1.Areas where new development tools could accelerate progress

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• 1. Areas where new development tools could
  accelerate progress
• -- Formulation
• -- Glycosylation
• 2. Potentially important future areas of medical
  development
• -- Nanotechnology
• -- Tissue Engineering

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Impact of TransForm Technology
Traditional
TransForm
of F F experiments

• 200-20,000

• 10-20

Ability to explore FF space more effectively and
efficiently
Timing

• 2 4 Weeks

• 1 2 Months

Informatics data mining, learning

• Deep iterative

• Minimal

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Case Study Ritonavir

• 1.5 years after launch, converted into
  unanticipated form II polymorph
• 50 less soluble
• Abbott compelled to recall reformulate

MPT 122 C
MPT 125 C
MPT 80 C
MPT 97 C
MPT 116 C
Form I
Form II
Form III
Form IV
Form V

• Within weeks at TransForm, using lt 2g
• Both known forms identified characterized
• Found three novel, previously unreported forms
• Novel, robust methods to make each form

Morissette et al. PNAS 100, 2180 (2003).
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New Tools

• Imaging
• Informatics
• Genomics
• Proteomics
• 5. Glycomics

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Cracking the Code of Sugars is Analogous to
the Sequencing of DNA

• The sequencing of DNA has laid the foundation for
  biotechnology revolution
• Like DNA and proteins, sugars play a central role
  in regulating basic biological activity, disease
  mechanisms, and drug action
• Sugars exist as sequences of building blocks
  similar to DNA, but there has been a lack of
  adequate sequencing tools
• Understanding of sugars is critical for
  polysaccharide drugs (e.g. Lovenox) and
  glycosylated proteins (e.g. Epogen)

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Inherent complexity of sugars has prevented
comprehensive understanding

• Structural complexity and information density
• Lack of amplification
• Heterogeneity

The Problem Lack of technology to and tools to
sequence sugars has made it difficult to
characterize and engineer sugars, and decipher
their role in biology.
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Convergence on unique solution to complex
sequences
Sequencing Complex Polysaccharides 1999 Science
286 537-542. Momenta Pharmaceuticals
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Future areas of medical development
1. Nanotechnology 2. Tissue Engineering
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Prototype Device
Silicon Nitride or Dioxide
Silicon
Active Substance
Cathode
Anode
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Implantable Drug Delivery System
Battery-powered, telemetry-controlled implant
Design based on pacemaker and ICD microelectronics
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Reservoir Opening Mechanism
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Pre-Clinical Studies Demonstrate in vivo Release

• Experimental Protocol
• Implant microchips subcutaneously in rats
• Release radioactive mannitol (388 ng/well
  non-metabolized sugar)
• Collect urine and analyze for radioactive
  content
• as an indicator of drug release

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Polymer Therapeutics Nanosized medicines
polymer-protein conjugate
polymeric drug or sequestrant
protein
Mw 5 - 40,000 Da
20nm
40-60 nm
5-15 nm
targeting residue
hydrophilic block
drug
linker
hydrophiobic block
drug
polymer-drug conjugates
polymeric micelle
60-100 nm
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1. How do you assess safety? 2. How do you
characterize nanomedicines --Biological --P
hysical/chemical 3. What animal models are
appropriate?
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Annual Tissue LossEnd Stage Organ Failure (U.S.)

• Over 500 billion in health care costs
• 40 to 90 million hospital days
• 8 million surgical procedures

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Incidence of Organ and Tissue Deficiencies

• Bone
• Joint replacement 558,000
• Bone graft 275,000
• Internal fixation 480,000
• Facial reconstruction 30,000
• Cartilage
• Patella 319,400
• Meniscus 250,000
• Arthritis (Knee) 149,900
• Arthritis (Hip) 219,300
• Small Joints 179,000

• Tendon 33,000
• Ligament 90,000
• Skin
• Burns, Sores, 3,650,000
• Ulcers 1,100,000
• Heart 754,000
• Blood Vessels 606,000
• Liver 205,000
• Pancreas 728,000

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Cartilage Tissue Engineering
BEFORE cell seeding
AFTER 2 weeks in culture
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System

• Modified PGA Tubes
• 8 Weeks SMC Culture, then EC
• Bio-Reactors Pulsatile Radial Stress

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Characteristics

• 50 Collagen
• Rupture Strengths gt 2000 mg Hg
• Suture Retention Strengths up to 90g
• Demonstrates Contractile Responses to Serotonin,
  endothelin-1, and Prostaglandin F2a

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Human Embryonic Endothelial Cells Form Functional
Blood-Carrying Microvessels
PECAM1
CD34
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1. How should safety be assessed?
2. What are appropriate markers?
3. How do you determine appropriate function?
4. What are appropriate animal models?