Overview of Current and future Contrast Agent and Statistical and design issues in clinical development of contrast agents Kohkan Shamsi, MD, PhD President,

Overview of Current and future Contrast Agent

andStatistical and design issues in clinical

development of contrast agents

Kohkan Shamsi, MD, PhDPresident,

Symbiotic Pharma ResearchPine Brook, NJ, USA

Former affiliation: Berlex Inc, Montville, NJ

Current Imaging Techniques• X-rays

• Ultrasonography

• Computed Tomography (CT)

• Magnetic Resonance Imaging (MRI)

• Nuclear Medicine (SPECT/PET)

• combination e.g. PET-CT

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

The MRI-Contrast Agents

Extracellular CM Blood-Pool CMTargeted/

Intracellular CM Targeted CM

* MagnevistOMNISCAN

Optimark

+ Gadovist 1.0

Protein-bindingMS 325BR 22

MacromolecularGadomer

P792

High-Reflexivity CMUSPIO

SupravistCombidex

Hepatocyte-specific+ PrimovistMultihance

Fibrin-targetedEP-2104

RES-specific+ Resovist

Plaque-imagingGadofluorin

+ RES-specific* Feridex

MRI CM

* Approved in the USA

+ Approved in Europe

Early Stage

Gadolinium: first MR contrast agent

Magnevist was first MR contrast agent>60 million injection experience gadolinium compounds are very safe

MR Blood-Pool Agents

Extracellular Contrast Agentse.g. Magnevist

Intravascular Contrast Agents

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

Ec

IvIv

IvIv

Iv

Iv

USPIO

ltrasmall uper-aramagnetic ron xide particles,coated withcarboxydextran

Optimized formulation for T1 w-imaging (MRA)

USPIO

60 nm

20 nm

SPIO

7 000 nmErythrocyte

USPIO

Blood-Pool Agents Gd-Based

GadoliniumChelates

(Paramagnetic)

Strong Protein Binding Macro-Molecules (no PB)

MS-325SAG/Epix

B-22956/1Bracco

Gadomer 17Schering

P-792Guerbet

No contrast agent has been approved by FDA for MRA

Potential indications for blood pool agents

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

MS-325 enhanced MRI

High resolution MRA: imaging of vessel wall

Targeted agents

for cells and for structures

Liver-specific MRI-CM

“Whiteners“Whiteners“ Imaging with T1-Effect

Multihance® (Gd-BOPTA) Teslascan® (Mn-DPDP) Primovist ® (Gd-EOB-DTPA)

Specific CM for Hepatocytes

Specific CM for RES

“Blackeners“ Imaging with T2-Effect

Feridex® (SPIO) Resovist® (SHU 555 A)

Metastases

Pre T1-GRE

Post Mn-DP T1-GRE

Pre FSE T2

Mangofodipir trisodium (Mn-DpDp):

Gd-BOPTA enhanced MRI and liver metastases

PRE-DOSEPRE-DOSE

POST-DOSEPOST-DOSE

40 min40 min 120 min120 min

Courtesy of: R. Caudana,Verona, Italy

Metastases: Gd-EOB-DTPA enhanced MRI

T1 w precontrast Flash 3 D postinjection (10min)additional metastasis (blue arrow)

Courtesy of Prof. Hosten, Greifswald, Germany

Hemangioma with hepatocyte specific contrast agent (Gd-EOB-DTPA)

T1w VIBE art

T2w VIBE pv

VIBE 20 min

T1w 20 min

precontrast dynamic hepatocyte phase

Courtesy of C. Czech, Munich, Germany

page 17

Pre T1Pre T2

Post T2

Metastases

Resovist® Lesion Detection

Robinson, MD, Leeds, UK

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

aortaaorta

1h1h

thrombusthrombusPlaque in Balloon-injured rabbits after high-cholesterol(Mcdonanld) dietCourtesy :Johnstone et al, Beth Israel/Deaconess Medical Center

Plaque imaging: Gadofluorine M

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

Plaque Imaging Gadofluorine M WHHL Rabbit

IR turbo FLASH (300/4/120/20°)

24 h post injection

Immune-Mediated Nerve Injury (EAN)6d after EAN, 24h after Gadofluorine,thigh

Peripheral Nerve Imaging

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

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