Blood-Brain Barrier: Bridging Options for Drug Discovery and Development

Blood-Brain Barrier: Bridging Options for Drug Discovery and Development

• Strategies to develop small- and large-mol-ecule CNS drugs capable of crossing the blood-brain barrier (BBB)
• Interviews with leading researchers who are aggressively tackling the BBB challenge in CNS drug discovery and development
• Analysis of results from a Blood-Brain Barrier Survey, responded to by a range of companies involved in CNS research and drug discovery/development

CNS diseases are a major focus of the pharmaceutical industry, with CNS drugs representing some of its most successful products. These include Pfizer’s Zoloft (sertraline, for treatment of depression and certain types of anxiety disorders), Lilly’s Cymbalta (duloxetine, for treatment of depression) and Bristol-Myers Squibb’s/Otsuka’s Abilify (aripiprazole, for treatment of bipolar disorder and schizophrenia). However, drug discovery and development researchers experience difficulty developing CNS drugs that complete clinical trials and win regulatory approval—especially drugs which meet major unmet needs in the CNS area, such as Alzheimer’s disease. The vast majority of drugs fail to cross the BBB, which is causing a major bottleneck in successful development of CNS drug candidates.

This report reviews the discovery, design and development of small- and large-molecule drugs that can efficiently cross the BBB. This includes more traditional, medicinal chemistry-based methods, as well as approaches that exploit carrier-mediated transport (CMT) and receptor-mediated transport (RMT). Also covered in the report is use of nanoparticle technology to enable BBB penetration. Further, the report presents in vitro and in vivo assays as well as imaging methods to ascertain a drug’s ability to cross the BBB and reach its target.

The report includes results of a survey of researchers and executives—from corporate and academic organizations—who are active in the CNS drug development area. The survey explores their involvement in BBB-related technologies and programs. The survey results are discussed in terms of what they reveal about the current state of BBB research and the future potential for developing drugs that are able to cross it. 
 

Chapter 1 - THE BLOOD-BRAIN BARRIER: A CHALLENGE FOR CNS DRUG DEVELOPMENT

1.1. Introduction to the BBB Bottleneck
1.2. Dearth of Drugs for CNS Diseases with High Unmet Need
Parkinson’s Disease
Multiple Sclerosis
1.3. New Approaches Needed to Overcome the BBB Hurdle
Tempting New CNS Targets…
…Belie an Underserved CNS Drug Market

Chapter 2 - PHYSIOLOGY OF THE BLOOD-BRAIN BARRIER

2.1. Specialized Brain Capillaries Present Barriers to Diffusion
2.2. Transcranial Delivery of Drugs to Bypass the BBB

Chapter 3 - DISCOVERY & DESIGN OF SMALL-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER

3.1. Crossing the BBB via Passive Diffusion across the Brain Endothelium
The “Rule of Five” for Determining “Drug-Like” Properties
3.2. Action of Efflux Transporters in Inhibiting BBB Penetration
P-Glycoprotein (P-gp)
Studies of P-gp Polymorphisms in Humans
Discovery and Design of Drugs That Use Nutrient Transporters to Cross the BBB
Solute Carrier Transporters in Active Efflux from the BBB
3.3. Design of Small-Molecule Drugs That Use Carrier-Mediated Transport to Cross the BBB
Companies Involved in Developing Small-Molecule Drugs That Exploit Transporter Biology
ArmaGen
XenoPort
3.4. In Vivo Methods for Evaluating Drug Penetration of the BBB
Traditional In Vivo Methods for Determining BBB Penetrance
In Vivo Methods for Determining BBB Penetrance by Use of Imaging
Positron Emission Tomography (PET)
Magnetic Resonance Imaging (MRI)
Functional Magnetic Resonance Imaging (fMRI)
3.5. In Vitro Methods for Determining BBB Penetrance
Cell Culture Models of the BBB
3.6. Use of Nanoparticle Technology to Enable BBB Penetration

Chapter 4- DISCOVERY & DESIGN OF LARGE-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER

