Overview of Current and future Contrast Agent and Statistical and design issues in clinical developm

1
Overview of Current and future Contrast
AgentandStatistical and design issues in
clinical development of contrast agents

• Kohkan Shamsi, MD, PhD
• President,
• Symbiotic Pharma Research
• Pine Brook, NJ, USA
• Former affiliation Berlex Inc, Montville, NJ

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Current Imaging Techniques

• X-rays
• Ultrasonography
• Computed Tomography (CT)
• Magnetic Resonance Imaging (MRI)
• Nuclear Medicine (SPECT/PET)
• combination e.g. PET-CT

3
Iodinated contrast agents

• Agents come in different concentrations
• Denoted by number after name (e.g. Ultravist 300)
• Number indicates mg iodine / mL of solution
• Different brands have different concentrations
  most common used conc. is 300mg/mL
• extensively used in Computer tomography
• Computer tomography is very widely used
  technique

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The MRI-Contrast Agents
MRI CM
Targeted/Intracellular CM
Blood-Pool CM
Targeted CM
Extracellular CM
Magnevist OMNISCAN Optimark
Protein-binding MS 325 BR 22
Hepatocyte-specific Primovist Multihance
Fibrin-targeted EP-2104
Gadovist 1.0
Macromolecular Gadomer P792
RES-specific Resovist
Plaque-imaging Gadofluorin
High-Reflexivity CM
RES-specific Feridex
USPIO Supravist Combidex
Approved in the USA Approved in Europe
Early Stage
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Gadolinium first MR contrast agent

• Magnevist was first MR contrast agent
• gt60 million injection experience
• gadolinium compounds are very safe

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MR Blood-Pool Agents
Ec
Iv
Ec
Ec
Iv
Ec
Ec
Ec
Iv
Ec
Ec
Iv
Ec
Ec
Ec
Iv
Ec
Ec
Iv
Extracellular Contrast Agents e.g. Magnevist
Intravascular Contrast Agents
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USPIO

• ltrasmall
• uper-
• aramagnetic
• ron
• xide particles,
• coated with
• carboxydextran
• Optimized formulation
• for T1 w-imaging (MRA)

U S P I O
SPIO
60 nm
7 000 nm
Erythrocyte
USPIO
20 nm
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Blood-Pool Agents Gd-Based
Gadolinium Chelates (Paramagnetic)
Strong Protein Binding
Macro-Molecules (no PB)
MS-325 SAG/Epix
Gadomer 17 Schering
P-792 Guerbet
B-22956/1 Bracco
No contrast agent has been approved by FDA for
MRA
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Potential indications for blood pool agents

• Potential indications
• MRA
• Cardiac
• Tumor angiogenesis
• Venography
• Open magnets (interventions)
• GI bleeding
• Neurological applications
• Whole body imaging
• Other?

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MS-325 enhanced MRI
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High resolution MRA imaging of vessel wall
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Targeted agentsfor cells and for structures
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Liver-specific MRI-CM

• Blackeners
• Imaging with T2-Effect
• Feridex (SPIO)
• Resovist (SHU 555 A)

• Whiteners
• Imaging with T1-Effect
• Multihance (Gd-BOPTA)
• Teslascan (Mn-DPDP)
• Primovist (Gd-EOB-DTPA)

Specific CM for Hepatocytes
Specific CM for RES
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Metastases
Mangofodipir trisodium (Mn-DpDp)
Pre T1-GRE
Pre FSE T2
Post Mn-DP T1-GRE
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Gd-BOPTA enhanced MRI and liver metastases
PRE-DOSE
Courtesy of R. Caudana,Verona, Italy
POST-DOSE
40 min
120 min
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Metastases Gd-EOB-DTPA enhanced MRI
Flash 3 D postinjection (10min) additional
metastasis (blue arrow)
T1 w precontrast
Courtesy of Prof. Hosten, Greifswald, Germany
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Hemangioma with hepatocyte specific contrast
agent (Gd-EOB-DTPA)
T1w
VIBE 20 min
VIBE art
T2w
VIBE pv
T1w 20 min
precontrast
hepatocyte phase
dynamic
page 16
Courtesy of C. Czech, Munich, Germany
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Resovist Lesion Detection
Pre T2
Pre T1
Metastases
Post T2
Robinson, MD, Leeds, UK
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Thrombus enhancing agent P-2104R Indications

• Pulmonary Embolism (PE)
• Deep venous thrombosis (DVT)
• Thrombus in left atrial appendage
• Venous coronary bypass grafts (CABG)
• Sinus vein thrombosis
• Mesenteric and portal thrombosis or emboli

thrombus
aorta
Plaque in Balloon-injured rabbits after
high-cholesterol(Mcdonanld) diet Courtesy
Johnstone et al, Beth Israel/Deaconess Medical
Center
1h
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Plaque imaging Gadofluorine M

• New water soluble, macrocyclic gadolinium
  chelates
• Micelle formation and longer half life, high
  relaxivity

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Plaque Imaging Gadofluorine M WHHL Rabbit
24 h post injection
IR turbo FLASH (300/4/120/20)
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Peripheral Nerve Imaging
Immune-Mediated Nerve Injury (EAN)
6d after EAN, 24h after Gadofluorine,thigh

• Potential applications
• Structural nerve damage in Polyneuropathies
• Nerve trauma,
• Visualization of the progress of Nerve
  regeneration

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Clinical trial design issues

• Dose finding in dynamic changing technology
  environment
• ? minimal effective dose identification that is
  based on development of machines
• Efficacy criteria sensitivity, specificity and
  accuracy vs. ROC
• ? interpretation of the data
• ? inter reader variability (kappa statistics)
• ? clinical practice vs. blinded read. FDA looks
  only at the BR data
• ? standard of reference (is usually old and is
  not really gold)
• ? lesion tracking across test modalities and SOR
• 3-4 efficacy evaluations for each patient (site
  evaluation 2-3 blinded reader evaluation) leads
  to multiple primary endpoints (e.g. 3
  sensitivities, 3 specificities and 3 accuracies
  lead to multiple permutation and combinations