Alzheimer's Disease Immunotherapy Pipeline: Vaccines, Therapeutic Antibodies and Emerging Strategies

This publication has been discontinued on July 4, 2011.

Introduction

Abstract

Current drug treatments for Alzheimer' s Disease (AD) are dominated by two drug classes: the cholinesterase inhibitors (e.g. Aricept®) and, more recently, an NMDA receptor antagonist (e.g. Ebixa®). While these drugs offer benefits to some AD patients, there is an urgent need for improved treatments and, in particular, for disease-modifying therapies. In recent years, new drug classes have entered the pipeline. However, the greatest growth in this field is the development of immunotherapeutic drugs.

Immunotherapeutic drugs broadly divide into two groups: vaccines that elicit an active immune response (generating antibodies that target the disease), and therapeutic antibodies that bypass the immune system and directly target the disease (so-called passive immune treatment). Today, the vast majority of these immunotherapies target amyloid beta (hereafter referred to as Abeta), which is believed to play a key role in the pathogenesis of AD.

This report identifies 35 candidate immunotherapy treatments for AD in the development pipeline: 17 vaccines and 18 therapeutic antibodies. Overall, these include eight candidates (22%) in early research, nine (26%) in pre-clinical research, 10 (29%) at Phase I, five (14%) at Phase II and three (9%) at Phase III. Of the 35 vaccines and therapeutic antibodies, 18 (51%) are in clinical development (Phase I-III). These developments involve 30 companies: 22 primary developers and eight commercial partners (international pharmaceutical companies). Of these 30 companies, 16 are SMEs (small to medium sized enterprises) and 14 are major international companies.

Of the immunotherapy candidates in development, >95% target Abeta. The first Abeta-targeting candidate immunotherapy for AD was AN1792, developed by Elan. This vaccine molecule, which entered Phase I in 1999, was based on a synthetic form of Abeta1 - 42. This trial was soon followed by a Phase II study, involving 372 patients with mild-to-moderate AD. However, this trial was terminated in January 2002 when it found that ~6% of patients developed meningoencephalitis and leukoencephalopathy.

Since then, significant efforts have been made to understand why AN1792 produced an adverse response in some patients, and to study other requirements such as the need to elicit an adequate immune response (i.e. antibody titre). Since 2002, research has identified other factors relevant to the development of AD-targeting vaccines and antibodies. These include strategies to avoid the inflammatory T-Cell mediated immune response (Th1, linked to the adverse reactions seen in the case of AN1792) and, instead, to elicit an antibody-producing anti-inflammatory B-Cell response (Th2). Other areas include the targeting or avoidance of epitopes associated with the Th1 and Th2 response; different mechanistic approaches to the targeting of Abeta (e.g. soluble Abeta, conformationally modified forms, Abeta fibrils, plaque); the selective targeting of the N-terminal or C-terminal ends of Abeta; and delivery and transport across the blood brain barrier. This research, together with innovation in the discovery, development and early testing of new molecules, has resulted in the development of 35 candidate immunotherapies seen in the pipeline today, most of which are differentiated by design, production or underlying Abeta targeting characteristics.

This report gives a comprehensive overview of developments in this field and, as part of this analysis, provides a summary of the research background to each developmental candidate and associated companies. Alongside the commercial pipeline, this report reviews current AD-targeted research (by academic research groups) relevant to vaccines and antibodies. These advances provide a source of new opportunities to address primary developmental challenges in this field.

This report:

• provides a comprehensive overview of the vaccine and therapeutic antibody development pipeline for the treatment of AD, up to July 2010;
• identifies and discusses the challenges of developing vaccines and antibodies targeting AD, and how these are being addressed by primary development companies and academic research groups;
• identifies new candidate opportunities, together with primary development companies (mostly SMEs) that are seeking partnerships and collaboration in this field;
• provides a review of emerging developments relating to AD candidate vaccines and antibodies that address current development limitations and offer new collaborative opportunities; and
• gives financial details of collaboration and licensing deals, relating to vaccines or antibodies being developed to target AD

Number of pages: 95

Table of Contents

Executive Summary

• The Development Pipeline
• Companies
• Emerging Opportunities
• General Conclusions

Chapter 1 - Background

• 1. Alzheimer's Disease
  • 1.1 Statistics and Costs
  • 1.2 Histopathology
  • 1.3 Amyloid Beta (Abeta
  • 1.4 Tau Proteins and Neurofibrillary Tangles
  • 1.5 Cholinergic
  • 1.6 Genetics
  • 1.7 Biomarkers
  • 1.8 Current Treatment
  • 1.9 Immunotherapeutic Strategies

Chapter 2 - Pipeline Developments

• 2.1 Summary
• 2.2 Companies
• 2.3 Pipeline
• 2.4 Vaccines
• 2.5 Antibodies
• 2.6 Companies, Vaccines and Antibodies

Due to the nature of this report, details of candidate immunotherapeutic vaccines and antibodies have been excluded, however, the number of candidates and their development stage are indicated below.

