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The Challenge of Translating Molecular Imaging Agents to the Clinic

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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The Challenge of Translating Molecular Imaging Agents to the Clinic

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  1. 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)

  2. 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 / V&V Discovery Research Human Clinical Testing

  3. 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 Surface Metal Chelates Gd3+ 111In 99mTc 177Lu Eu3+ Lipid coat inclusions Dyes (Rhodamine, Cypate, FITC, AlexaFluor) Drugs (Fumagillin, Rapamycin, Doxorubicin) Cytolytic Peptides (Mellitin) Fibrinolytic enzymes

  4. 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 Yes No

  5. “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

  6. Chiral centers: Require enantiomer synthesis, purification Thalidomide sedative teratogenic Integrin homing ligand αvβ3-targeted peptidomimetic conjugated to PEG(2000)-Phosphatidylethanolamine

  7. 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 < TNP-470 Winter, … Wickline, Lanza. FASEBJ 2008; 22:2758-2767.

  8. 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

  9. 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

  10. 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

  11. 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 Gd+3 by HPLC-ICP-MS • Total Gd+3 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

  12. 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

  13. 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.

  14. 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.

  15. 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 Post injection (2h) Pan, D. et al. Chem Comm. 2009 (22): 3234-3236

  16. 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)

  17. 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 !!)

  18. Washington University School of Medicine Consortium for Translational Research in Advanced Imaging and Nanomedicine C-TRAIN Group

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