DEFINITY

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DEFINITY

• Perflutren Lipid Microsphere Injectable
  Suspension
• FDA Advisory CommitteeMicrobubble Contrast
  AgentsWashington DCJune 24, 2008

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Clinical and Post-marketing SafetyMichael Main,
MDMedical Director, Echocardiography
LaboratorySaint Lukes Mid-America Heart
InstituteKansas City, MONon-clinical
SafetySimon Robinson, PhDSenior Director
Pre-Clinical DiscoveryLantheus Medical
ImagingBillerica, MA
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Overview

• Clinical trials
• Special population and placebo controlled studies
  provide value in understanding safety, as
  exemplified by DEFINITY trials
• Non-clinical safety studies
• Animal models can be useful at different stages
  of development to demonstrate safety, as shown
  with DEFINITY studies when compared to clinical
  trials
• Post-marketing safety surveillance
• Going beyond spontaneous reporting, large
  retrospective database mining is valuable to
  demonstrate and understand the safety of contrast
  agents, as exemplified by DEFINITY
• Overall, the data show DEFINITY enhanced
  echocardiography provides a diagnostic test with
  a positive benefit-risk profile

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DEFINITY Background

• Approved in U.S. in 2001 following extensive
  non-clinical and clinical programs
• for use in patients with suboptimal
  echocardiograms to opacify the left ventricular
  chamber and to improve the delineation of the
  left ventricular endocardial border.
• Vial contains PFP and blend of three endogenous
  lipids (one conjugated to MPEG) that is activated
  by rapid agitation
• DEFINITY dosing I.V. bolus and infusion (1.3ml
  max) over 30-60 sec
• According to AMR data, approximately 2 million
  patients have been dosed since product launch

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Clinical Safety
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DEFINITY Clinical Trials

• 48 pre and post-approval clinical trials
• 26 echocardiography,12 abdominal US (liver,
  kidney), 8 special safety assessment/PK, 2
  retrospective safety evaluation
• 27 in NDA 40 in EU Marketing Authorization
  Application 8 post-MAA
• 5 pivotal studies in echocardiography (359
  DEFINITY treated 42 placebo subjects)
• 3 pivotal studies in abdominal US (309 DEFINITY
  treated)
• 3,985 subjects
• 3,616 with at least one dose of DEFINITY
• 369 placebo
• ? DEFINITY has been extensively studied in
  clinical trials

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Adverse Events in Clinical Trials

• Serious Adverse Events
• Total 34 - all reported as unrelated to
  DEFINITY
• 8 (0.2) fatal outcomes all gt24 hr after DEFINITY
  administration
• All occurred at least 35 hours after DEFINITY
  dosing (35 hours, 4, 5 (2), 7, 12 (2) and 15
  days)
• All gt58yo with underlying medical conditions
  and/or complications from surgical procedures
• Except 33-year old man with heart transplant
• Most had serious cardiac illnesses and/or cancer
• Frequency of SAEs in clinical trials 1

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Adverse Events in Clinical Trials

• Adverse Events fully evaluated in 2,951
  subjects in 40 studies (MAA studies)
• 26 subjects had at least one AE
• 7.6 AE were reported as drug related
• The most common drug related AEs (gt1)
• Fatigue, headache, dyspnea, back pain, nausea,
  flushing, and dizziness
• No dose response relationship found with either
  bolus or infusion

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Adverse Events in Placebo Controlled Clinical
Trials

• Placebo-Controlled Studies
• 126 AE in 224 placebo subjects (56)
• 259 AE in 543 DEFINITY subjects (48)
• Profile of AEs are the same
• No clear difference between placebo and dosed
  groups
• Rest-Stress Placebo-Controlled Studies
• 106 AE in 168 placebo subjects (63)
• 194 AE in 345 DEFINITY subjects (56)
• 125 AE in 516 rest only subjects (24)
• ? AEs attributable to stress procedures, not
  DEFINITY

