Delivery Technologies for Protein Therapeutics: Assessment and Outlook

Published by: CHI Insight Pharma Reports

Published: Mar. 1, 2007 - 164 Pages

Table of Contents

Chapter 1

INTRODUCTION: TRENDS IN TECHNOLOGY FOR DELIVERING PROTEIN THERAPEUTICS

1.1. Why Better Delivery For Therapeutic Proteins Is Needed

Alternatives to Injection

1.2. Organization of this Report

1.3. Protein Engineering Technologies

1.4. Non-Injection Technologies

1.5. Insulin: El Dorado of Protein Delivery Tech

Multiple Products, Multiple Mechanisms

1.6. Business and Market Outlook

Competition Among Noninjection Technologies

1.7. When Will Tech Trends Merge?

Chapter 2

ENGINEERING THERAPEUTIC PROTEINS FOR LONGER HALF-LIFE

2.1. Introduction

PEGylated Interferons

2.2. Increasing Half-life by PEGylation

Releasable PEGylation

2.3. Increasing Half-life by Site-specific PEGylation

ReCODE Technology

2.4. Increasing Half-life by Conjugation with Polysialic Acid

PolyXen Technology

2.5. Increasing Half-life by Albumin Gene Fusion

2.6. Increasing Half-life by Albumin Conjugation

DAC and PC-DAC Technologies

2.7. Increasing Half-life by Albumin-binding Fatty Acids

2.8. Increasing Half-life by Albumin-binding Peptides

2.9. Increasing Half-life with the Streptococcal Albumin-binding Domain

2.10. Increasing Half-life by Transferrin Gene Fusion

2.11. Increasing Half-life by Hyperglycosylation

2.12 Increasing Half-life by Glycosylation Completion and GlycoPEGylation

2.13. Increasing Half-life by Humanized Glycosylation

2.14. Increasing Half-life by Protease-resistant Point Mutations

Chapter 3

OTHER PROTEIN ENGINEERING TECHNOLOGIES TO IMPROVE PROTEIN DELIVERY

3.1. Reducing Immunogenicity through Bioinformatics

Epibase Software

3.2. Reducing Protein Aggregation through Bioinformatics

AggreSolve Algorithms

3.3. Refolding Protein Aggregates through High Pressure Technology

PreEMT Technology

Chapter 4

TECHNOLOGIES FOR TRANSDERMAL DELIVERY OF PROTEINS

4.1. Introduction

4.2. Delivery by Radio Frequency (RF) Microelectrode Array

4.3. Active Delivery by Ultrasound

U-Strip Ultrasound Module

4.4. Passive Delivery by Ultrasound

SonoPrep Device

4.5. Delivery by Thermal Burst

PassPort System

4.6. Delivery by Iontophoresis

Actyve Patches

4.7. Delivery by Transfersomes

Chapter 5

Technologies for Oral Delivery of Proteins

5.1. Introduction

5.2. Oral Protein Delivery using Carrier Molecules

Eligen Technology

5.3. Oral Protein Delivery using Crystallization Technology

Crystalomics

5.4. Oral Protein Delivery by Calcium Phosphate Nanoparticles

BioOral System

5.5. Oral Protein Delivery by Buccal Mouth Spray

RapidMist and Oral-lyn

5.6. Oral Protein Delivery using Amphiphilic Oligomers

HIM2 to IN-105

Chapter 6

TECHNOLOGIES FOR PULMONARY AND NASAL DELIVERY OF PROTEINS

6.1. Pulmonary Delivery using Dry Powder Inhalers

Milestone: Exubera

6.2. Other Protein Inhaler Technologies

Competing Products in Clinical Trials

6.3. Pulmonary Delivery using Antibody Transcytosis Fusion Proteins

FcRn Pathway

6.4. Nasal Delivery using Mucosal Absorption Enhancers, Part 1

IntraVail Technology

Pro Tek Excipients

6.5. Nasal Delivery using Mucosal Absorption Enhancers, Part 2

6.6. Nasal Delivery via Tight Junction Modulation

Chapter 7

EXPERT INTERVIEWS

7.1. Abe S. Abuchowski, PhD, CEO, Prolong Pharmaceuticals

7.2. Ajay K. Banga, PhD, Professor and Chair, Department of Pharmaceutical Sciences, Mercer University

7.3. Eric Tomlinson, DSc, PhD, President and CEO, Altea Therapeutics

7.4. Manuel Vega, PhD, CEO Nautilus Biotech

APPENDIX: CHI INSIGHT REPORTS - PROTEIN DRUG DELIVERY SURVEY - DECEMBER 2006

COMPANY INDEX WITH WEB ADDRESSES

REFERENCES

Tables

Table 1.1. Companies Targeting Improved Insulin Delivery

Table 1.2. Companies Targeting Improved Erythropoietin Delivery

Table 1.3. Companies Targeting Improved Growth Hormone Delivery

Table 1.4. Companies Targeting Improved Interferon Delivery

Table 1.5. Companies Targeting Improved Parathyroid Hormone Delivery

Table 2.1. Technologies for Extending Therapeutic Protein Half-life

Table 2.2. FDA-Approved Therapeutic Proteins Engineered for Extended Half-life

Figures

Figure 2.1. Multiple Benefits of Extending Half-life

Figure 2.2. PEG Mechanisms for Drug Delivery

Figure 2.3. SWOT Analysis for Releasable Pegylation

Figure 2.4. ReCODE: Biosynthetic Incorporation of Chemically Specified Amino Acids

