The Challenge of Translating Molecular Imaging Agents to the Clinic

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The Challenge of Translating Molecular Imaging
Agents to the Clinic
Gregory M. Lanza MD PhD CTRAIN Washington
University Medical School St. Louis, MO
Conflicts Kereos, Inc. Co-founder Philips
Healthcare/Research Equipment support NIH Funding
(NCI, NHLBI, NAID)
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Drug Development Life Cycle Overview
IND FDA /IRB OVERSITE IND Active
Throughout Clinical Trials
No IND Clinical Hold
From Concept to Preclinical Testing
Phase III
IND Submitted to FDA 30-Day Review Prior to
Starting Clinical Study
NDA Approval To Market
Phase II
Phase I
START (No Clinical Hold)
GLP/GMP Pre-Clinical Development Testing / VV
Discovery Research
Human Clinical Testing
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Multidimensional Platform Technologies What to
develop for which indication?
Target Ligand to Fibrin (Ab, Fab,
peptides) Integrins (Ab, peptidomimetics,
peptides) Tissue Factor (Ab) Necl2 (Receptor)
Robo4 (Ab) Selectins, Notch (Ab)
Inherent Fluorine MRI/MRS
250 nm
Surface Metal Chelates Gd3 111In 99mTc 177Lu Eu
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Lipid coat inclusions Dyes (Rhodamine, Cypate,
FITC, AlexaFluor) Drugs (Fumagillin, Rapamycin,
Doxorubicin) Cytolytic Peptides
(Mellitin) Fibrinolytic enzymes
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Reproducible process chemistry for parts and
whole! Too complicated ?
Nanoparticles versus small molecules have a 3D
aspect all the parts there appropriately
oriented Each component must be GMP or
Pharmaceutical Grade Simplicity of
process Process scalability
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Drugable Chemistry, Process, and Anticipated
Drug Form
Chiral centers Unstable chemistry Bioeliminatio
n Process scalable, commercial, and
controllable Does the formulation fit into the
clinical environment
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Chiral centers Require enantiomer synthesis,
purification
Thalidomide
sedative
teratogenic
Integrin homing ligand avß3-targeted
peptidomimetic conjugated to PEG(2000)-Phosphatidy
lethanolamine
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Unstable chemistry in process, bottle or in vivo
avoid!!

• Are the component compounds stable over time
  e.g., fumagillin
• The fumagillin molecule notably has
• two, highly reactive epoxide rings
• photosensitive decatetraenedioic tail
• ester-linkage

anb3-Fumagillin-Gd-PFC nanoparticles
Reduce Tumor Volume Improve Oxygenation Improve
Drug Penetration
30µg/kg x3 - 10,000-fold lt TNP-470
Winter, Wickline, Lanza. FASEB J 2008
222758-2767.
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Good Manufacturing Practices (GMP) Establish
identity, strength, potency, purity

• Most IND and NDA fail inadequate GMP.
• The manufacture of pharmaceuticals
• must be robust, reproducible and exquisitely
  controlled.
• The Crux of GMP involves
• Well-defined, written procedures
• Adequately controlled equipment and
  manufacturing environment
• Accurate and consistent recorded data from
  manufacturing

http//www.clinaudits.com/images/servicepic.jpg
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Early process considerations
Reaction scale-up issues (10 ml - 10L - 100L
-1000L) Pharmaceutically acceptable solvent and
residue issues (no chloroform) Demonstrate
process control with in-process
testing (variability validation
Characterization raw materials, (API), and
final product Sterility and pyrogenicity
(terminal sterilization, sterile
processing) Stability of materials, API, and
final product
Lab
umich.edu
Plant
cmvdata.be
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Begin Analytical Definition Early