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Safety in Pivotal Studies

• AE rates DEFINITY-treated subjects in all pivotal
  studies
• 85/359 (24) in pivotal echocardiography
• 77/309 (25) in pivotal radiology
• AE rates in placebo-controlled pivotal
  echocardiography studies
• 11/42 (26) in placebo 49/169 (29) in DEFINITY
  group no significant difference
• AE Profile in pivotal studies is consistent with
  other DEFINITY studies
• No significant difference in AE rates between
  DEFINITY and placebo patients

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Overall Cardiovascular Evaluation

• ECG parameters
• PI describes 221 subjects with 64 (29) gt30msec
  increase in QTc
• Analysis performed for EMEA approval with
  aggregate data (n672) indicates no difference in
  change from baseline between placebo and DEFINITY
  groups
• Premature ventricular beats
• Retrospective evaluation of 75 subjects exposed
  to a variety of US imaging protocols indicates
  DEFINITY did not produce premature beats
• US PI recommends Mechanical Index of lt 0.8
• Systemic Arterial Pressure (from all Registration
  studies)
• Frequency of transient hypertension or
  hypotension lt 1
• No associated clinical sequelae
• ? Clinical trials did not reveal evidence of
  systemic or hemodynamic compromise

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Electrocardiogram (ECG Analysis in 672 Subjects)
Change category Placebo Placebo Definity Dosed Definity Dosed
Total Subjects with ECG Data 191 (100) 481 (100)

Increase 30 msec 34 (18.6) 77 (16.9)
Decrease 30 msec 47 (25.7) 92 (20.2)
Both increase and decrease 0 1 (0.2)

Number () of Subjects with Percent Change in ECG Parameters 10 from Baseline Number () of Subjects with Percent Change in ECG Parameters 10 from Baseline Number () of Subjects with Percent Change in ECG Parameters 10 from Baseline Number () of Subjects with Percent Change in ECG Parameters 10 from Baseline Number () of Subjects with Percent Change in ECG Parameters 10 from Baseline
Ventricular rate 106 (57.9) 268 (58.6)
PR interval 138 (78.4) 344 (78.2)
QRS interval 137 (75.3) 355 (77.7)
QT interval 160 (87.4) 378 (82.9)
QTc interval 126 (68.9) 313 (68.6)
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Overall Cardiovascular Evaluation

• ECG parameters
• PI describes 221 subjects with 64 (29) gt30msec
  increase in QTc
• Analysis performed for EMEA approval with
  aggregate data (n672) indicates no difference in
  change from baseline between placebo and DEFINITY
  groups
• Premature ventricular beats
• Retrospective evaluation of 75 subjects exposed
  to a variety of US imaging protocols indicates
  DEFINITY did not produce premature beats
• US PI recommends Mechanical Index of lt 0.8
• Systemic Arterial Pressure (from all Registration
  studies)
• Frequency of transient hypertension or
  hypotension lt 1
• No associated clinical sequelae
• ? Clinical trials did not reveal evidence of
  systemic or hemodynamic compromise

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Assessment of Immune Response

• In a high dose safety study (50 ?l/kg) involving
  12 healthy and 12 COPD subjects
• No meaningful change
• IgA, E, G, and M, (blood)
• Total complement (CH50)
• Tryptase and histamine
• Transient increase C3a with 50 ?L/kg DEFINITY
• No anaphylactoid responses observed
• ? Independent immunologist concluded complement
  activation is not causing mast or basophil cell
  activation

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Safety Evaluation in Special Patient Populations

• COPD Patients
• Prospective study
• 12 COPD and 12 healthy subjects - bolus DEFINITY
  (50  ? L/kg).
• Lung clearance of PFP rapid (t ½ 1-2 min) and
  similar in both groups
• No SAEs were reported
• AEs were reported 7/12 for COPD and 4/12 for
  healthy group
• DEFINITY related AEs 1/12 for COPD vs 3/12 for
  healthy group
• Integrated Summary of Safety Analyses
• 46 of 765 patients in 12 echocardiography studies
  were identified with COPD
• AEs were reported in 29.3 of COPD vs 32.5
  non-COPD
• DEFINITY related AEs 7.6 in non-COPD and 6.5
  in COPD patients
• ? AE frequency not increased in COPD patients and
  no new AE types observed

