Disease Modifying Osteoarthritis Drugs - The Search for the 'Holy Grail' Continues

SUMMARY

Scope and coverage

• The lack of accuracy and reproducibility of radiography as the method ofend-point assessment has created difficulties for clinical trials.
• Research into biomarkers offers a possible solution to both end-pointassessment and earlier diagnosis.
• Doxycycline, Amgen's Kineret and a MMP Inhibitor from P&G offer themost promising DMOAD prospects in the pipeline.
• Success in this area will depend heavily of clinical trial design, dosingregimes and formulation properties of the drug.

Key findings and highlights

• Research is predominantly at an early discovery or pre-clinical stage,with only three products in human trials. P&Gs MMP inhibitor, althoughat an early stage, has shown promising results in a well-designed trial.Tissue engineering also has great potential as a disease modifying approach,Biosyntech currently have a product, BST-Cargel, in PI.
• The main issues dominating DMOAD research are, elucidation of the precisemechanism and pathways involved in OA, and selection of the most effectivedrug delivery approach. Delivery of the drug to the affected joint in asufficient concentration, without adversely affecting the rest of the body,is proving problematic.
• The gold standard radiographic method of measuring trial outcome can lackclinical relevance and rarely produces consistently accurate measurements.Symptomatic outcome measurements are subjective and can be influenced bytreatments that do not alter the cartilage such as commonly used analgesicsand NSAIDs.

Reasons to purchase

• Understand the current research
• Compare DMOADs in the pipeline
• Identify the drivers and constraints in DMOAD research

TABLE OF CONTENTS

EXECUTIVE SUMMARY

Introduction

Scope and coverage of the Brief

Key findings about the topic

SECTION 1 INTRODUCTION

Epidemeology

Current treatments available

What is required of a DMOAD?

Clinical trial design for DMOADs

Measuring the outcome

Radiography

Other methods

Biomarkers

Cleaved Type II collagen molecules

New collagen synthesis

Protoglycan aggrecan

COMP (Cartilage oligomeric matrix protein)

Bone

Pain Scales

Drug delivery

Ethnic differences in response

SECTION 2 DMOADS IN THE PIPELINE

Preventing cartilage degradation

Overview table

Matrix Metalloproteinase (MMP) Inhibition

Doxycycline – Indiana University – Phase II

Oral MMP inhibitor - P&G - Pre-clinical

CMT-3 – Collagenex – Discovery

Esculetin – National Defense College, Japan– Pre-clinical

Interleukin –1 (IL-1) inhibition

Kineret – Amgen – Phase I

Diacerein - University Rene Descartes, France –PII

Insulin

Slow release Insulin – Genentech –Pre-clinical

Steroidal compounds

DHEA – Seoul National University Hospital –Pre-clinical

Enhancing cartilage repair

Overview table

Growth factors

Transforming Growth Factor (TGF)

Insulin-like Growth Factor (IGF-1)

Biomechanical and tissue engineering technologies

Autologous chondrocyte transplantation (ACT)

Polymer scaffold - Rice University/ NIH - Pre clinical

BST-CarGel – Biosyntech – Phase I

Chondrogen – Osiris – Pre-clinical

Other mechanisms

Overview table

Photodynamic treatment

Electromagnetic fields

Glucosamine and Chondroitin Sulphate (GCS)

Estrogen

Estrogen receptors

Conclusions

Discontinued trials

MMP inhibitor (BAY 12-9566) – Bayer – PIIdiscontinued

Insulin Growth Factor (IGF) – Chiron – PIIdiscontinued

SECTION 3 COMPARISON OF DMOAD METHODS

DMOAD deadlock

Comparison of technologies

APPENDIX

Contributing experts

Bibliography

Epidemiology

Clinical trial design

Clinical trial data

Research methodology

Disclaimer

List of Tables

Table 1: OA current and future estimated prevalence bycountry, 2003 and 2010

Table 1: Combination and monotherapies, in the sevenmajor markets, %, 2003

Table 2: Pros and cons of other end-point measurementmethods

Table 3: DMOADs using the cartilage degradationprevention mechanism, 2003

Table 4: Pain responses in knee OA after a singleintra-articular injection of Kineret (anakinra)

Table 5: Cartilage repair enhancing drugs ortechnology, 2003

Table 6: ACT trials from the Journal of Bone and JointSurgery, 2003

Table 7: Other mechanisms of disease modification,2003

Table 8: Summary of DMOADs in development

List of Figures

Figure 1: Combination and monotherapies, in the sevenmajor markets, 2003

Figure 2: Cartilage remodeling

Figure 3: Generation of some of the cartilagebiomarkers

Figure 4: Constraints and drivers of DMOAD development

Figure 5: Comparison of products addressing thebalance of cartilage degradation or repair, 2003