• Nanobody “antibody”, Preclinical stage
• Antibody, Phase I; Vaccine Phase I
• Three vaccines, Phases I, I and III
• Vaccine, Research stage; Antibody, Research stage
• Two vaccines, both Preclinical stage
• Antibody, Research stage
• Antibody, Phase III
• Vaccine, Phase II
• Antibody, Preclinical stage
• Two antibodies, Phase III and Preclinical stage; vaccine, Phase II
• Antibody, Phase III
• Antibody, Phase I; vaccine Phase I
• Antibody, Preclinical stage; two vaccines, Preclinical stage
• Two antibodies, Research stage; two vaccines, Research stage
• Vaccine, Phase I
• Antibody, Phase I
• Antibody, Preclinical stage
• Antibody, Phase II
• Antibody, Phase II
• Vaccine, Research stage
• Antibody, Phase I
• Vaccine, Phase I

Chapter 3 - Emerging Developments

• 3.1 Summary
• 3.2 Emerging Developments
  • 3.2.1 Abeta-KEK
  • 3.2.2 Abeta1-9 & Abeta 28-40 Bacteriophage
  • 3.2.3 Abeta1-15 (4 x Abeta15) Candidate Vaccine
  • 3.2.4 DNA beta-amyloid(1-42) trimer
  • 3.2.5 Chitosan Nanoparticles
  • 3.2.6 New AD Mouse Models
  • 3.2.7 Truncated Abeta
  • 3.2.8 Segmented Abeta
  • 3.2.9 Abeta-Cys peptides
  • 3.2.10 N-Terminal Epitopes
  • 3.2.11 Abeta1-42 Derivatives
  • 3.2.12 Microglia Cells
  • 3.2.13 Mannan-Abeta28 conjugate
  • 3.2.14 Abeta(1-15)
  • 3.2.15 Adenovirus Vector Encoding 4 x Abeta(15)
  • 3.2.16 DNA Epitope Vaccine
  • 3.2.17 Blocking CD40-CD40L Interaction
  • 3.2.18 Abeta(1-11)
  • 3.2.19 Preventative vs. Therapeutic Vaccinations
  • 3.2.20 Viral Vectors
  • 3.2.21 Abeta cDNA (AAV/Abeta) Vaccine
  • 3.2.22 UBITh immunotherapeutic vaccine
  • 3.2.23 Abeta-VLP vaccine

Chapter 4 - Discussion and Conclusions

• 4.1 Discussion
• 4.2 The Immunotherapy Pipeline
• 4.3 Efficacy
• 4.4 Safety
• 4.5 Targeting Abeta
• 4.6 N-Terminal vs. C-Terminal
• 4.7 B-Cell vs. T-Cell Response
• 4.8 General Conclusions

Figures

• Figure 1. Diagram indicating the two cleavage positions of APP (by β- and γ-secretases), generating Abeta
• Figure 2.1 Candidate vaccines and antibodies in development for the treatment of Alzheimer's Disease (Development Phase).
• Figure 2.2 Candidate vaccines in development for the treatment of Alzheimer's Disease (Development Phase).
• Figure 2.3 Candidate therapeutic antibodies in development for the treatment of Alzheimer's Disease (Development Phase).
• Figure 4.1 Candidate therapeutic antibodies in development for the treatment of AD (Development Phase).
• Figure 4.1 Candidate vaccines in development for the treatment of AD (Development Phase).

Tables

• Table 2.1 Candidate vaccines and antibodies in development for the treatment of Alzheimer's Disease (Company, Partner, Generic Name, Development Phase and Drug Type).
• Table 4.1 Candidate vaccines and antibodies in development for the treatment of Alzheimer's Disease (Company, Partner, Generic Name, Development Phase and Drug Type)

Press Release

Alzheimer's Disease: What are the Treatment Options?

Related Reports