Alzheimer Disease: Altstiel LD

Altstiel LD. · Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. · Alzheimer Dis Assoc Disord. · Pubmed #12070359 No free full text.

Abstract: The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets. Advances in biotechnology have generated new insights into disease mechanisms, increased the number of lead compounds, and accelerated biologic screening. The majority of costs associated with drug development are in clinical testing and development activities, many of which are driven by regulatory issues. For most biotechnology companies, the costs of such trials and the infrastructure necessary to support them are prohibitive. Another significant barrier is the definition of therapeutic benefit for AD drugs; Food and Drug Administration (FDA) precedent has established that a drug must show superiority to placebo on a performance-based test of cognition and a measure of global clinical function. This restrictive definition is biased toward drugs that enhance performance on memory-based tests. Newer AD drugs are targeted toward slowing disease progression; however, there is currently no accepted definition of what constitutes efficacy in disease progression. Despite these obstacles, the biotechnology industry has much to offer AD drug discovery and development. Biotechnology firms have already developed essential technology for AD drug development and will continue to do so. Biotechnology companies can move more quickly; of course, the trick is to move quickly in the right direction. Speed may offset some of the problems associated with lack of scale. Additionally, biotechnology companies can afford to address markets that may be too restricted for larger pharmaceutical companies. This advantage will have increasing importance, as therapies are developed to address subtypes of AD.

Fillit HM, O'Connell AW, Brown WM, Altstiel LD, Anand R, Collins K, Ferris SH, Khachaturian ZS, Kinoshita J, Van Eldik L, Dewey CF. · The Institute for the Study of Aging, Inc., New York, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #12070355 No free full text.

Abstract: Alzheimer disease (AD) is a neurodegenerative condition leading to progressive, irreversible loss of cognitive and behavioral function. Despite considerable investments in neuroscience research, only four drugs, all cholinesterase inhibitors, have been approved for the symptomatic management of AD in the United States. Although basically safe and modestly effective, these drugs are far from ideal, being neither universally efficacious nor disease modifying. AD exacts a considerable toll in direct medical costs, quality of life, and caregiver burden for persons and society. In addition to the obvious clinical benefit, therapeutic agents for AD and related dementias represent a considerable market opportunity for the pharmaceutical and biotechnology industries. There are currently 8-10 million AD sufferers in the seven major pharmaceutical markets. The market will grow rapidly in coming decades, as the developed world experiences an enormous increase in its elderly population. Given the great need for new therapeutic agents to manage and prevent AD, the Institute for the Study of Aging and the Fidelity Foundation organized a workshop, "Barriers to the Discovery and Development of Drugs for Alzheimer's Disease," to examine ways to expedite drug discovery and development. The identified barriers and potential solutions will be discussed here and in the accompanying articles in more detail.

Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE. · Elan Pharmaceuticals, Inc., South San Francisco, CA 94080, USA. · J Neurochem. · Pubmed #11145990 No free full text.

Abstract: Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.