- Respiratory (rat, rabbit)

- CNS (mouse)

- Gastrointestinal (rat)

- Renal (rat)

Pharmacology Studies: SonoVue
key findings safety pharmacology studies sonovue
CONSCIOUS DOGS:

- No cardiovascular effects at 0.3 mL/kg (10-times clinical dose)

- At 1.0 mL/kg transient hypotension in 2/7 dogs

ANESTHETIZED DOGS (Pulmonary Hypertension model):

- Transient and minimal (2.5 ± 1.3 mmHg) increase in

PAP at 1 mL/kg

No other significant Cardiovascular, CNS, Respiratory, GI or Renal findings in mouse, rats, rabbits, monkeys

Key Findings Safety Pharmacology Studies: SonoVue
toxicology studies sonovue
Intravenous bolus administration

Clinical formulation used

Max doses 27-54 times the human dose (MHDbsa)

Single dose studies (rat, monkey)

4-week repeated dose studies (rat, monkey)

Genetic toxicology

Reproductive toxicology (rat, rabbit)

Other studies (local tolerance; blood compatibility)

Toxicology Studies: SonoVue
key findings toxicology studies sonovue
No significant findings in single and repeat dose studies up to the dose of 5 mL/kg (rat, monkey)

Repeat dose NOEL in monkeys 5 mL/kg (50 MHDbsa)

Cecum lesions in rats: considered rodent specific and observed with other contrast agents; otherwise NOEL 5 mL/kg

No signs of immunological reactions in either species (thymus, spleen, lymph nodes)

No lung lesions or emboli in either species

No brain lesions after direct injection in carotid artery in rats (1 mL/kg)

Key Findings Toxicology Studies: SonoVue
studies with sonovue and concurrent ultrasound exposure
RATS: No histological lesions in organs with SonoVue (1 and 5 mL/kg) and exposed to ultrasound at high acoustic pressure (up to MI 1.9)

DOGS: No effect of ultrasound exposure (up to MI 1.2) on ECG (QTc) and on heart histopathology in conscious dogs administered with SonoVue (up to 1 mL/kg)

Studies With SonoVue and Concurrent Ultrasound Exposure
conclusion of the nonclinical animal studies on sonovue
SonoVue was well tolerated in standard toxicological and safety pharmacology studies when administered alone or with concurrent ultrasound exposure

Cardiovascular effects (transient hypotension) observed only at very high doses in dogs (1 mL/kg)

Nonclinical study results corroborated the overall safety profile of SonoVue in humans

Conclusion of the Nonclinical Animal Studies on SonoVue
mechanism of anaphylactoid reactions
Low incidence (~ 0.01%) of allergic-like (anaphylactoid) reactions in humans found in post-marketing surveillance

 Additional in vitro and animals studies were designed to investigate potential mechanism(s) of these reactions

Mechanism of Anaphylactoid Reactions
mechanism of anaphylactoid reactions10
Hypothesis: allergic-like (anaphylactoid) reactions are related to the particulate nature of ultrasound contrast agents

Cardiopulmonary studies at imaging dose in pigs

Cardiovascular studies at very high doses in rats

In vitro complement activation (pig, human)

In vitro basophil activation (human)

Mechanism of Anaphylactoid Reactions
the use of the pig pros cons
Common large animal used in echocardiography (eg. size of heart ~ human)

Known to have severe reactions to injection of particulates

Have high concentrations of pulmonary intravascular macrophages (PIMs) relative to other species including humans

Imaging studies of UCA in pigs are routinely done with pretreatment with indomethacin or aspirin

While useful for imaging, pig not considered as an animal model for safety pharmacology studies due to its over-reaction to all injected particles, however…

Based on rare human reactions, Bracco pursued studies in naïve pigs to possibly gain insight into the mechanism of these anaphylactoid reactions

The Use of the Pig: Pros & Cons
changes in pap and sap in pigs following sonovue and other ucas at imaging doses

Product B at 0.03 mL/kg

Injection

NAF 216

100

90

80

SAP

(mm Hg)

70

60

50

Blood pressure

40

30

20

PAP

10

0

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Time (s)