4.1. Exploiting Receptor-Mediated Transport in Design of Large-Molecule Drugs That Cross the BBB
Molecular Trojan Horses
4.2. Use of a Diphtheria Toxin Mimetic as a Molecular Trojan Horse for BBB Transport
4.3. Use of a Neurotropic Virus Glycoprotein Mimetic as a Molecular Trojan Horse for BBB Transport
4.4. Need for Basic Research to Find Additional Receptors That Can Be Exploited to Get Large-Molecule Drugs across the BBB
Genomics and Proteomics Research Aimed at Discovery of Novel BBB Transporters

Chapter 5 - OUTLOOK FOR MEETING THE CHALLENGE OF THE BLOOD-BRAIN BARRIER IN DRUG DISCOVERY AND DEVELOPMENT

5.1. Blood-Brain Barrier Survey Results
5.2. Conclusions

Chapter 6 - EXPERT INTERVIEWS

6.1. Pieter J. Gaillard, PhD
Founder & Chief Executive Officer
to-BBB, Leiden, The Netherlands
6.2. William M. Pardridge, MD
Chairman & Chief Scientific Officer
ArmaGen Technologies, Santa Monica, CA
6.3. Christopher L. Shaffer, PhD
Senior Principal Scientist, Neuroscience
Pharmacokinetics, Pharmacodynamics and Metabolism
Pfizer, Groton, CT
6.4. Noa Zerangue, PhD
Research Director
XenoPort, Santa Clara, CA

Chapter 7 - SELECTED COMPANY PROFILES

7.1. Amgen
7.2. Cellial Technologies
7.3. GlaxoSmithKline
7.4. Merck & Co.
7.5. MethylGene
7.6. Pfizer
7.7. Wyeth
7.8. XenoPort

TABLES

Table 1.1. CNS Conditions Not Treatable With Current Drugs
Table 3.1. “Rule of Five” for Oral Drugs vs. Rules for CNS-Penetrant Drugs
Table 3.2. Substances Subject to P-gp Efflux from the Brain
Table 4.1. Selected Receptor-Mediated Transport Systems Used for Development of Large-Molecule Drugs That Can Cross the BBB
Table 4.2. ArmaGen’s Pipeline of Large-Molecule Drugs Based on Molecular Trojan Horse (MTH) Technology

FIGURES

Figure 2.1. Structure of Brain Endothelium
Figure 3.1. Role of SLC and ABC Transporters in Active Efflux of Drugs across the BBB
Figure 3.2. Structures of L-DOPA and Dopamine
Figure 3.3. Co-Culture In Vitro Model of the BBB
Figure 5.1. Respondents by Organization Type
Figure 5.2. Increased Involvement by Therapeutic Area
Figure 5.3. CNS Drugs in Early Pipeline
Figure 5.4. Pipeline Indications
Figure 5.5. CNS Drug Development Bottlenecks
Figure 5.6. Increased Involvement by Drug Type
Figure 5.7. BBB R&D Programs
Figure 5.8. BBB Programs: Small Molecule
Figure 5.9. BBB Technology Development
Figure 5.10. BBB Programs: Large Molecule
Figure 5.11. Use of Imaging Methods
Figure 5.12. Types of Imaging Methods

APPENDIX FIGURES

Figure 1A. Respondents by Organization Type
Figure 2A. Respondents by Functional Role
Figure 3A. Respondents by Job Title
Figure 4A. CNS Product Areas Pursued
Figure 5A. Change in CNS Drug Involvement
Figure 6A. Increased Involvement by Drug Type
Figure 7A. Increased Involvement by Therapeutic Area
Figure 8A. Estimated CNS Drug Launches, 2008/2009
Figure 9A. CNS Drugs in Early Pipeline
Figure 10A. Pipeline Indications
Figure 11A. CNS Drug Development Bottlenecks
Figure 12A. BBB R&D Programs
Figure 13A. BBB Programs: Small Molecule
Figure 14A. BBB Programs: Large Molecule
Figure 15A. BBB Technology Development
Figure 16A. Use of Imaging Methods
Figure 17A. Types of Imaging Methods