DEFINITY .


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Clinical and Post-showcasing Safety Michael Main, MD Medical Director, Echocardiography Laboratory Saint Luke\'s Mid-America Heart Institute Kansas City, MO Non-clinical Safety Simon Robinson, PhD Senior Director Pre-Clinical Discovery Lantheus Medical Imaging Billerica, MA. . Diagram. Clinical trialsSpecial populace and fake treatment controlled studies give esteem in comprehension wellbeing, as exe
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DEFINITY® Perflutren Lipid Microsphere Injectable Suspension FDA Advisory Committee Microbubble Contrast Agents Washington DC June 24, 2008

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Clinical and Post-showcasing Safety Michael Main, MD Medical Director, Echocardiography Laboratory Saint Luke\'s Mid-America Heart Institute Kansas City, MO Non-clinical Safety Simon Robinson, PhD Senior Director Pre-Clinical Discovery Lantheus Medical Imaging Billerica, MA

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Overview Clinical trials Special populace and fake treatment controlled reviews offer some benefit in comprehension wellbeing, as exemplified by DEFINITY trials Non-clinical security concentrates Animal models can be helpful at various phases of improvement to exhibit security, as appeared with DEFINITY thinks about when contrasted with clinical trials Post-promoting wellbeing observation Going past unconstrained announcing, vast review database mining is profitable to exhibit and comprehend the wellbeing of difference operators, as exemplified by DEFINITY Overall, the information demonstrate DEFINITY upgraded echocardiography furnishes a symptomatic test with a positive advantage hazard profile 3

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DEFINITY Background Approved in U.S. in 2001 after broad non-clinical and clinical projects "for use in patients with imperfect echocardiograms to opacify the left ventricular chamber and to enhance the outline of the left ventricular endocardial fringe." Vial contains PFP and mix of three endogenous lipids (one conjugated to MPEG) that is enacted by fast unsettling DEFINITY dosing I.V. bolus and mixture (1.3ml max) more than 30-60 sec According to AMR information, around 2 million patients have been dosed since item dispatch

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Clinical Safety

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DEFINITY Clinical Trials 48 pre and post-endorsement clinical trials 26 echocardiography,12 stomach US (liver, kidney), 8 extraordinary wellbeing appraisal/PK, 2 review security assessment 27 in NDA; 40 in EU Marketing Authorization Application; 8 post-MAA 5 essential reviews in echocardiography (359 DEFINITY treated; 42 fake treatment subjects) 3 crucial reviews in stomach US (309 DEFINITY treated) 3,985 subjects 3,616 with no less than one dosage of DEFINITY 369 fake treatment  DEFINITY has been broadly contemplated in clinical trials

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Adverse Events in Clinical Trials Serious Adverse Events Total 34 - all announced as "irrelevant" to DEFINITY 8 (0.2%) deadly results all >24 hr after DEFINITY organization All happened no less than 35 hours after DEFINITY dosing (35 hours, 4, 5 (2), 7, 12 (2) and 15 days) All >58yo with basic therapeutic conditions as well as intricacies from surgical methodology Except 33-year old man with heart transplant Most had genuine heart ailments and additionally malignancy Frequency of SAEs in clinical trials ~1%

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Adverse Events in Clinical Trials Adverse Events – completely assessed in 2,951 subjects in 40 thinks about (MAA ponders) 26% subjects had no less than one AE 7.6% AE were accounted for as medication related The most well-known medication related AEs (>1%) Fatigue, migraine, dyspnea, back torment, queasiness, flushing, and wooziness No measurement reaction relationship found with either bolus or implantation

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Adverse Events in Placebo Controlled Clinical Trials Placebo-Controlled Studies 126 AE in 224 fake treatment subjects (56%) 259 AE in 543 DEFINITY subjects (48%) Profile of AEs are the same No reasonable contrast amongst fake treatment and dosed gatherings Rest-Stress Placebo-Controlled Studies 106 AE in 168 fake treatment subjects (63%) 194 AE in 345 DEFINITY subjects (56%) 125 AE in 516 rest just subjects (24%)  AEs owing to stress techniques, not DEFINITY

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Safety in Pivotal Studies AE rates DEFINITY-treated subjects in all vital reviews 85/359 (24%) in critical echocardiography 77/309 (25%) in urgent radiology AE rates in fake treatment controlled vital echocardiography studies: 11/42 (26%) in fake treatment; 49/169 (29%) in DEFINITY bunch; no huge distinction AE Profile in vital reviews is reliable with other DEFINITY concentrates No huge distinction in AE rates amongst DEFINITY and fake treatment patients

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Overall Cardiovascular Evaluation ECG parameters PI portrays 221 subjects with 64 (29%) >30msec increment in QTc Analysis performed for EMEA endorsement with total information (n=672) demonstrates no distinction in change from standard amongst fake treatment and DEFINITY bunches Premature ventricular thumps Retrospective assessment of 75 subjects presented to an assortment of US imaging conventions shows DEFINITY did not deliver untimely pulsates US PI prescribes Mechanical Index of < 0.8 Systemic Arterial Pressure (from all Registration considers) Frequency of transient hypertension or hypotension < 1% No related clinical sequelae  Clinical trials did not uncover confirmation of systemic or hemodynamic trade off

