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FDA explains draft Alzheimer's guidance in NEJM editorial

Intends to relax requirements in patient function and cognition

FDA Alzheimer's guidance

The US FDA looks set to relax the requirement for new Alzheimer's medicines to improve patients' functioning as well as cognition as part of its development of new guidance for drug developers.

The agency has published an editorial covering its recently-issued guidance document on Alzheimer's drug development in the New England Journal of Medicine, explaining that cognition alone may be used in trials involving patients with no obvious symptoms of dementia.

For trials in patients with poverty symptoms the dual endpoint of function and cognition will likely still apply, according to the FDA's Nicholas Kozauer and Russell Katz.

In the very early stages of the disease even cognitive impairment can be subtle and hard to assess, so gauging a functional impact is practically impossible. Meanwhile, it is now thought that deposition of amyloid is a very early event in the disease process, perhaps as much as 15 years before symptoms develop.

"The premise that effective cognitive improvement will be manifested in the functional assessment of patients is untenable in the case of early-stage Alzheimer's disease, which is increasingly the target of drug-development efforts," write the authors.

The move comes after the failure of several late-stage studies of drugs targeting beta amyloid plaques - one of the hallmarks of Alzheimer's dementia - and a shift in R&D efforts towards earlier intervention in the disease before beta amyloid exerts its neurotoxic effects.

The last couple of years have seen disappointing trial results for Lilly's solanezumab (although it remains in development and could benefit from the policy change at the FDA), the demise of an intravenous formulation of Pfizer's bapineuzumab, and failures for other drugs such as Lilly's gamma secretase inhibitor semagacestat and Elan's ELND007.

Lilly is also looking at earlier-stage intervention with solanezumab, while Genentech/AC Immune are going even further upstream by testing their crenezumab candidate in a healthy group of high-risk patients.

"Improvement in function … could lag substantially behind cognitive improvement mediated by pharmacologic agents early in the course of the disease," note Katz and Kozauer, adding that increasingly studies are looking at trying to prevent the onset of Alzheimer's in patients at elevated risk.

The current proposal is for cognitive tests to be linked to biomarkers, such as cerebrospinal fluid (CSF) levels of beta amyloid and tau protein, although Katz and Kozauer concede that there is currently no hard evidence that drugs affecting these biomarkers will have a clinical benefit.

Nevertheless, it is clear that the pharma industry is moving in this direction. Earlier this week, Merck announced a deal with Luminex for a companion diagnostic that would measure beta amyloid and tau in CSF and help the company to develop its lead Alzheimer's candidate MK-8931.

15th March 2013

From: Research, Regulatory

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