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Safety Evaluation in Special Patient Populations

• Mechanical Ventilation Study (n38)
• No clinically significant abnormalities reported
• Arterial O2 saturation, temperature, ETCO2 BP,
  HR, CVP, PCWP
• Heart Failure Study (n211)
• No SAEs observed
• Overall incidence of new-onset AE was not
  statistically different between DEFINITY and
  Placebo treated patients
• Acute Myocardial Infarction Study (n100)
• One SAE, mild chest pain, 2 days after dosing
• Not drug related
• New-onset AE rate observed in subjects with acute
  MI was low (14)
• 5 Drug related AE
• ? AE rate not increased in Special Patient
  population and no new AE types observed

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Peer-Reviewed PublicationsSafety Information

• Clinical Studies 52 publications described
  DEFINITY use
• 23,772 patients
• 21,573 echocardiography
• 2,199 radiology
• Four publications and 1 case report provide
  safety data (n1836)
• DEFINITY was generally well tolerated
• AE rates reported are similar to clinical trial
  rates
• One SAE reported (lt0.1) patient recovered
• 83 yo female sepsis, AF, hypovolemic, pacemaker,
  CAD, DM, GI bleed, meningitis
• Developed hemodynamic instability, respiratory
  distress, rapid AF 3 min post dosing
• Presumptive treatment for anaphylaxis with
  Benadryl, sepsis with antibiotics and hypovolemia
  with fluids

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Clinical Trial Perspective

• Overall Clinical Findings
• Low SAE rate (1) despite patient population with
  multiple co-morbidities including cardiac and
  oncologic diseases
• No dose response relationship noted for AEs
• Placebo Controlled Studies
• Demonstrated majority AE were not DEFINITY
  related
• AE rate is higher in rest/stress studies but
  similar between placebo and DEFINITY groups
• Special Studies
• AE rate not increased in Special Patient
  Populations (COPD, mechanical ventilation, acute
  MI, HF)
• No increase in cardiovascular effects
• Efficacy
• Demonstrated efficacy for Left Ventricular
  Opacification and Endocardial Border Delineation
• ? DEFINITY has a positive benefit/risk profile in
  a variety of clinical settings and patient
  populations

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Non-Clinical Safety
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Safety Pharmacology and Toxicology General
Findings

• Cardiovascular Safety (dogs)
• No cardiopulmonary effects at up to 25x clinical
  dose
• Respiratory rate, PAP, AP and cardiac
  contractility effects at higher doses
• Toxicology (rat and primate)
• Clinical signs seen (15 X rat, 50X primate) high
  multiple clinical dose consistent with
  cardiopulmonary effects
• Effects influenced by dose rate
• ? Safety margin consistent with safe clinical use
  at recommended dose levels

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Mechanism Behind Clinical Signs

• Primate (150x clinical dose)
• Clear clinical signs following high DEFINITY dose
  
• No meaningful change in hematology parameters or
  plasma levels of histamine, tryptase or
  complement (SC5b-9)
• Abnormal electrocardiographic changes, including
  ST-T segment depression followed by cardiac
  arrhythmias within 1 minute
• Suggest transient myocardial ischemia not an
  anaphylactoid response
• Pig- Literature reports (Grauer et al 1996,
  Chantal et al 2005)
• Clinical dose of DEFINITY
• mild and transient pulmonary artery pressure
  change
• no change in Heart rate, systemic pressure,
  partial pressure of oxygen, or left ventricular
  systolic function.
• Pulmonary intravascular macrophage make pig good
  for screening for possible risk but less valuable
  for mechanism studies
• ? Non-clinical testing suggests frequent
  anaphylactoid mediated events at clinical dose
  are unlikely. Consistent with clinical experience

