By Hank Safferstein, Ph.D., J.D.
PLSG Executive In Residence
Cognitive disorders, such as Alzheimer’s dementia, are devastating and will put an increasing strain on our healthcare system as the population ages. As of February 2016, there were approximately 174 drugs in clinical development, with only 5 marketed therapeutics. This disparity, in large part, is due to difficulties demonstrating efficacy in clinical trials.
Efficacy can be difficult to demonstrate for two primary reasons. First, Alzheimer’s patients likely comprise a heterogeneous population where the disease can stem from disparate pathologies. Patients are segmented primarily on the presentation of symptoms. This is important because two patients with similar symptoms may have dysfunction in different pathways, meaning a therapeutic may work for one patient but not the other. When an investigational new drug is given to a specific patient population, it provides more power to a clinical trial. Second, traditional outcome measures are centered around cognition, a relatively “soft” and imprecise clinical endpoint. Cognition is considered “soft” because it naturally changes from morning to evening, from day to day, and between individuals. Additionally, patients in both the placebo and drug groups learn these cognitive tasks over the course of a clinical trial. Identification of factors that consistently report the severity of the disease across time and individuals will also provide more power to a clinical trial.
Identification of Alzheimer’s specific biomarkers can bridge these challenges. Biomarkers can provide important information on the presence and progression of the disease. An ideal biomarker can effectively link a drug’s mechanism of action to its intended effects on disease pathways. Therefore, instead of relying solely on cognitive function, drug efficacy can be based on changes in expression of molecular biomarkers. Likewise, these biomarkers can be used to segment the population based on the presence or expression of specific biomarkers instead of subjective measures of symptoms. Failure rates in Alzheimer’s clinical trials could be reduced significantly if patients were segmented based on molecular profiling.
Our challenge, to both clearly measure outcomes and segment patient populations, boils down to a core need to identify specific biomarkers of these diseases. Plasma, cerebrospinal fluid (CSF), and imaging (MRI, PET) biomarkers have the potential to improve diagnosis, stratify or otherwise segment patients, and provide measures on which to track disease progression and the effects of therapeutic and lifestyle interventions. There is a real need for the successful translation of biomarker data generated through the use of mass spectrometry, immunoassays, and imaging into patient endophenotypes. Researchers believe this will happen, but the question remains: Will regulatory agencies accept biomarkers as clinical endpoints?
The PLSG continues to conduct outreach and engage in direct involvement with life sciences innovators working to better understand and treat these cognitive disorders.
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