Product C at 0.01 mL/kg

Injection

NAF 39

100

90

80

(mm Hg)

70

SAP

60

50

Blood pressure

40

30

PAP

20

10

0

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Time (s)

Changes in PAP and SAP in Pigs Following SonoVue, and other UCAs at Imaging Doses
thromboxane release parallels pap increase with sonovue and another uca
Thromboxane Release Parallels PAP Increasewith SonoVue and another UCA

Kinetics of pulmonary arterial pressure and TXB2 changes following SonoVue® or another UCA (Product B)injections in the pig at the human imaging dose (mean of 5 injections)

key findings mechanistic studies pig model
SonoVue and other marketed UCAs were tested on naïve, anesthetized pigs

Doses in the range of 1- 4x human imaging dose

↓ SAP ↑ PAP ↑ HR

↑ Airway resistance ↓ Lung compliance

Effects are dose and injection rate dependent

↑ Plasma Thromboxane B2

No detectable increases in C3a/C5a in vivo

Effects blocked by aspirin pretreatment

Effects similar to other injected particulates (liposomes, micellar lipids, etc)

Key Findings Mechanistic Studies: Pig Model
key findings mechanistic studies pig model16
Marked individual variation but consistent response in pigs at imaging dose of UCA

Pig shows sensitivity to SonoVue not seen in humans

Symptoms & cardiovascular effects resemble anaphylactoid reactions in humans

Release of vasoactive mediators considered key event in pigs

Relevance to humans unknown

Key Findings Mechanistic Studies: Pig Model
key findings mechanistic studies rat model
Transient hypotension observed  5 mL/kg (25 MHDbsa)

↑ Plasma thromboxane B2 (similar to pigs), however…

Hypotension NOT blocked by aspirin pretreatment (contrary to pigs)

Hypotension blocked by PAF-antagonist (ABT-491) pretreatment (contrary to pigs)

Hypotension blocked by complement depletion with cobra venom factor (CVF)

Rats & pig mechanisms may differ in mediators or target cells involved

Key Findings Mechanistic Studies: Rat Model
hypotension in rats only at high dose levels
Hypotension in Rats only at High Dose Levels

Systemic arterial blood pressure changes induced by a single administration of SonoVue in non-anesthetized rats (Dose levels correspond to 100 – 300 MHDbw or 17 – 50 MHDbsa)

key findings mechanistic studies in vitro complement and basophil activation
SonoVue and another UCA tested at very high dose levels show similar findings after incubation in vitro

Dose-dependent increase in C3a/C5a in pig plasma

Dose-dependent increase in C3a/C5a/SC5b-9 in human serum

No marked differences between pigs & humans in vitro

No effects on human basophil activation (CD203c)

Key Findings Mechanistic Studies: In Vitro Complement and Basophil Activation
summary of mechanistic studies sonovue
Symptoms observed in pigs are similar to human anaphylactoid reactions (cardiopulmonary changes)

Incidence of anaphylactoid reactions in pigs >>> humans

Sensitivity of pigs may be due to high density of PIMs relative to other species

Rats show hypotension at very high dose

Complement activation could be one of the mechanisms involved in the reactivity in rats, pigs and humans

Summary of Mechanistic Studies: SonoVue
sonovue lessons learned for future
SonoVue was well tolerated in nonclinical studies and this was corroborated by the clinical trials

The lack of cardiovascular effects of SonoVue in safety pharmacology studies at doses relevant to humans correlates with the lack of anaphylactoid reactions in clinical trials

Anaphylactoid reactions similar to humans are seen in naive pigs with various classes of particulate agents including UCA

Reactions in pigs attributed to high density of PIMs

The relevance of the findings in pigs to humans is unknown

SonoVue: Lessons Learned for Future
sonovue lessons learned for future22
In vitro complement activation may be an early triggering event in the reactions observed in humans and represents a potential screening tool

Bracco is incorporating in vitro and in vivo testing in selection of next generation products

Results in in vitro and in vivo models may be useful qualitatively but not quantitatively for risk assessment

The rare anaphylactoid reactions may be reduced through these screening efforts

SonoVue: Lessons Learned for Future
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