• Typical Small Molecule Product Release Complexity
• Small molecule injectable API release
  specifications (9)
• Appearance
• Assay/Impurities by HPLC
• Identity by HPLC
• Identity by MS
• Chiral Verification by USP
• Moisture by USP
• Organic Volatile Impurities by GC
• Elemental Analysis
• Heavy Metals by USP
• Small molecule injectable drug product release
  specifications (8)
• Appearance
• API Assay/Impurities by HPLC
• API Identity by HPLC
• pH by USP
• Osmolality by USP
• Endotoxin by USP

Typical total number of release specifications
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Complexity of Ligand-Targeted Nanoparticle is
Many Fold Greater
Total Drug Product Release Specifications (52)
Product release specifications after release for
each API

• Appearance
• Gd chelate assay by HPLC
• Gd chelate impurities by HPLC
• Targeting ligand assay by HPLC
• Targeting ligand impurities by HPLC
• EYP (lipid) assay by HPLC
• EYP impurities by HPLC
• PFOB assay by GC
• Particle Size
• 10
• 50
• 90
• Zeta Potential
• pH by USP
• Free Gd3 by HPLC-ICP-MS
• Total Gd3 by ICP-MS
• Heavy Metals by ICP-MS

• Gd-chelate Chiral Purity by HPLC
• TL-29 Chiral Purity by HPLC
• Specific Gravity by USP
• Osmolality by USP
• Endotoxin by rabbit pyrogen
• Sterility
• Particulates

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Shelf-life and In Vivo Stability
Shelf life stability should be 12 to 24
months Need minimum of 6 month stability for
Phase 1
Do all of the parts stay together in vivo and
reach the Target site? Does the drug track with
the particle? Abraxane is an excipient
improvement not a stable nanoparticle construct.
www.callicrate.com/ woodmen/gallery.htm
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Colloidial Iron Oxide Nanoparticle (CION) conquer
the dark side Rapid, Sensitive - T1w Imaging with
Iron oxides
Sensitive detection to low nM
Ctrl T1-TSE
Targ. T1-TSE
Targ. T1-FFE
Targ. T2-FFE
Back to T1 baseline
Below T2 baseline
Senpan et al. ACS Nano 2009 3 (12) 3917-3926.
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Beware of New Safety Barriers to Approval
Gd-Based Contrast Agents Linked to NSF

• FDA Box Warning

NSF is a debilitating disease that leads to
excessive formation of connective tissue in the
skin and internal organs. It is characterized by
high blood pressure, burning, itching, swelling
and hardening of the skin. Other symptoms
include red or dark patches on the skin pain
deep in the hip bones or ribs and muscle
weakness. NSF can progress to the point of
causing severe stiffness in joints, and it can
lead to death. It appears that NSF only develops
in people with pre-existing kidney disease
Cowper SE. Nephrogenic Fibrosing Dermopathy
ICNSFR Website. 2001-2009. Available at
http//www.icnsfr.org.
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Manganese nanocolloids with high T1 relaxivity
for fibrin and angiogenesis molecular imaging
Angiogenesis MR
Particulate relaxivities 91,127 2.323
(smmol ManOC)-1 423,420 10.564 (smmol
ManOL)-1
Site of Matrigel implant
avb3 -targeted ManOL
Pre
Post injection (2h)
Pan, D. et al. Chem Comm. 2009 (22) 3234-3236
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For Systemically Injected Pharmaceuticals What
goes in, must come out !!
It is not adequate for nanomaterials to remain in
the body indefinitely. They must be
bio-eliminated in a reasonable timeframe
Issues with nondegradable particles gt 6nm
particles, Nonmetabolizable polymers, etc.
SPECTRAL/CT requires high metal density to
overcome partial volume dilution. We used
organometallic bismuth rather than bismuth
sulfide.
Pan et al. Nature Nanotech. (In review)
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Summary
Plan for Success choose the right platform, the
right indication, and document the
technology. The key is to simplify everything
in all respects (KISS !!)
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Washington University School of
Medicine Consortium for Translational Research in
Advanced Imaging and Nanomedicine C-TRAIN Group