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Published on: August 3, 2016
by Kenneth L. Davis for Forbes:
The search for medicines that can prevent Alzheimer’s disease is showing more promise than ever, thanks in part to human genome mapping and advanced brain scanning capabilities. Yet, as scientists utilize new capabilities to peel away at the onion holding the answers to Alzheimer’s, they’re discovering the onion is larger than it had appeared.
A strategy for fighting Alzheimer’s that is the focus of much attention is to attempt to prevent, or at least delay, onset of the disease by developing drugs that can slow, or perhaps even stop, the growth of beta-amyloid protein fragments that destroy synapses, reducing the ability of neurons to transmit signals, and eventually clump into plaques that kill off nerve cells. Scientists are also targeting the neurofibrillary tangles of tau protein that cut off the transport of nutrients within a nerve cell, leading to its death.
This process of protein clumping and nerve cell injury begins up to 30 years before symptoms are apparent. A major challenge in designing the right drugs for Alzheimer’s is determining how to select a time for intervention that is early enough to prevent the protein clumping but minimizes the time during which patients are exposed to medications that may have strong side effects. Long-term statin treatment of high cholesterol illustrates this approach. Statins are often begun early in adult life and continued for decades in order to control cholesterol, thereby helping to prevent arteries from becoming blocked and averting heart attacks and strokes. Medications that control brain protein clump buildup could similarly save brain cells, allowing those at risk to avoid the devastating consequences of dementia, assuming that we can identify a medicine that is both safe and effective for decades. Many of the brain protein clump buildup drugs that we are testing now, however, require intravenous administration and have quite important side effects.
The search for a breakthrough is exceedingly challenging, particularly because Alzheimer’s drug testing takes a very long time, to some extent because the protein clumping progresses very slowly. In fact, the complete process can take nearly as long as the 20-year patents these drugs are granted. To succeed in developing a drug that can actually prevent or delay Alzheimer’s, we need to study people who, on imaging studies of their brain, already show Alzheimer’s pathology but do not yet have significant clinical symptoms of the disease.
So let’s do some quick math. Preclinical studies and animal toxicology studies will require at least two years, but could need as long as five. Phase I human safety trials will take at least a year. Studies of pre-symptomatic patients would require about three to five years for a phase II trial, then another year to analyze the data. Phase III trials are large and expensive, and the FDA, to date, has required two independent phase III trials, which are typically done in a series, the second conducted after the first delivers promising results. Each phase III trial involves a three-to-five-year cycle followed by a year of data analysis. Finally, comes preparation of the FDA submission and the FDA review. At this point, we have practically run out of patent life.
To add another challenge, Alzheimer’s trials must rely upon biomarkers of the beta-amyloid plaque and tau tangles that indicate the disease, rather than analysis of clinical symptoms. Yet the Food and Drug Administration has never approved a medicine based solely on biomarker evidence.
Given the considerable hurdles pharmaceutical companies must jump, it’s no wonder they are choosing other, less challenging diseases for drug development rather than developing medicines to slow the accumulation of beta amyloid plaque and tau tangles in people at risk of Alzheimer’s. High-risk, long, costly trials of experimental drugs that leave little patent life once approved hardly make for a compelling business model. There is little assurance of the ability to recoup investments, no less earn a profit, even if a company succeeds in the arduous effort of creating, testing and winning approval of an Alzheimer’s medicine.
Congress can do something about this by creating a period of marketing exclusivity for Alzheimer’s drugs that is independent of patent life. Such exclusivity periods have successfully incentivized development of biologics (treatments from proteins manufactured in living cells, including vaccines and gene therapy), which have a 12-year exclusivity period enacted by the Affordable Care Act, and development of drugs for rare diseases, thanks to the Orphan Drug Act that established a seven-year period of exclusivity. It is time for Congress to create such an exclusivity period for drugs that will slow the onset or progression of Alzheimer’s. Pharmaceutical companies need this incentive to minimize the risk inherent in the development of an Alzheimer’s drug.
More than five million Americans suffer from Alzheimer’s disease and other dementias that rob victims of their minds, including vascular dementia, frontotemporal dementia and dementia with Lewy bodies. As baby boomers age, the number of victims and families whose lives are affected will rise substantially.
But it’s not only for medical and humane purposes that Congress must act. Dementias are among the most costly diseases we face, causing a crushing financial burden for the United States. Nearly one of every five Medicare dollars is spent on people with Alzheimer’s and other dementias, and by 2050 that will rise to one in every three dollars, according to the Alzheimer’s Association. Spending this year on healthcare, long-term care and hospice for dementia patients will reach $236 billion, the analysis finds.
If a new drug could slow the progress of Alzheimer’s by 50%, most of those who now exhibit signs of dementia in their 70s would not be severely impaired until their 90s, which would dramatically bend the cost curve of this terribly expensive brain disease, while enhancing quality of life for patients and their loved ones.
But it has been decades since a new Alzheimer’s drug came to market. In fact, three of the four available drugs date back to research I conducted in 1978 that suggested restoring levels of acetylcholine, a chemical in the brain that underlies short-term memory, could be helpful for treating Alzheimer’s. I conducted the first successful proof-of-concept study and coordinated the first multicenter National Institutes of Health ngIf: ticker -funded trial, which led to FDA approval of the drugs.
The fact that there have been few successes since speaks volumes to the importance of accelerating Alzheimer’s research. We desperately need new drugs, and the search should become a national priority. So Congress must set aside its partisan bickering and incentivize pharmaceutical companies to aggressively invest in research on Alzheimer’s disease and other dementias that has the potential to save millions of lives while saving tens of billions of dollars in healthcare spending.
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