With some tests to diagnose Alzheimer’s disease approved and therapeutics to improve, halt or even reverse disease progression currently in late-stage clinical trials, the next hurdle is to translate these advances into clinical practice. Unfortunately, that’s not as straightforward as it may appear.
Consider Aduhelm (aducanumab), approved by the FDA last year and lecanemab, currently undergoing FDA review under the accelerated approval program, with a decision expected in early January. Both drugs were developed by Biogen to treat the underlying causes of Alzheimer’s disease.
“Both are associated with significant brain swelling and microhemorrhages,” said Neil Cashman, M.D., CSO and co-founder of ProMIS Neurosciences in Toronto.
“When lecanamab treatment enters the ‘real world’ after approval, it will necessitate very careful monitoring of patients - i.e., frequent MRI scanning to monitor ARIA - which will be expensive and require a level of specialization and equipment that’s usually only available at major medical centers, severely restricting patient access," he told BioSpace.
ProMIS also is developing a therapeutic, PMN310, which is currently in preclinical studies. This investigational monoclonal antibody binds selectively to neurotoxic Aβ oligomers and aims to modify the course of the disease.
Bridging the Translational Gap
The Davos Alzheimer’s Collaborative is working to bring these therapeutics and diagnostics to patients through implementation science.
“Not giving someone an accurate diagnosis is tragic, and it’s one of the reasons we started the [DAC] in 2021,” said Phyllis Barkman Ferrell, healthcare system program director, and executive on loan from Eli Lilly & Company. “There’s a ton of innovation that’s available today.”
To bridge the translational gap, the DAC is focusing on implementation science – putting Alzheimer’s disease diagnostics in real-world settings with 19 programs in 12 countries, and collecting the operational facilitators and barriers.
“Researchers often think they will publish their research in (a prestigious journal), and that it will be read and implemented,” Ferrell told BioSpace. “In reality, health systems are highly structured environments with many competing priorities. Physicians have real operational barriers in the way they manage their time and run their practices, and those things have a lot of variability.”
Agile Implementation
To identify specific challenges, “We are testing implementation (of cognitive tests and diagnostics) in lots of different situations,” said Deanna Willis, M.D., a DAC principal investigator and interim chair, family medicine at Indiana University.
Those situations include multiple types of clinics, patient populations and economic and geographic environments. Because innovations are being introduced in an Agile sprint rather than a clinical study, feedback can occur continually, and lessons learned are shared and incorporated into subsequent iterations of the rollout.
Nobody is translating scientific advances in Alzheimer’s diagnostics into routine patient care particularly well, Willis said. “Even with a highly motivated staff and providers, the healthcare system still has a lot of things that have to be addressed.”
The beauty of the program is that it includes sites in high- low- and middle-resource countries. Good ideas are emerging and being shared to address a variety of situations.
For James Richardson, M.D., M.P.H., chief of geriatric medicine at Ascension St. Agnes Hospital in Baltimore, and adjunct professor at the University of Maryland School of Medicine, the reluctance of physicians to recognize and diagnose dementia is the most significant barrier.
“I attribute this reluctance to the lack of training regarding the multiple presentations these patients may have and the belief that physicians in other specialties should make the diagnosis," he told Biospace.
Routine and Early Detection
In the United States, “One of the main things on the primary care side is that routine early detection and cognitive assessment screening has not been endorsed by the U.S. Preventive Services Taskforce,” Willis said. Medicare wellness visits, however, do request a baseline cognitive assessment, so there are conflicting recommendations for physicians.
Having information early about cognitive impairment can be quite valuable to patients and families in terms of helping them understand what’s coming and what they can do now to prepare. It also enables people with mild cognitive impairment to modify their lifestyles – improving their diet, exercise, sleep and smoking status.
Lifestyle modifications won’t prevent the onset of Alzheimer’s disease. “If it’s coming, it’s coming,” Ferrell said, “but we know from studies at the Karolinska Institute, the Mayo Clinic and other institutions, that up to 40 percent of dementia could be preventable with lifestyle modification, which may make the brain more resilient.”
