Transcript Document

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)
Drug Development Life Cycle Overview
No IND Clinical Hold
From
Concept to
Preclinical
Testing
IND
Submitted to FDA
30-Day Review
Prior to Starting
Clinical Study
Phase III
Phase II
NDA
Approval
To
Market
Phase I
GLP/GMP
Discovery
Research
Pre-Clinical
Development &
Testing / V&V
START
(No
Clinical
Hold)
Human Clinical Testing
K.FULLER – UMMS
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
19F
250 nm
Lipid coat inclusions
Dyes (Rhodamine, Cypate, FITC, AlexaFluor)
Drugs (Fumagillin, Rapamycin, Doxorubicin)
Cytolytic Peptides (Mellitin)
Fibrinolytic enzymes
Surface Metal
Chelates
Gd3+
111In
99mTc
177Lu
Eu3+
Reproducible process chemistry for parts and whole!
Too complicated ?
Nanoparticles versus small
molecules have a 3D aspect
all the parts there
appropriately oriented
Yes
Each component must be
GMP or Pharmaceutical Grade
Simplicity of process
Process scalability
No
“Drugable” Chemistry, Process, and
Anticipated Drug Form
Chiral centers
Unstable chemistry
Bioelimination
Process scalable, commercial, and controllable
Does the formulation fit into the clinical environment
Thalidomide
teratogenic
Integrin homing ligand
αvβ3-targeted peptidomimetic conjugated to PEG(2000)Phosphatidylethanolamine
sedative
Unstable chemistry in process, bottle or in vivo – avoid!!
Are the component compounds stable over time: e.g., fumagillin
The fumagillin molecule notably has:
anb3-Fumagillin-Gd-PFC nanoparticles
Reduce Tumor Volume
Improve Oxygenation
Improve Drug Penetration
30µg/kg x3 - 10,000-fold < TNP-470
Winter, … Wickline, Lanza. FASEB J 2008; 22:2758-2767.
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
Early process considerations
Reaction scale-up issues
(10 ml - 10L - 100L -1000L)
Lab
Pharmaceutically acceptable
solvent and residue issues (no
chloroform)
Demonstrate process control
with in-process testing
(variability – validation
umich.edu
Characterization raw materials,
(API), and final product
Sterility and pyrogenicity
(terminal sterilization, sterile
processing)
Stability of materials, API, and
final product
Plant
cmvdata.be
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
•Sterility by USP
•Particulates by USP
Typical total number of
release specifications: 17
Complexity of Ligand-Targeted
Nanoparticle is Many Fold Greater
Total Drug Product Release Specifications: (52)
Product release specifications after release for each API
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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 Gd+3 by HPLC-ICP-MS
Total Gd+3 by ICP-MS
Heavy Metals by ICP-MS
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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
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
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.
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.
Cowper SE. Nephrogenic Fibrosing Dermopathy
[ICNSFR Website]. 2001-2009. Available at
http://www.icnsfr.org.
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
Manganese nanocolloids with high T1 relaxivity for
fibrin and angiogenesis molecular imaging
Angiogenesis MR
Particulate relaxivities:
91,127 ± 2.323
(s·mmol [ManOC])-1
423,420 ± 10.564
(s·mmol [ManOL])-1
Site of Matrigel
implant
avb3 -targeted ManOL
Pre
Pan, D. et al. Chem Comm. 2009 (22): 3234-3236
Post injection (2h)
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 > 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)
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 !!)
Washington University School of Medicine
Consortium for Translational Research in Advanced Imaging and Nanomedicine
C-TRAIN Group