Alzheimer’s disease (AD) is projected to become a major drain on global health-care systems, with the cost of care for the United States alone amounting to more than $214 billion in 2014 and estimated to grow to $1.2 trillion annually by 2050.1 With limited treatment options, the disease is putting a large and growing humanistic toll on patients and their families. Research efforts have so far been disappointing, as a large number of developmental agents have failed to demonstrate efficacy in reducing symptoms or, preferably, alter progression of the disease. The recent news of positive early stage trial results for Biogen’s aducanumab has renewed hope for effective solutions for this devastating disease. However, many challenges remain in finding and funding new treatments.
Public awareness of the devastating impact of Alzheimer’s disease on patient quality of life has greatly increased over the last decade. Particularly in later stages of the disease, the impact on patient and caretaker certainly cannot be considered a normal part of aging. Progression of the disease in clinical terms is well described. I find it of particular interest how some researchers have described AD’s impact on a patient’s visual world through the observation of the evolution of artwork of some famous painters with the disease, such as Willem de Kooning.2,3 As the disease progresses, an artist’s works are increasingly affected by delusional misperceptions, spatial errors and changes in color perception. These observations illustrate how the patient’s worldview is increasingly distorted far beyond a collection of “senior moments.” As symptoms evolve over time from forgetfulness to personality changes, inability to perform daily living-related functions and social misbehavior, patients require around-the-clock professional care and become a strong emotional burden on their partner and families.
Drug development challenges
Unfortunately, the current generation of AD drugs, including Aricept (donezepil) and Namenda (memantine), only offer very limited symptomatic relief to patients. Many drug developments have had disappointing results.
Understanding the fundamental science behind the disease is an essential component of finding disease-modifying treatments. I have the privilege of serving on the board of directors of the BrightFocus Foundation, an organization that does great work in funding essential scientific research that can ultimately lead to new drug candidates and through this sponsorship encourages academic talent to become active AD researchers. Although vast progress has been made in understanding the science and to develop diagnostic tools, the disease still holds many secrets that create uncertainty with respect to the approach toward disease modification or even a cure. We hope that the current approaches will provide breakthroughs, but many challenges and questions remain.
The brain of an Alzheimer’s disease patient shows two distinct abnormalities, which formed an area of focus for many researchers:
- The formation of a beta-amyloid plaque
- Neuron tangles, presumably caused by disintegration of the “tau protein”
It is generally assumed that these two abnormalities are linked to AD. A large proportion of research efforts stems from investigators’ hypotheses that the avoidance or reduction of beta-amyloid plaque will arrest the devastating symptoms and disease progression of Alzheimer’s patients. The recent introduction of PET imaging techniques with the radiotracer Amyvid (florbetapir, Lilly) has enabled researchers to measure plaque levels in the brain. Prior to this introduction, analysis was only possible postmortem.
Drugs, such as Lilly’s solanezumab, have not lived up to the expectation that their anti-amyloid activity would have a disease-modifying effect on Alzheimer’s patients. As a result of this and other setbacks, investigators are now hoping that earlier application of the drug in the prodromal or mild cognitive impairment (MCI) stage of the disease will help to avoid future cognitive decline.
Recently, aducanumab (Biogen) demonstrated significant reductions in amyloid plaque levels and a decline in clinical impairment in patients with prodromal and mild disease in the recently complete PRIME Phase Ib study. The results are highly encouraging, although a robust Phase III clinical trial program needs to confirm them first. Many drugs have failed in this setting of clinical evidence generation.
Funding of new treatments
In the post-Sovaldi era, questions with respect to funding of new treatments for Alzheimer’s disease should be top of mind. Any new biotech drug with proven or highly promising potential for disease modification will be in high demand with AD patients. For drugs that are most effective in the prodromal stage of the disease, good diagnostics for treatment candidate selection will be critical to allow for targeted treatment. High-cost preventative treatments for a highly prevalent condition such as AD are likely to have a significant impact on health-care budgets.
An important question will be what evidence private and public payers worldwide will require before they adopt new AD treatments on their drug formularies. Demonstrating disease modification through treatment in the prodromal disease state will likely take very long, as symptoms emerge gradually over many years. Insistence on conclusive evidence of meaningful disease modification is likely to pose a great challenge to pharma companies and may impede them from undertaking significant development efforts.
The challenges in coverage decision making can be further illustrated by the history of AD drug reviews in England and Wales, where the National Institute for Health and Care Excellence (NICE) finally accepted proof of efficacy for Aricept in the mild disease state in October 2010 in a U-turn decision. NICE Chief Executive Sir Andrew Dillon said: "Since we published our guidance in September 2007, clinical trials have continued to show the positive effects of these drugs and, in the case of memantine, have reduced the uncertainty about its clinical effectiveness.”
“Welcoming the news, Clive Ballard, professor at King’s College, London, and director of R&D at the Alzheimer’s Society, said NICE’s justification for reversing its decision was “face saving,” arguing that little new evidence had come to light that did not already exist. He also pointed out that, given the drugs involved are approaching patent expiry, the economic burden on the National Health Service will be short lived.”
A factor in the above case can be that efficacy has unfortunately been fairly limited. A complicating factor in new effective treatments lies in the longer time horizon to establish efficacy and the potentially broad patient population that may qualify for the treatment.
To solve this challenge it will be important to consider two aspects in relation to coverage decision making and funding of a new drug treatment:
- The adoption of “risk sharing” (RS) or “coverage with evidence development” (CED) arrangements to avoid another case where approval takes place just before patent expiration; these programs should be true risk-sharing deals, not the current discount arrangements that often carry that name
- Learning from the Sovaldi history, explore alternate funding and pricing mechanisms to avoid restrictions to a small proportion of eligible patients due to health-care budget constraints.
The battle in finding and funding for Alzheimer’s disease treatments will continue to be an interesting one to monitor. We can only hope that new drug treatments will be so effective that the above funding issues are real.
This blog post also appeared on PharmaExec.com on April 23, 2015.
- Fisher, Nicole. New Test Claims It Can Tell If You Will Develop Alzheimer's... But Do You Want To Know? Forbes Magazine, February 6, 2015
- Maurer K., Prvulovic D. Paintings of an artist with Alzheimer's disease: visuoconstructural deficits during dementia. J Neural Transm. 2004 Mar;111(3):235-45
- L. R. Fornazzari, L.R. Preserved painting creativity in an artist with Alzheimer’s disease. European Journal of Neurology 2005, 12: 419–424