Alzheimer’s disease continues to be a costly and frustrating minefield for drug developers. Most recently, Boehringer Ingelheim halted development of the phosphodiesterase type 9 (PDE9) inhibitor BI 409306 after it failed in phase 2. Merck also ended its trial of verubecestat, the company’s beta-secretase-1 (BACE1) inhibitor, in early stage Alzheimer’s disease patients for futility, a few months after stopping a similar trial in mild-to-moderate Alzheimer’s disease. BACE1 makes the raw materials that form amyloid plaques, one of the two hallmarks of the disease, along with tangle-forming tau. Unfortunately, both this study and others targeting amyloid have yet to show positive results in clinical trials.
Drug developers have been seeking to push studies of new compounds earlier and earlier in the onset of Alzheimer’s disease, ideally before any symptoms appear and well before the onset of dementia, in an attempt to prevent or slow disease onset. However, testing the efficacy of a drug in a patient population without physical symptoms poses obvious challenges for clinical trial design — what would be a measurable endpoint for such a trial? That’s where biomarkers could provide a surrogate readout that correlates with clinical trial success.
We’ve written about the push toward earlier trials and the need for new biomarkers of Alzheimer’s before, in this blog, our LinkedIn posts, and our recent In Vivo publication. Drug developers recently received encouragement from the U.S. Food and Drug Administration (FDA), who issued a new set of draft guidelines for comment. The guidelines suggest an approval pathway for Alzheimer’s disease therapeutics based on hitting acceptable biomarkers that indicate the drug is working. Such a move by the FDA would be a big change from current policy, which supports drug approvals based on evidence that a new therapy not only slows cognitive decline but also helps to preserve functional performance that could keep an Alzheimer’s affected patient independent for a longer period of time. Once a drug is approved based on biomarkers, the new draft guidelines suggest the developer would need to conduct further studies to confirm that the treatment offers a benefit, notably an effect on cognition.
However, it is still unclear which biomarker(s) could be used for this purpose. The Alzheimer’s Association Research Group has suggested that drug developers might use a mix of markers for amyloid-beta and tau, two of the main players in Alzheimer’s disease, alongside biochemical and other markers of neurodegeneration to identify pre-symptomatic patients who could be enrolled at very early stages of the disease before any signs of illness appear. Others fear, however, that shifting approval towards biomarkers that are still not well defined or validated, raises the prospects of approving new drugs that eventually are shown to be ineffective.
We wonder: Will these newly issued guidelines spur research and investment into the field of Alzheimer’s disease biomarkers? Or will using biomarkers as surrogates merely postpone the failure to a later time in the life cycle of a drug?