LONDON – Cytox Ltd. has been rescued from liquidation and raised £3.5 million (US$5.5 million) in new money to reinvigorate efforts to develop a simple, definitive blood test for the early diagnosis of Alzheimer's disease.

That would both provide an advance in terms of the care of people with the disease and in enabling drugs to be tested in the earlier stages of the disease when there is a greater likelihood of showing a significant clinical effect.

The recent Phase III failures of two antibodies targeting amyloid plaques, solanezumab and bapineuzumab, have led clinicians to believe that trials need to be conducted in patients in earlier stages of disease.

"The failures of solanezumab and bapineuzumab have raised the stakes in amyloid targeting. First of all, are drugs targeting an appropriate mechanism at all? If they are, we need to get them to patients at an earlier stage of disease. At the moment, the damage is already done," said Richard Pither, Cytox CEO. "What's wanted is a good in vitro diagnostic."

Currently, the diagnosis of Alzheimer's disease depends on cognitive testing, which is not effective in distinguishing Alzheimer's from mild cognitive impairment (MCI), or by PET imaging. Pither was involved in the development of a 18F-PET radiopharmaceutical for imaging amyloid deposition in the brains of Alzheimer's disease patients in his former post at GE Healthcare (Medical Diagnostics), and as he noted, PET is high cost and low volume, and so not accessible to most people.

Cytox's ADpredict test by contrast is based on a single indicator – of a fault in the cell cycle – which was identified by the founding scientist Zsuzsanna Nagy of Birmingham University.

She postulated that dysfunction of the G1/S regulatory mechanism allows brain neurons to abnormally progress to the late stages of the cell cycle, causing them to produce the plaques and tangles that are the hallmarks of Alzheimer's. That builds on the controversial proposition Nagy made in the 1990s that neurons, although they may not replicate, possess cell cycle machinery and, under certain conditions, can enter the cell cycle.

"We don't expect to replace cognitive testing or imaging, but these are used late in the disease process, and may not be definitive. With a proper diagnosis, there are things you would do to intervene, and you would be able to divert people to therapy trials," Pither said.

The £3.5 million allows Cytox to carry out clinical trials to validate the test by comparing it in a blinded fashion with diagnoses made by other methods.

Most cases of Alzheimer's disease begin with a diagnosis of MCI. "Around 25 percent of those diagnosed with MCI develop Alzheimer's, and there's a big problem with overdiagnosis at that point. We will test that we can identify the people with a diagnosis of MCI who progress to Alzheimer's," Pither said.

The company is talking to expert clinicians and Pither said it will be possible to get the test into clinical use in the National Health Service relatively quickly. Cytox is setting up a laboratory in Manchester to process the tests, and Pither said that will have the capacity to provide a nationwide service.

In parallel, it will establish partnerships with pharma companies that want to use the diagnostic to select individuals for clinical studies in what can be a fuzzy, heterogeneous group of patients.

Pither said the test is relevant, regardless of what aspect of Alzheimer's pathology a drug targets. Before Cytox's earlier liquidation the diagnostic was used by F. Hoffman La Roche in three clinical studies and this has provided validation of its use in stratifying patient populations. The results will be used to refine the next steps in assay validation and clinical development.

ADpredict has now been tested in close to 300 subjects, and the data from the Roche trials have been submitted for publication.

The diagnostic also has potential utility in drug re-purposing since it could be used to reposition cell-cycle inhibitors under development in other indications, particularly cancer.

Cytox originally raised $1 million in a Series A round in July 2009 after obtaining preliminary validation for the cell cycle biomarkers from a study conducted in collaboration with the Oxford Project to Investigate Memory and Ageing (Optima), a UK longitudinal study, ongoing since 1988, in which normal volunteers have been compared to patients with various memory deficits.