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Disease Model Testing

• Occlusion microcirculation
• Examined by intravital microscopy in rat
  spinotrapezius muscle
• Low proportion (1.2) microspheres transiently
  (85 dislodged by 10 min) retained
  microcirculation
• No detrimental effect regional microcirculation
  even at 40X clinical dose
• Pulmonary hypertension model
• Dogs administered sephadex microspheres to induce
  either moderate (15mm Hg) or severe(30 mm Hg)
  acute pulmonary hypertension.
• DEFINITY 10X clinical dose did not influence
  cardiac or pulmonary function.
• ? Consistent with clinical testing in COPD
  subjects

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Disease Model Testing

• Mechanical ventilation
• DEFINITY (25X clinical dose) did not influence
  cardiopulmonary parameters in mechanically
  ventilated anaesthetized dogs
• Persistence of DEFINITY in the circulation was
  not changed by mechanical ventilation
• ? Consistent with clinical testing in
  mechanically ventilated patients
• Bioeffects
• Literature reports of cellular and tissue effects
  with combinations of high contrast agent/ high
  Mechanical Index and extended ultrasound exposure
• Low dose of DEFINITY in combination with low
  Mechanical Index and short durations of scan in
  any particular plane will mitigate the potential
  to produce microscale bioeffects.
• ? Clinical findings have suggested no bioeffect
  issues with DEFINITY with ALARA approach

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Perspective

• Non-clinical / Early Clinical
• Use disease models to assess theoretical risks
  with new classes of agents (i.e. pulmonary
  hypertension, mechanical ventilation)
• Late Clinical
• Use in vitro/in vivo models in support of
  clinical observations from trials to help address
  identified issues
• Post Marketing
• Use in vitro/in vivo systems to examine
  mechanisms/pathways involved in safety concerns
  identified from clinical usage

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Post Marketing Experience
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DEFINITY POST MARKETING SAFETY EVALUATION

• Post Marketing Spontaneous Reporting
• In accordance with CFR
• Single-center Safety Outcomes Studies
• Herzog et al, JAMA, 2008
• Kusnetsky et al, JACC, 2008
• Multi-center Safety Outcomes Database
• Premier Perspective DB (submitted JACC, 2008)

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Summary of Post Market Experience

• Studies
• Approximately 2 million administered doses based
  on Arlington Medical Resources database
• Use (approximate)
• 60 resting and 40 stress echocardiography
• 67 inpatients and 33 outpatients
• Location
• Majority of use in the USA
• Other regions include Canada, EU, Australia
  Latin America

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Spontaneous SAE Reports

• December 2000 through December 2007
• 277 patients with SAEs (0.014)
• 14 fatalities 7 (within 30 minutes of dosing)
• Patients who died mostly critically ill and
  unstable
• Type
• 91 serious cardiopulmonary events (61 cases,
  including data through April 2008)
• 106 serious hypersensitivity cases
• Frequency of SAE appears low (0.01) and often
  occurs in medically complex patients
• Spontaneous reports provide SAE profile but do
  not assess impact of pseudocomplications

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Pseudocomplications

• Adverse events occurring in association with a
  medical procedure may be due to either the
  procedure or the underlying disease state
  (pseudocomplication) (Hildner et al, 1973
  Hildner et al, 1982 Main et al 2007)
• DEFINITY is often used in patients with serious
  underlying heart disease and other co-morbidities
• Important to distinguish pseudocomplications from
  DEFINITY related effects to understand true
  adverse event rates

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Risks with Alternative Diagnostic Modalities

• Cardiac angiography mortality rate 1/1000
• Exercise test mortality or MI rate 1/2500
• Lifetime rate of fatal malignancy from SPECT/ or
  RVG 1/1000 1/10,000
• TEE causal mortality rate 1/10,000
• DEFINITY contrast echo estimated associated rate
  of serious event 1/10,000 and mortality
  1/100,000
• ? Contrast echocardiography risk appears lower
  than commonly utilized alternatives

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Single Institution Safety Assessment