Today, the diagnosis of Alzheimer’s disease typically is made late, often in the emergency room.
“Nearly half of those with Alzheimer’s are never diagnosed, and half of those who are diagnosed are in the severe phase,” Ferrell said. Yet, the pathology starts in the brain 10 to 20 years before symptoms appear. Like with cancer or any disease, there’s more that can be done when the disease is diagnosed at an earlier stage.”
One of these issues is personal awareness. “People don’t recognize (mild cognitive decline) or they cover the symptoms for a while, so they may not bring up concerns with their doctor,” Willis said.
Furthermore, she noted that physicians who are having a logical discussion with a patient may not realize anything is amiss.
“That’s why systematic, structured, regular assessments are so important. You can’t do this based on when your gut tells you. You’ve got to do it routinely, with a structured tool that’s been tested and validated.”
Standardizing Testing
As new tools are added, reimbursement is always an issue. In the U.S., for Alzheimer’s disease, that means Medicare. Currently, the cost of early detection tools is not reimbursed, Ferrell said, although some CPT codes do allow physicians to be reimbursed for their time to administer the test and analyze the results.
“The second step is accurate diagnosis,” she continued. “There are FDA-approved diagnostics – including PET scans and blood tests – but none of those are paid for by Medicare.” The CDC, therefore, is working to develop a CPT code for physicians to be reimbursed for conducting diagnostic procedures and interpreting their results.
The benefits of making cognitive screening routine are legion. By making cognitive testing a standard part of a health exam that everyone receives at age 65, the stigma of having a cognitive assessment can be reduced. As Willis said, “The more we can get structured, validated assessments into daily practice, the better this will be.”
The other benefit of routine cognitive screening relates to health equity.
“People of color are less likely to get a diagnosis, and people who are living with lower social determinants of health are at much greater risk of this disease,” Ferrell said. “For example, African Americans are two times more likely, and the Latin population is one and a half times more likely, to develop Alzheimer’s disease.”
Therefore, performing cognitive impairment assessments for everyone at a certain age helps ensure that everyone, regardless of their ethnicity or geographic location not only receives an assessment but receives the same assessment. Consequently, if there is a problem, it is more likely to be diagnosed.
Convincing Doctors
Physicians will also need to be brought on board.
There is a nihilist belief by some physicians that there is no reason to make the diagnosis as there is no treatment for patients with dementia,” Richardson said. “A concerted educational effort, tied to new therapeutics, would help overcome these barriers.”
These physicians believe that medications only provide temporary, symptomatic relief, said Michal Schnaider Beeri, director of the Joseph Sagol Center for Neuroscience Research at Sheba Medical Center and professor of psychiatry at the Icahn School of Medicine at Mount Sinai.
“The new medications that target brain amyloid plaque are more complex with more side effects. Clinical trials were conducted with stringent eligibility criteria and therefore weren’t necessarily tested on people with comorbidities…so once it (is used) in the larger community, we won’t know the effects for regular people. Medical doctors, therefore, may want more evidence.”
The remaining question the DAC is trying to answer is how routine cognitive assessments can be integrated into physicians’ practices, especially with limited resources and competing priorities.
The solution is multifactorial. “It’s not just physician training or developing the right CPT codes, or educating patients on brain health,” Ferrell said, or even about changing healthcare policies. It requires an “all of the above” solution. As the DAC learns more about the challenges, it has the opportunity to begin addressing each of them, based on real-world data.
“We expect complete data from the first set of projects to be available in mid-2023. The second set of project grants will go a bit longer,” Ferrell said. The DAC also plans to issue new requests for proposals in 2023.
Ultimately, the DAC plans to make its findings public, possibly in a toolkit so patient-facing physicians can integrate the findings into their own practices.
https://www.biospace.com/article/bridging-the-translational-gap-between-alzheimer-s-advances-and-patients-/