Figure 2.5. SWOT Analysis for Site-specific Pegylation

Figure 2.6. Polysialic Acid Protects Against Proteases

Figure 2.7. Extending Therapeutic Protein Half-Life with Human Serum Albumin Fusion Technology

Figure 2.8. SWOT Analysis for Albumin Gene Fusion

Figure 2.9. SWOT Analysis for Albumin Conjugation

Figure 2.10. Structure of Insulin Detemir

Figure 2.11. SWOT Analysis for Albumin-binding peptides

Figure 2.12. Tertiary Structure of an Affibody Molecule

Figure 2.13. Peptide Fused via a Peptide Linker to the N Terminus of Transferrin

Figure 2.14. SWOT Analysis for Hyperglycosylation

Figure 2.15. Glycolylation Pattern Depends on Expression System

Figure 2.16. Enzymes Add Missing Sugars

Figure 2.17. PEGylation of a Protein on a Carbohydrate Chain

Figure 2.18. SWOT Analysis for Glycopegylation

Figure 2.19. SWOT Analysis for Humanized Glycosylation in Yeast

Figure 2.20. SWOT Analysis for Pretease-Resistant Point Mutations

Figure 3.1. Typical Effects of PreEMT System Pressure on Protein Aggregates

Figure 4.1. Micro Processor

Figure 4.2. Delivery of Insulin in Humans

Figure 4.3. SWOT Analysis for Transdermal Delivery of Proteins via RF-Microchannels

Figure 4.4. SWOT Analysis for Active Delivery by Ultrasound

Figure 4.5. SWOT Analysis for Passive Delivery by Ultrasound

Figure 4.6. Transdermal Delivery by Charge Repulsion

Figure 4.7. Dosage Patterns for Actyve

Figure 4.8. SWOT Analysis for Delivery by Iontophoresis

Figure 4.9. SWOT Anslysis for Delivery by Transferomes

Figure 5.1. Oral Delivery by Carrier Molecules

Figure 5.2. SWOT Analysis for Oral Protein Delivery Using Carrier Molecules

Figure 5.3a. Toxic Metabolites in the Blood Before Therapy

Figure 5.3b. Metabolite Gradient Set in Motion by Protein Crystals

Figure 5.4. SWOT Analysis for Oral Protein Delivery by Protein Crystalization

Figure 5.5. Calcium-PEG-Insulin-Casein

Figure 5.6. SWOT Analysis for RapidMist Buccal Protein Delivery

Figure 5.7. SWOT Analysis for Protein Delivery with Amphiphilic Oligomers

Figure 6.1. SWOT Analysis of Pulmonary Protein Delivery Using Dry Powder Inhalers

Figure 6.2. Epithelial Pinocytosis of Fc Therapeutic Fusion Proteins

Figure 6.3. Structures of Syntonix Therapeutic Fusion Proteins

Figure 6.4. SWOT Analysis of Pulmonary Protein Delivery Using Antibody Transcytosis Fusion Proteins

Figure 6.5. SWOT Analysis of Intranasal Protein Delivery Using Aegis Therapeutics’ Mucosal Absorption Enhancers

Figure 6.6. SWOT Analysis of Intranasal Protein Delivery Using Bentley Pharmaceuticals’ Mucosal Absorption Enhancers

Figure 6.7. Junctions Between Epithelial Cells

Appendix Figures: CHI Insight Pharma Reports - Protein Drug Delivery Survey - December 2006

Figure 1A. Respondents by Sector

Figure 2A. Focus of Respondents

Figure 3A. Delivery Technologies and New Indications for Drugs

Figure 4A. Technologies and Competitiveness

Figure 5A. PEGylation Dominance in the Marketplace

Figure 6A. Trend in Increasing Half-Life of Therapeutic Proteins

Figure 7A. Competitors’ Use of Longer Half-Life Proteins

Figure 8A. Alternatives to Injection

Figure 9A. Competitors and Injection

Figure 10A. Noninjection and Patient Compliance

Figure 11A. Improved Technologies and Prices of Treatments

Figure 12A. Involvement with Approved Therapies

Figure 13A. Oral Protein Delivery vs. Transdermal

Figure 14A. …. vs. Pulmonary

Figure 15A. …. Nasal

Figure 16A. Specialist vs. Primary Care

Figure 17A. Longer Half-Lives vs. Injection

Figure 18A. Noninjection Monoclonal Antibodies

Abstract

• clotting factors
• anticoagulants
• modern insulins
• growth hormone
• follicle-stimulating hormone
• hematopoietic growth factors
• interferons
• interleukins

• improved insulin delivery
• improved erythropoietin delivery
• improved interferon delivery
• improved growth hormone delivery

• transdermal protein delivery
• oral protein delivery
• pulmonary protein delivery
• nasal protein delivery

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