• Herzog, JAMA 2008
• Hennepin County Medical Center, Minneapolis, MN
• Study Design - retrospective
• 12,975 DEFINITY enhanced echos
• All AEs documented by nursing staff reviewed
• Electronic charts abstracted and relationship to
  DEFINITY adjudicated
• Non-fatal complications attributable to stress
  testing excluded
• Results for AEs occurring within 30 min
• AE rate 0.12
• SAE rate 0.03
• No fatalities
• ? SAE frequency low and similar to spontaneous
  reporting

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Single Institution Safety Assessment

• Kusnetsky et al., JACC, 2008
• St Lukes Health System, Kansas City, MO
• Study design - retrospective
• 18,671 echocardiogram patients identified from
  Jan 2005 - Oct 2007
• 12,475 non-contrast echos 6,196 DEFINITY
  enhanced echos
• Vital status within 24 hours of echo reviewed
  from records
• Results Mortality within 24 hours
• Non-contrast 0.37
• DEFINITY enhanced 0.42 (p0.6)
• DEFINITY patients had higher clinical acuity and
  more co-morbidity than non-contrast patients
• ? No increased risk of fatality associated with
  DEFINITY
• ? Ambient short term (24 hour) mortality rate in
  hospitalized patients undergoing echocardiography
  0.4

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Multi-Center Safety Outcomes Database

• Main et al, JACC 08, submitted
• Premier Perspective DB (hospital claims data)
  Jan 1, 02 - Oct 31, 07
• Study Design - retrospective
• 4,300,966 resting transthoracic echo exams
  identified
• 4,242,712 non-contrast echos
• 58,254 DEFINITY enhanced echos
• Analysis
• Severity of illness and risk of mortality
  variables were calculated using 3M APR-DRG
  Software
• All cause 1-day mortality available for all
  patients
• Multivariate logistic regression compared 24 hour
  mortality for non-contrast vs. DEFINITY,
  controlling for case mix covariates

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Multi-Center Safety Outcomes Database

• Results
• Mortality rates
• 1.08 for non-contrast echos (n45,789/4,242,712)
  
• 1.06 for DEFINITY enhanced echos (n616/58,254)
  (p0.613)
• Multivariate logistic regression analysis
• DEFINITY enhanced echocardiography was associated
  with a 24 statistically significant reduction in
  mortality
• Risk adjusted odds ratio 0.76 (95 CI
  0.70-0.82)
• ? Decreased risk-adjusted mortality rate observed
  in patients receiving DEFINITY
• ? Background 1-day mortality rate of 1 among an
  inpatient population

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PostMarketing Safety Summary

• Spontaneous Reporting
• Demonstrated a low SAE reporting frequency
  (0.01)
• Confounded by pseudocomplications
• Herzog report
• Suggests low AE (0.12) and SAE (0.03)
  frequencies
• SAE rate similar to spontaneous reporting
• Kusnetsky report and Premier Perspective DB
• Indicate DEFINITY is used in patient population
  with high ambient mortality rate (0.4 to 1)
• No increased risk of fatality associated with
  DEFINITY

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Perspective

• Low event frequency implies
• Need extremely large subject population to
  quantify in prospective studies
• Need control/ background population to identify
  agent involvement
• Based on our experiences, requires assessment of
  large institution / outcome databases
• Safety Surveillance Approaches
• Database mining to identify safety in
  sub-populations
• Evaluated periodically post approval for
  significant trends
• Findings incorporated into Medical Association
  Guidelines
• Appropriate safety information incorporated into
  product labeling

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Summary

• Clinical trials
• Special population and placebo controlled studies
  provide value in understanding safety, as
  exemplified by DEFINITY trials
• Non-clinical safety studies
• Animal models can be useful at different stages
  of development to demonstrate safety, as shown
  with DEFINITY studies when compared to clinical
  trials
• Post-marketing safety surveillance
• Going beyond spontaneous reporting, large
  retrospective database mining is valuable to
  demonstrate and understand the safety of contrast
  agents, as exemplified by DEFINITY
• Overall, the data show DEFINITY enhanced
  echocardiography provides a diagnostic test with
  a positive benefit-risk profile

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