New FDA draft rules for Alzheimer’s trials may open the door to earlier treatment

A new set of FDA draft guidelines for assessing Alzheimer’s disease (AD) drugs could accelerate approval of early interventions against this devastating disease. More broadly, the new rules have intriguing ramifications for drugs targeting aging and longevity in humans.

The challenge of developing effective AD medications is severe: the disease advances invisibly for years before symptoms are clinically detectable, and the earliest signs are subtle and variable among patients. By the time unambiguous symptoms emerge, neurons have died en masse, and countless brain circuits have been disrupted. Even if we could stop the progress of the disease at that point, the damage is irreversible.

Making matters more difficult, the historical criteria for enrollment in AD clinical trials have been very stringent: the FDA required that eligible patients have both cognitive and functional impairment (i.e., defects in thought as well as difficulties performing daily activities). Furthermore, to be considered efficacious, a drug had to be able to improve both types of endpoints.

These demanding conditions may underlie the failure of multiple trials of promising medications: In clinical trials initiated after the onset of dementia, antibody therapies such as bapineuzumab and solanezumab have successfully decreased Aβ aggregation in the brain, but did not lead to effective recovery from dementia symptoms. Consequently, despite the favorable molecular outcome, the trials had to be considered failures—possibly because the interventions simply came too late, after the damage was done.

Acknowledging that progress toward pharmaceuticals capable of treating complex neurological conditions has been “uneven,” the FDA has proposed revising its guidelines for trials aimed at early AD (link):

The FDA has been working closely with patients and the scientific community to gain the knowledge that will support intervention in very early AD in ways that have the potential to stop the disease before it causes clinical problems. This document describes innovative approaches to studying very early disease before the onset of dementia, including strategies for trials incorporating patients with Alzheimer’s who haven’t experienced any visible impairment (in the form of cognitive or functional deficits), but who may be identified through the use of sensitive cognitive screening, imaging tests, or biomarkers.

The new draft guidelines, which you can read in their entirety here, update the FDA’s thinking on AD treatment to reflect the most current understanding of this illness.

To overcome some of the obstacles created by the stringency of the previous criteria for efficacy, the new guidelines abolish the cognitive/functional dichotomy and allow that cognitive improvements are independently importance in their own right.

More importantly in regard to the earliest stages of AD, the new rules open the door to drugs whose primary endpoints are neither cognitive nor functional in nature, but instead are “biomarkers” — serological or radiological measurements that reflect the pathophysiological changes that precede even the sublest neuropsychological symptoms. On the assumption that these molecular changes precede AD symptoms because they are causative, treatments capable of normalizing AD biomarkers in presymptomatic patients have the potential to delay disease progression or prevent it altogether.

If the FDA is willing to consider biomarker endpoints for a complex, age-related condition such as AD, it could set a valuable precedent for how to assess drugs aimed directly at the aging process. The logistical challenges confronting clinical trials of anti-aging medications are staggering, exacerbated by the controversies surrounding endpoint selection. Mortality, functional status, and time-to-event (e.g., onset of age-related disease, as proposed for the TAME trial) have all been considered as endpoints, but each has its own logical and practical disadvantages, not least of which is the time required to make the necessary observations. If we could evaluate drug efficacy by monitoring the real-time effect on well-established biomarkers of aging, it could dramatically accelerate the testing and approval of longevity-enhancing compounds.

Currently, the new guidelines are under review as the FDA collects feedback from patients, researchers, and industry. Presumably, a favorable response from clinician researchers and pharmaceutial industry will increase the likelihood that the guidelines will be formally adopted.