The latest blow in the search for successful pharmacological treatment of Alzheimer’s disease came in February when drug company Merck announced it is halting the late stage trial of verubecestat, the latest promising drug for the neurodegenerative disease based on the beta amyloid theory.
According to a report by CNN, Merck stopped the drug trial in a group of patients with mild-to-moderate Alzheimer’s disease after an independent study found it had “virtually no chance of working.” Verubecestat, a drug known as a BACE inhibitor, controls an enzyme involved in the forming of amyloid plaques, an abnormal protein cluster in the brain that has been suspected as a main cause of the neurodegenerative disease.
Merck will continue its research of the drug for patients in earlier stages of dementia with results due in two years.
CNN also reported that the drug company, Eli Lilly, decided in late 2016 to end its clinical trial of the drug, solanezumb, after patients demonstrated no improvement compared to a group taking a placebo.
The failure of drugs in the family of BACE inhibitors developed to reduce amyloid adds doubts to the amyloid theory.
Around the same time that these two drug trials have failed, a classification system has been proposed for Alzheimer’s disease based solely on biomarkers. The new descriptive classification scheme, known as A/T/N that refers to amyloid, tau, and neuronal injury, leaves out neuropsychological testing results, clinical observations and other data such as caregiver reports.
The authors of A/T/N, first published in Neurology in August 2016, said the system will be useful in cognitive aging research because it is an unbiased descriptive classification scheme independent from any clinically defined system. Clifford Jack, M.D., lead author of the research, is a consultant for Eli Lilly.
In order to obtain a score in the new A/T/N system the patient is required to have a positron emission tomography (PET) scan or spinal tap. Four years ago the Alzheimer’s Association and stakeholders in the pharmaceutical industry made a concerted effort to convince the Center for Medicare and Medicaid to cover the approximate $3,000 cost of an amyloid PET scan for widespread clinical use.
A Medicare Advisory Panel determined in January 2013 that the research evidence was insufficient to conclude the use of PET imaging was reasonable and necessary for the diagnosis and treatment of Alzheimer’s.
During the Medicare Advisory Committee meeting CMS learned that a comprehensive neuropsychological evaluation included recommendations about everyday functioning such as needed level of care, healthy life style advice, emotional health, ways to reduce caregiver stress, safety and driving.
However, in September 2013 CMS partially reversed its decision and allowed coverage of one amyloid PET scan per patient through coverage in research studies that meet specific criteria. A CMS 2016 announcement listed three clinical trials that met the coverage requirements.
According to Peter J. Whitehouse, M.D., Ph.D, professor of neurology at Case Western Reserve University, “There is no evidence that the A/T/N description system improves patient outcomes.”
He said the reliability of biomarkers even in research is questionable. “It is not clear that the diagnosis will be more precise except that numbers with arbitrary cutoffs will be used. Amyloid imaging is difficult to interpret.”
Cameron Camp, Ph.D., director of research and development at the Center for Applied Research in Dementia, (Solon, Ohio) agrees. “The idea that you can get pure cases of AD driven by amyloid deposits assumes that amyloid is the real cause and that model has not been supported adequately in empirical research.”
Geoffrey Lane, Ph.D., geropsychologist at the Veterans Administration Palo Alto Health Care System, said, “Until drug development is at the point whereby effective treatments can significantly decrease the debility and functional decline in those with dementia, I don’t see biomarker-based diagnostic systems becoming widespread in the clinical realm, much less supplanting the need for neuropsychological testing.”
Camp was not as optimistic. “The A/T/N descriptive system looks like one more attempt to ‘medicalize’ AD and marginalize families, psychologists, and anyone who doesn’t have a medical degree from the process of diagnosis and treatment. This is especially problematic when drugs like Aricept at doses as high as 23 mg do not impact behavioral measures of improvement yet stay on the market.”
Paula Hartman-Stein, Ph.D. is a geropsychologist, trainer and educator who had served on the Medicare Advisory Committee. Her email is email@example.com