Potential brain biologic marker for AD identified

Berlex Pharmaceuticals identifies potential brain biologic marker specific for the diagnosis of Alzheimer's Disease; Schering AG shares jump on Alzheimer's Discovery

Berlex Pharmaceuticals, from Richmond, CA, US, a US affiliate of Schering AG Germany, has discovered that a receptor protein molecule, CCR1 that is usually found on the surface of white blood cells also is pre-sent in the brains of patients with Alzheimer's Disease (AD). Further, increasing levels of CCR1 in the brain correlate with advancement of the disease. These human, clinicopathologic findings will be published in the November edition of the Annals of Neurology and may lead to the development of an Alzheimer's specific, brain imaging biomarker for early diagnosis and tracking of disease progression.

'Our research has demonstrated that CCR1 is evident in the brains of patients very early in the disease process, even in patients with mild cognitive impairment,' said Dr Meredith Halks-Miller, head of pharma-copathology for Berlex and lead investigator. 'CCR1 is present in swollen neuronal fibres that are associated with a molecule called amyloid beta 1-42 (Abeta42), a sticky peptide that builds up and creates the "senile plaques" that are the hallmark pathological sign of AD. As the disease progresses, the number of abnormal CCR1-containing neuronal fibres also increases.'

Based on this discovery, Schering AG has initiated the first phase of clinical studies to determine if targeting CCR1 with a radiolabeled, small molecule CCR1-antagonist can provide physicians with a highly specific, brain- imaging biomarker of AD for both early detection and tracking of progression.

An international team of scientists at Berlex and Schering developed the small molecule, called 'BX471' The phase I/II study, which will validate the safety and utility of the diagnostic agent, is being conducted at the University of Dresden in Germany, which has been designated by the EU as a centre specialized in imaging early Alzheimer's disease. Preliminary results of the study should be available in 2004.

'Today there are no well established, specific diag-nostic tests or validated surrogate markers for Alzheimer's,' said Dr Edgar Salazar-Grueso, vice presi-dent, clinical development for central nervous system and cardiovascular, Berlex. 'We believe that targeting CCR1 has the potential to provide the medical community with a specific diagnostic test that can identify Alzheimer's even at early stages of mild cognitive impairment and provide physicians with a validated surrogate marker to track disease progression.'

The recently published study "Alzheimer's disease in the US population" estimates that 4.5 million Americans have Alzheimer's today and that prevalence will increase by 20 percent by the year 2020 and nearly 300 percent by the year 2050.

CCR1 is present in the human body on the surface of immune system cells (like white blood cells) in order to direct them to the site of injury. It is not normally present in the brain. However, the research conducted by Halks- Miller and scientists in the US and Germany, found that CCR1 is present on the abnormally swollen parts of nerve fibres within or immediately adjacent to senile plaques. Abeta42 is thought to activate micro-glia and astrocytes - brain cells that, when stimulated, release a variety of inflammatory molecules. Scientists believe that these released molecules may eventually damage nerve fibres in the brain.

'We found that increases in CCR1 within nerve fibres could predict an increasing amount of Abeta42 in the brain and visa versa,' said Halks-Miller. 'Further, we evaluated brain tissue from patients with other forms of dementia and found no evidence of CCR1 unless Abeta42 also was present. These findings demonstrate that CCR1 is only found in association with Abeta42-positive senile plaques and, therefore, may be considered a specific biological marker for Alzheimer's.'

Scientists at Berlex conduct research in neurology, cardiology, cancer and dermatology, building on a strong foundation in the understanding of the human immune and central nervous systems. They develop small molecules as well as biologic, cell and gene therapies. CCR1, and the small molecule which targets it, represent the first 'home grown discovery' of this team of scientists to move from the laboratory bench to the clinic. In addition to clinical research to evaluate BX471 as an Alzheimer's diagnostic targeting CCR1, Schering is initiating Phase 2 clinical studies to evaluate its safety and efficacy as a therapeutic agent for multiple sclerosis and psoriasis.

'Our team has been incredibly successful not only conducting its own bench research, but also in taking novel discoveries from academia and smaller biotechnology companies and creating breakthrough therapeutic approaches to disease," said Dr Daniel Perez, president of Berlex Biosciences, the research arm of Berlex. 'Berlex scientists have advanced several discoveries that started elsewhere to clinical research and the market place: the first gene therapy for the regeneration of microvessels of the cardiovascular system; a cell therapy for the treatment of Parkinson's Disease; and our breakthrough work on Betaseron, which reached market in 1994 and is a leading treatment in multiple sclerosis.

'The use of our small molecule antagonist for CCR1 represents not only our first work specifically in Alzheimer's, but also demonstrates the depth of our discovery strength by identifying multiple potential utilities for this product, as a therapeutic and as a diagnostic.'