Scales to assess Alzheimer’s disease are not nearly sensitive enough to pick up on clinically meaningful changes in progression for patients with early-stage disease. That’s a problem as more and more pharmaceutical companies tackle this patient population with disease-modifying treatments in clinical trials.
So, do we throw out the scales and start over? A new study from the Alzheimer’s Association says no: We work with what we’ve got.
In a study published Tuesday in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, a working group confirmed that the common scales used in clinical trials of the disease, which measure severity, symptoms and progression, are not sensitive enough to show benefit when used in patients who may have few symptoms but confirmed Alzheimer’s pathology. But the key to the disease-modifying treatments under development is that any slowed progression in the near term can mean a huge difference in a patient’s life over the long term.
These scales are commonly used in randomized clinical trials for Alzheimer’s to assess a patient. One such scale, the clinical dementia rating sum of boxes, or CDR-SB, is used to diagnose cognitive impairment by scoring a patient on functioning such as memory, personal care, problem solving and more.
The study found that these scales “may lack the scoring precision necessary to signify robust statistically significant meaningful change” in early Alzheimer’s. But the group determined that “we cannot further delay the development of, or patient access to, potentially [disease-modifying treatments] while developing and adopting new and improved scales.” One option would be to extend clinical trials, but the group dismissed the idea of extending patient monitoring to 10 years as “neither practical nor necessary.”
Assessments of clinical meaningfulness are crucial in the life cycle of drug development. Government agencies, such as the FDA, public and private payers—like Medicare—use these determinations to decide whether to approve a drug or cover its use in patients.
The working group said that the problematic scales underscore the need for combination therapy in Alzheimer’s as more anti-amyloid monoclonal antibodies become available. Eisai and Biogen recently received an accelerated approval for Leqembi, and Eli Lilly is close behind with a regular filing expected later this year.
While these treatments have shown they can spur change on these scales—even if to a limited degree—they will someday need to be tested with anti-tau antibodies as an adjuvant to see if clearing both tau and amyloid can have a greater impact.
“The more we learn about the pathophysiology of [Alzheimer’s disease] and build on the success of clinical trials that show clear evidence of slowing disease progression in a broad range of mechanisms of action, the greater the likelihood that we will discover a combination of therapeutic interventions that are effective in certain patients and in particular phase(s) of the disease,” the study said.
The authors pointed to the treatment of hypertension, which combines a handful of medicines to reduce blood pressure, and cancer, where combo therapies have led to major breakthroughs. In cancer, different meds are given at different stages of the disease. The group suggested this approach could also work in Alzheimer’s.
As the Alzheimer’s Association points out in a statement, changes during clinical trials for the disease may seem small, but even a tiny delay of decline can be monumental when spread out over succeeding years. For instance, if cognitive function is preserved for six extra months and the patient can maintain independence and autonomy, that’s meaningful to the patient and their caregiver. This could delay severe onset and give families more time together.
This is a great step forward, even if the holy grail in Alzheimer’s treatment—halting the disease entirely—remains elusive.