Alzheimer’s disease (AD) is a brain disease that progresses through sporadic AD to overt dementia. AD affects more than 5 million Americans and is the sixth leading cause of death in the U.S. Despite intensive R&D efforts by a number of drug companies, drug development to tackle AD has had very limited success. At present, only a handful of approved drugs are on the market which only reduce or stabilize the cognitive symptoms associated with AD (e.g. memory loss, confusion and problems with thinking and reasoning), but none have approvals for halting disease progression or reversing the disease.

Currently available drug treatments consist of two categories that affect chemical signal carriers in the brain: cholinesterase inhibitors (such as donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne)) and memantine (Namenda) with acts on glutamate activity. These drugs are approved for various stages of the disease; donepezil is approved for all stages, rivastigmine and galantamine for mild to moderate stages, and memantine for moderate to severe stages of disease. Further, there are at least a dozen treatments in phase III clinical development, such as azeliragon, which targets the RAGE receptor, and aducanumab (Biogen) and lanabecestat (AstraZeneca), which target the amyloid hypothesis.

The reasons for the lack of available therapeutics for AD are several fold: there is not a full understanding of the disease, there is difficulty in accurately diagnosing the various stages of the disease and there is a lack of clearly defined and accepted biomarkers that would predict the halting or reversal of disease progression. In addition, AD develops over a long period and different patients progress at different rates, making it difficult to design clinical trials. This often results in lengthy trials with a large numbers of subjects, which balloons clinical trial costs. Also, it is thought that for an AD therapy to be successful, treatment may have to be started at an early stage in disease when disease may not be as evident and cognitive assessment may not be able to show benefit due to the stage of disease, further complicating clinical trial design.

A 2013 FDA draft guidance for early-stage AD clinical trial design called for reliance on specific biological signals based on widespread evidence-based agreement in the research community. FDA is now modernizing its approach in a newly issued draft guidance. In this guidance FDA is widening the accepted outcome measures and defining specific stages of early AD that can be used for patient identification in clinical trials. Also depending on the stage, it may now allow for cognitive-only endpoints whereas in the past, efficacy required a co-primary endpoint of cognitive and functional improvement where cognitive changes were not considered inherently clinically meaningful.

The new guidance calls out specific categories of early-stage disease (Stage 1 to 3) and includes specific guidance on the selection of efficacy outcome measures for each of these early-stage AD categories. The guidance does not cover the later stage (Stage 4) where patients have overt dementia.

Stage 1 – Patients show characteristic pathophysiology changes of AD but with no evidence of clinical impact. Patients are asymptomatic with no subjective complaints.

At this stage, a clinically meaningful benefit cannot be measured; therefore, an effect on pathophysiological changes of AD, through an effect on various biomarkers, may be measured and serve as a primary outcome efficacy measure and form the basis for accelerated approval. The biomarker effect would need to be found reasonably likely to predict a clinical benefit in this case, and to be confirmed through a post-approval requirement showing the predicted clinical benefit.

Stage 2 – Patients show characteristic pathophysiology changes of AD and subtle detectable abnormalities on sensitive neurophysiological measures, but no functional impairment.

FDA recognizes that at this stage it still may be difficult to show a clinically meaningful benefit on subtle cognitive deficits. A sponsor may able to design studies of sufficient duration to show clinical benefit, but alternatively a persuasive effect on sensitive measures of neurophysiological performance (preferably by multiple neurophysiological tests) supported by effects on pathophysiological changes of AD may form the basis of a drug approval for this stage.

Stage 3 – Patients show characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neurophysiological measures, and mild but detectable function impairment.

Drugs targeting this stage will need to show a meaningful clinical benefit through sensitive neurophysiological performance where the efficacy outcome measure provides an assessment of meaningful cognitive function. An integrated scale that adequately and meaningfully assesses both daily function and cognitive effects in patients at this stage would be acceptable as a single primary efficacy outcome measure, where daily function and cognitive effects could be analyzed independently as efficacy outcome measures.

Further, the guidance suggests a time-to-event analysis approach for primary efficacy measures for early-stage AD. Also to provide evidence that the drug has permanently altered the course of AD, FDA suggests using a randomized-start or randomized-withdrawal trial design. It further comments that assessment of biomarkers may provide supportive evidence for a drug that has an established meaningful benefit, but given that the effect of biomarkers on AD are not sufficiently understood this would not provide evidence for a persistent effect on disease course. At present, there is no consensus on which particular biomarker would be predictive of clinical findings in early-stage AD. Trials therefore cannot be designed to include these as secondary outcome measures. However, the guidance encourages sponsors to analyze biomarkers in their trials, which based on the overall scientific understanding of these biomarkers at the time of the marketing submission, may contribute to the approval of the drug.

With this new framework of earlier and more specific selection of patients at early stages of AD and the means to assess efficacy for each of these stages, FDA hopes to promote more early-stage AD drug development.

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