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Electrocardiogram (ECG Analysis in 672 Subjects)

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Overall Cardiovascular Evaluation ECG parameters PI depicts 221 subjects with 64 (29%) >30msec increment in QTc Analysis performed for EMEA endorsement with total information (n=672) demonstrates no distinction in change from benchmark amongst fake treatment and DEFINITY bunches Premature ventricular pulsates Retrospective assessment of 75 subjects presented to an assortment of US imaging conventions shows DEFINITY did not create untimely thumps US PI suggests Mechanical Index of < 0.8 Systemic Arterial Pressure (from all Registration examines) Frequency of transient hypertension or hypotension < 1% No related clinical sequelae  Clinical trials did not uncover proof of systemic or hemodynamic bargain

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Assessment of Immune Response In a high measurements wellbeing study (50  l/kg) including 12 solid and 12 COPD subjects No important change: IgA, E, G, and M, (blood) Total supplement (CH50) Tryptase and histamine Transient increment C3a with 50 L/kg DEFINITY No anaphylactoid reactions watched  Independent immunologist closed supplement initiation is not bringing on pole or basophil cell enactment

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Safety Evaluation in Special Patient Populations COPD Patients Prospective review 12 COPD and 12 sound subjects - bolus DEFINITY (50   L/kg). Lung leeway of PFP quick (t ½ 1-2 min) and comparable in both gatherings No SAEs were accounted for AEs were accounted for 7/12 for COPD and 4/12 for sound gathering DEFINITY related AE\'s 1/12 for COPD versus 3/12 for solid gathering Integrated Summary of Safety Analyses 46 of 765 patients in 12 echocardiography studies were related to COPD AEs were accounted for in 29.3% of COPD versus 32.5% non-COPD DEFINITY related AEs: 7.6% in non-COPD and 6.5% in COPD patients  AE recurrence not expanded in COPD patients and no new AE sorts watched

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Safety Evaluation in Special Patient Populations Mechanical Ventilation Study (n=38) No clinically noteworthy irregularities detailed Arterial O 2 immersion, temperature, ETCO 2 BP, HR, CVP, PCWP Heart Failure Study (n=211) No SAEs watched Overall frequency of new-onset AE was not measurably extraordinary amongst DEFINITY and Placebo treated patients Acute Myocardial Infarction Study (n=100) One SAE, mellow trunk torment, 2 days in the wake of dosing Not tranquilize related New-onset AE rate saw in subjects with intense MI was low (14%) 5% Drug related AE  AE rate not expanded in Special Patient populace and no new AE sorts watched

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Peer-Reviewed Publications: Safety Information Clinical Studies: 52 distributions depicted DEFINITY utilize 23,772 patients 21,573 echocardiography 2,199 radiology Four productions and 1 case report give wellbeing information (n=1836) DEFINITY was for the most part all around endured AE rates announced are like clinical trial rates One SAE revealed (<0.1%); persistent recuperated 83 yo female: sepsis, AF, hypovolemic, pacemaker, CAD, DM, GI drain, meningitis Developed hemodynamic precariousness, respiratory pain, fast AF 3 min post dosing Presumptive treatment for hypersensitivity with Benadryl, sepsis with anti-infection agents and hypovolemia with liquids

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Clinical Trial Perspective Overall Clinical Findings Low SAE rate (1%) notwithstanding tolerant populace with numerous co-morbidities including heart and oncologic maladies No measurements reaction relationship noted for AEs Placebo Controlled Studies Demonstrated dominant part AE were not DEFINITY related AE rate is higher in rest/stretch reviews however comparative amongst fake treatment and DEFINITY bunches Special Studies AE rate not expanded in Special Patient Populations ( COPD, mechanical ventilation, intense MI, HF) No expansion in cardiovascular impacts Efficacy Demonstrated adequacy for Left Ventricular Opacification and Endocardial Border Delineation  DEFINITY has a positive advantage/hazard profile in an assortment of clinical settings and patient populaces

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Non-Clinical Safety

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Safety Pharmacology and Toxicology; General Findings Cardiovascular Safety (canines) No cardiopulmonary impacts at up to 25x clinical dosage Respiratory rate, PAP, AP and heart contractility impacts at higher measurements Toxicology (rodent and primate) Clinical signs seen (15 X rodent, 50X primate) high various clinical dosage steady with cardiopulmonary impacts Effects affected by measurements rate  Safety edge predictable with safe clinical use at prescribed measurement levels

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Mechanism Behind Clinical Signs Primate (150x clinical measurement) Clear clinical signs taking after high DEFINITY dosage No significant change in hematology parameters or plasma levels of histamine, tryptase or supplement (SC5b-9) Abnormal electrocardiographic changes, including ST-T portion despondency took after via heart arrhythmias inside 1 minute Suggest transient myocardial ischemia not an anaphylactoid reaction Pig-Literature reports (Grauer et al 1996, Chantal et al 2005) Clinical dosage of DEFINITY gentle and transient pneumonic corridor weight change no adjustment in Heart rate, systemic weight, halfway weight of oxygen, or left ventricular systolic capacity. Aspiratory intravascular

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