Paisley & Habermas, Inc. Report

Table of Contents

Contents..... i

Appendices..... iii

Tables and Charts ..... iv

Introduction ..... I

Executive Summary ..... III

Monoclonal Antibody Technologies and Products

The AF Mouse Colony, American Biogenetic Sciences' Enabling Technology ..... 1

Immunologically naive AF mice mount an intense and highly-selective
response upon immunization ..... 1

The AF technology provides access to highly-selective, high affinity MAbs
to 'difficult' antigens ..... 2

AF technology may aid in the creation of high-value MAb diagnostic and
therapeutic agents ..... 3

Humanized and Human MAbs can be generated by several techniques ..... 3

Monoclonal antibody therapeutics are based on proprietary enabling technologies ..... 4

Thrombin Precursor Protein (TpP(tm)) ..... 9

Thrombotic disorders are extremely prevalent ..... 9

Thrombosis, soluble fibrin, and the TpP test ..... 9

The Clotting Cascade and the Rationale for the TpP Test ..... 10

Fibrinogen, Fibrin, and Intermediate Species ..... 10

The Fibrinogen Assay (FiF) ..... 13

The MH1-Based In Vivo Thrombus Imaging Agent ..... 15

Diagnosis of DVT is often difficult ..... 15

Identification of PE is often difficult; but rapid diagnosis can be life-saving ..... 16

Radiolabeled antibodies may be used to image DVT and PE ..... 16

Preclinical and clinical experience with the ABS thrombus-imaging agent ..... 17

The MH1-based imaging agent may face little competition ..... 18

MH1-Based Therapeutic Agents 19

MH1 may provide a unique antithrombotic agent ..... 19

MH1 may deliver a thrombolytic enzyme to the site of a fibrin clot ..... 19

MH1 may be used to deliver therapeutic agents to fibrin rich tumors ..... 20

Notes ..... 21

Neuroscience Initiative

"The Decade Of The Brain" And Decades Of Blockbuster CNS Drugs ..... 23

Vast and growing unmet medical need. ..... 23

Tremendous Commercial Success of New CNS Drugs ..... 23

Physicians Have Found Numerous Applications For Well-Tolerated CNS Drugs ..... 24

New Prospects for Altering the Course of Neurodegenerative Conditions ..... 24

ABS-103R - Next-Generation Valproate ..... 25

Valproate Introduction ..... 25

Anti-Epileptic Drugs May Have Numerous Clinical Applications ..... 25

The Markets ..... 26

Epilepsy ..... 26

Prevalence ..... 27

Social and Economic Cost ..... 27

Cost of Epilepsy ..... 27

Great Unmet Medical Needs ..... 27

Efficacy vs. Tolerability ..... 27

Current Anti-Seizure Drugs ..... 28

Bipolar Disorder ..... 33

Prevalence ..... 33

Social and Economic Costs ..... 33

Economic Cost of Bipolar Depression ..... 33

Major Unmet Medical Need ..... 33

Drug Therapy - Limitations, Advances, and Prospects ..... 34

Migraine ..... 35

Prevalence ..... 35

Social and Economic Costs ..... 35

Burden of Migraine in the U.S. ..... 35

Migraine Therapies - Major Medical Needs Remain ..... 36

Abbott Labs - The Ideal Partner for ABS-103 ..... 41

Depakote is a Key Franchise for Abbott ..... 41

Potential Market for ABS-103 ..... 42

Current U.S. Market for Anticonvulsant Drugs ..... 42

The Markets for Valproate-Base Pharmaceuticals ..... 43

Potential Market Opportunity for ABS-103 ..... 44

ABS-205 - A Cognition Enhancer for Neurodegenerative Diseases ..... 54

Neurological Disorders - High Prevalence and Immense Social Cost ..... 54

An Overview of Neurocognitive Disorders ..... 56

Alzheimer's Disease ..... 56

Prevalence and Cost ..... 56

Therapeutic Approaches ..... 57

Parkinson's Disease ..... 59

Prevalence and Cost ..... 59

Therapeutic Approaches ..... 59

Schizophrenia ..... 60

Prevalence and Cost ..... 60

Market and Therapeutic Needs ..... 60

Notes ..... 62

A Unique Model for Screening Neurotrophic Drugs ..... 66

NCAM - a multifunctional protein ..... 66

NCAM sialylation and learning ..... 66

ABS-205 - Discovery, Characterization, and Prospects ..... 67

ABS-205 exhibits "NGF-like" effects with cultured neural cells ..... 67

Preclinical Studies Overview ..... 68

Acute administration of ABS-205 enhances learning and memory ..... 68

Chronic administration of ABS-205 enhances learning and memory ..... 69

ABS-205 blocks chemically-induced amnesia ..... 69

Chronic administration of ABS-205 alters NCAM PSA expression ..... 70

Additional ABS-205 studies suggest safety and provide mechanistic insights ..... 70

