Rethinking Healthcare

Preemptive strike against Alzheimer's

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Disappointing clinical trial results are driving researchers and drug developers to rethink their approach. Should the focus be on drugs for people before the onset of symptoms?

The field of Alzheimer’s drugs have suffered several major setbacks this summer. And now researchers and drug developers are regrouping to plot a fresh course, one that focuses on preemptive therapies. Nature News reports.

This summer, Johnson & Johnson and Pfizer learned that their biological drug bapineuzumab failed to show any benefit in two large clinical trials. Then, Eli Lilly announced that its drug solanezumab hadn’t hit its goal of significantly slowing memory decline and dementia.

Both of the failed drugs targeted amyloid-β, a protein that forms plaques in the brains of Alzheimer’s patients.

Amyloid-β plaques are thought to cause Alzheimer’s disease by killing neurons and severing their connections to their neighbors. But the evidence is circumstantial. Autopsies of patients show that larger numbers of plaques occur in more severe cases of the disease. Also, mutations in the gene responsible for amyloid-β seem to have either a risk-enhancing or a protective effect.

Yet despite all the money invested in amyloid-targeting drugs, scientists have yet to confirm or refute the amyloid hypothesis. Solanezumab was meant to recognize and block amyloid-β before it forms plaques. Bapineuzumab is an antibody drug targeting amyloid-β plaques, in hopes of awakening the immune system to clear them from the brain.

And now, many worry that investors will be reluctant to support the continuing search.

Increasingly though, researchers think that the problem lies not so much with the strategy of targeting amyloid-β as with the timing of treatment. Are patients being treated too late?

So rather than abandoning the amyloid hypothesis, scientists are pinning their hopes on innovative clinical-trial designs and new diagnostics that would allow them to test compounds earlier in the disease. Since amyloid-β plaques accrue over a lifetime, perhaps amyloid-blocking drugs given in middle age may prevent Alzheimer’s.

Three studies beginning next year will test whether anti-amyloid drugs can forestall early symptoms of Alzheimer’s, arresting cognitive decline in patients who – based on genetic pre­disposition or amyloid levels -- have been identified as being at increased risk.

  1. The Alzheimer’s Prevention Initiative will test Genentech’s crenezumab in people who have mutations in the presenilin 1 gene and other genes that cause Alzheimer’s in middle age. This 5-year study will cost $100 million.
  2. The Dominantly Inherited Alzheimer Network will test 3 drugs on asymptomatic people with Alzheimer’s-linked mutations in genes for presenilins 1 and 2, and amyloid precursor protein. $60 million for 2 years.
  3. A trial called ‘Anti-amyloid treatment in asymptomatic Alzheimer’s disease’ will asymptomatic people who have high levels of amyloid-β, and some who have a gene variant that increases their risk of Alzheimer’s. $110 million for 3 years.

In theory, approval for preventive drugs could be assessed on the basis of clinical trials measuring changes in biomarkers, such as such as amyloid levels from brain scans and in cerebrospinal fluid.

But these would be considered surrogates, instead of traditional measures of cognitive improvement. And regulatory agencies are likely to set a very high bar for what constitutes a proven surrogate.

[From Nature News]

Image: PET scan of the brain via Wikimedia

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Janet Fang

Contributing Editor

Janet Fang has written for Nature, Discover and the Point Reyes Light. She is currently a lab technician at Lamont-Doherty Earth Observatory. She holds degrees from the University of California, Berkeley and Columbia University. She is based in New York. Follow her on Twitter. Disclosure