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In recent years, there has been a resurgence in the number of Alzheimer’s disease (AD) clinical trials, led by major efforts from Biogen, Lilly, Genentech/Roche, and others. These trials involve drugs that target the underlying pathology of AD – specifically, beta-amyloid plaques – and hold promise of disease modification. For the estimated 28 million Americans that are projected to be diagnosed with AD dementia by 2050, and for the insurers, providers, and public health agencies faced with managing the disease, the success of even one pivotal trial would represent a new era of hope for AD treatment and prevention.  

Many of the AD drugs in development operate on the premise that the buildup of beta-amyloid is the initial step in a cascade of events that eventually leads to the devastating symptoms of brain degeneration and, ultimately, death. One class of drugs in development, monoclonal antibodies, binds to amyloid and clear the harmful protein plaques from the brain before they can cause irreversible damage. Therefore, in order to improve the chances of clinical trial success, drugmakers are using advanced diagnostic techniques to ensure that trials enroll only patients that (1) have confirmed amyloid pathology, and (2) have not progressed so far that they may not benefit from an amyloid-targeting treatment.  By studying early-stage, biomarker-positive patients, the hope is that the potentially disease-modifying drug candidates in development will succeed at addressing the underlying pathophysiology of AD and thereby slow disease progression.

However, with the first of these novel AD therapies potentially coming to market as early as 2017/2018, there are a number of critical and as yet unanswered questions surrounding the economics and policy of AD diagnostic screening.

1. Who Will Seek Diagnostic Screening for Alzheimer’s Disease?

Along with the development of the next generation of AD treatment comes a shift in the way we must view the disease of Alzheimer’s itself. Historically, Alzheimer’s was known for the clinical symptoms of dementia – namely memory loss and cognitive dysfunction severe enough to impact independent functioning. A definitive diagnosis was only possible postmortem by looking at the brain for evidence of amyloid plaques along with intracellular tangles of tau protein.

Scientific evidence gathered over the past two decades suggests that damage may begin to occur up to 20 years before the onset of traditional cognitive symptoms in AD. Amyloid plaques in particular are now known to start building up in the brain far earlier in life, in an estimated 17 percent of cognitively normal individuals over the age of 50. These individuals – in addition to those with early-stage clinical AD – are prime candidates for treatments with monoclonal antibodies targeting amyloid. Yet, in order for an individual, symptomatic or otherwise, to know that he/she has amyloid pathology – and become eligible for treatment (FDA guidelines will likely limit use of amyloid-targeting antibody therapies to those with confirmed amyloid buildup) – he/she must first undergo diagnostic screening.

Figure 1. Clinical trajectory of Alzheimer’s disease

Today, there are two primary ways to determine whether an individual has amyloid buildup – 1) testing the cerebrospinal fluid (CSF) for biomarkers and 2) positron emission tomography (PET). Both methods have drawbacks. CSF screening involves an invasive spinal tap, in which fluid is drawn using a needle inserted into the patient’s back. Although the procedure is relatively safe and painless, it will be a challenge to convince at-risk individuals who have not yet developed symptoms to undergo the procedure. PET screening involves costly scanner time and tracer compounds that are not currently commercially reimbursed by Medicare and most commercial insurance companies. The total out-of-pocket cost for an amyloid PET scan averages $3000. These factors have kept current rates of screening very low: according to a recent Trinity Partners analysis of Medicare claims data, fewer than 1 percent of AD patients received CSF or PET tests in the four-year period between 2010 and 2013.

Figure 2. Screening rates in the AD population: Data presented by Trinity Partners at the October 2015 Academy of Managed Care Pharmacy (AMCP) Nexus conference. The analysis took a random 5% sample of Medicare fee-for-service beneficiaries aged 65+ as of 2010, filtered for AD diagnosis, and calculated rates of screening based on claims data. Screening tests included amyloid ligand PET scans (PET), cerebrospinal fluid (CSF) tests and experimental tests (e.g., natriuretic peptide and homocysteine assays) as well as more traditional cognitive assessments (CA) and brain CT and MRI scans (brain imaging that does not identify amyloid pathology specifically).

These screening rates are not surprising given that there are currently no approved amyloid-targeting therapies available.  If one of the potentially disease modifying AD therapies in development is successful, AD diagnostic testing rates are bound to increase. Since any healthy older adult may test positive for amyloid – and therefore be a candidate for drug treatment – there may be many tens of millions of individuals for whom diagnostic screening could be conducted once amyloid-targeting therapies are approved.

2. Who Will Pay for Diagnostic Screening, and Where Do We Go from Here?

With a potential target population of this magnitude, costs become a major concern. Even if PET screening prices drop to half of their current level and only 15 percent of Americans over 50 seek screening, the total potential price tag for AD diagnostic screening alone may be as much as $25 billion. Add on top of that the cost of the new drugs, which analysts estimate could cost between $5,000-$25,000 per patient per year, and the total costs associated with treating AD quickly surpass any other disease to date.

In addition, the economic benefits of screening for and taking an amyloid-targeting drug, especially for those with preclinical AD, may be largely deferred. Although taking the drug may slow the progression or even prevent the development of AD, the cost savings may be realized many years after an individual begins treatment. For commercial payers, that may mean paying for screening and treatment for many years, during a period in which the treated population would not have developed symptomatic AD. There is a health economics argument to be made for delaying the onset of AD dementia, which is expected to cost over $1 trillion by 2050, but the actual value of a disease modifying treatment may be dispersed across time and payer organizations.   

Therefore, in order to ensure access to new AD treatments and effectively curb the tidal wave of AD dementia diagnoses on the horizon, all stakeholders in the US healthcare system must align towards an integrated, balanced solution to dealing with the many challenges associated with the future of AD:

  • Commercial payers and the Centers for Medicare & Medicaid Services (CMS) must agree on a mutually accountable approach that allows for early-life screening and preventative therapy while considering these new early costs of care alongside the costs associated with later-life disease management.
  • Diagnostic companies must continue to invest in the development of novel biomarker tests such as PET ligands for tau, blood assays, saliva testing, and other approaches that can make screening cheaper and more accessible.
  • Providers must help the public redefine its perceptions of AD so that eligible individuals seek screening and accept treatment, even without symptoms of dementia.
  • Drug manufacturers must set reasonable prices that do not overburden the healthcare system.
  • Regulators will have to contend with new trial endpoints that are better suited for the preclinical AD population than the cognitive and functional measures currently used in AD trials, and must set reasonable eligibility criteria.

The approval of a disease-modifying AD treatment promises to transform both the diagnostic and treatment paradigm for AD. With careful consideration of the many challenges that lie ahead, we can maximize that transformative potential.  

Acknowledgments

Gretchen Chiu, Gavin Miyasato, David Small, and Zheng Wang performed the Medicare claims data analysis cited in this article.

 

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