ABS-205 strengthens NCAM-mediated memory consolidation ..... 71

ABS-205 is at an early stage of development, but the compound has many meritorious properties ..... 72

A therapy that relieved impaired cognitive function would address vast potential markets ..... 72

Appendices

Appendix 1

Monoclonal Antibodies and the Immune Response ..... 75

The Normal Antibody Response ..... 75

Monoclonal Antibodies ..... 76

Antibodies as Therapeutic Drugs ..... 76

Chimerized and Humanized Antibodies ..... 77

Human Antibodies ..... 78

Human Monoclonal Antibodies from Human Immune Cells ..... 78

Human Monoclonal Antibodies From Phage Derived Combinatorial Antibody Libraries ..... 79

Human Monoclonal Antibodies From Mice With Human Antibody Genes ..... 79

Appendix 2

The TpP Diagnostic Assay ..... 81

TpP can help diagnose, or exclude, acute myocardial infarction ..... 81

Diagnosis of acute MI is often difficult ..... 81

But prompt diagnosis of acute MI can save lives and reduce morbidity ..... 81

A major medical opportunity for the TpP test ..... 82

Improved diagnosis and rapid, reliable exclusion of MI could save $billions ..... 83

Clinical Results with TpP - Diagnosis of possible Acute Myocardial Infarction ..... 83

Other applications of TpP test with acute arterial thromboses 85

Unstable Angina - Monitoring of Patients Admitted to Hospital for that Condition ..... 85

Diagnosed MI Patients ..... 86

Perioperative Testing of Patients Undergoing Invasive Cardiac Procedures ..... 86

Prevention and Diagnosis of Venous Thrombosis ..... 87

Venous thrombosis is a serious medical problem ..... 87

The TpP assay may detect imminent venous thrombosis ..... 87

Anticoagulation reduces the risk of DVT ..... 87

The TpP Test Offers a Direct Measure of the Adequacy of Anti-Coagulation ..... 88

The TpP test may help diagnose DVT, or exclude DVT ..... 88

Clinical studies of the TpP assay - post-surgical monitoring ..... 89

Clinical studies of the TpP assay - DVT diagnosis and treatment ..... 89

Preoperative TpP levels predict the risk of DVT in neurosurgery patients ..... 90

The TpP test may predict complications of PTCA ..... 91

The TpP assay may help in the clinical management of DIC and other hypercoagulable states ..... 91

The TpP Test May Predict the Risk of Preeclampsia, a Serious Complication of Pregnancy ..... 92

Notes ..... 93

Appendix 3

Epilepsy Notes ..... 95

The Classification of Epileptic Seizures ..... 95

Appendix 4

Alzheimer's Disease Therapeutics ..... 97

Tables and Charts

Tables

Table 1 Monoclonal Medicine Ascendant - Companies with Enabling Antibody Technologies in 1997 and 2000 ..... 6

Table 2 Anti-Seizure Drugs Currently Approved in U.S. ..... 30

Table 3 Anti-Epileptic Drugs ..... 31

Table 4 Bipolar Therapeutics ..... 38

Table 5 Migraine Therapeutics ..... 39

Table 6 The U.S. Anticonvulsant Market - by Prescriptions ..... 46

Table 7 The U.S. Anticonvulsant Market - by Sales ..... 47

Table 8 Valproate Pharmaceuticals 1987-2005E ..... 48

Table 9 Valproate Drug Market Forecast 2005E-2011E ..... 51

Table 10 Depakote and ABS-103 Sales Forecast ..... 53

Table 11 Some Major Neurological Disorders ..... 63

Table 12 Side Effects of Principal Anti-Seizure Drugs ..... 96

Thrombosis and Fibrinolysis ..... 11

Simplified Model of Alzheimer's Disease Pathology ..... 64