Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.

Requirements for a lead compound to become a clinical candidate.

A drug candidate suitable for clinical testing is expected to bind selectively to the receptor site on the target, to elicit the desired functional response of the target molecule, and to have adequate bioavailability and biodistribution to elicit the desired responses in animals and humans; it must also pass formal toxicity evaluation in animals. The path from lead to clinical drug candidate represents the most idiosyncratic segment of drug discovery and development. Each program is unique and setbacks are common, making it difficult to predict accurately the duration or costs of this segment. Because of incidents of unpredicted human toxicity seen in recent years, the regulatory agencies and public demands for safety of new drug candidates have become very strict, and safety issues are dominant when identifying a clinical drug candidate.

Novel class of pain drugs based on antagonism of NGF.

Nerve growth factor (NGF) was identified originally as a survival factor for sensory and sympathetic neurons in the developing nervous system. In adults, NGF is not required for survival but it has a crucial role in the generation of pain and hyperalgesia in several acute and chronic pain states. The expression of NGF is high in injured and inflamed tissues, and activation of the NGF receptor tyrosine kinase trkA on nociceptive neurons triggers and potentiates pain signalling by multiple mechanisms. Inhibition of NGF function and signalling blocks pain sensation as effectively as cyclooxygenase inhibitors and opiates in rodent models of pain. Several pharmaceutical companies have active drug-discovery and development programs that are based on a variety of approaches to antagonise NGF, including NGF 'capture', blocking the binding of NGF to trkA and inhibiting trkA signalling. NGF antagonism is expected to be a highly effective therapeutic approach in many pain states, and to be free of the adverse effects of traditional analgesic drugs.

Regulatory issues in aging pharmacology.

Many current drugs increase the average lifespan by preventing fatal diseases or by slowing down the progressive degenerative diseases that increase mortality. The existing strategies and guidelines for the development and regulatory approval of new drugs are designed for such compounds. Rapid advances in understanding molecular mechanisms of aging make it possible to envisage future drugs that extend the lifespan by regulating aging mechanism outside of disease pathways. Strategies for development and regulatory approval of such drugs remain to be defined. Since the drug candidates will be given to healthy, elderly subjects, safety requirements will be extremely high. Clinical studies of many years' duration will be necessary to prove changes in longevity. These time intervals may exceed those of patent protection and thus minimize commercial incentives. Despite these challenges, two broadly defined pathways are feasible. First, it may be possible to obtain public funding for studies with voluntary participation of humans consuming existing drugs or natural compounds in the 'expected to be safe' category. Second, the development of novel drugs may proceed on the basis of well-defined biomarkers of aging that can serve as surrogate end points in clinical studies. The emerging approaches will prompt the regulatory agencies into taking the first steps towards regulatory guidance.

(18)F-AV-133: A Selective VMAT2-binding Radiopharmaceutical for PET Imaging of Dopaminergic Neurons.

The early detection and monitoring of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, dementia with Lewy bodies and other dementias, and movement disorders, represent a significant unmet medical need. Tools for accurate and early differential diagnosis are necessary to determine the appropriate treatment for patients and to minimize inappropriate use of potentially harmful treatments. Such diagnostic imaging tools are expected to permit monitoring of disease progression and will thus accelerate testing and development of disease-modifying drugs. The new imaging tests may be useful as prognostic tools by identifying humans with neurodegenerative diseases before the clinical manifestations become evident.