Failure of Lilly’s Solanezumab Not Seen as Conclusive Proof That Amyloid Theory Is Flawed

Failure of Lilly’s Solanezumab Not Seen as Conclusive Proof That Amyloid Theory Is Flawed

The Alzheimer’s community lamented Eli Lilly’s recent announcement that its experimental therapy solanezumab failed to demonstrate efficacy in treating the disease in recent clinical trials. In the announcement, released Nov. 23, Lilly said it would not pursue regulartory approval for the drug.

Solanezumab’s inability to demonstrate effectiveness in people with mild demential due to Alzheimer’s disease, however, represents more than just a one-drug failure. After one amyloid-targeting drug trial disappointment after the other, some in the Alzheimer’s community viewed the solanezumab trial as the final test of the amyloid hypothesis for treating Alzheimer’s disease. Lilly’s announcement gave critics of the amyloid theory plenty of reason for “I told you so” responses.

Nevertheless, the hypothesis that amyloid-beta is the villain causing Alzheimer’s disease continues to have its supporters among researchers and caregivers alike, and numerous trials are still testing various drugs that aim to lower the levels of amyloid-beta as a way of preventing cognitive decline in patients.

Solanezumab is an antibody that sweeps up soluble single molecules of amyloid proteins from the blood and cerebrospinal fluid, so they cannot go on to form plaques. Both animal studies and earlier human trials of the drug showed promising results. The EXPEDITION3 trial (NCT01900665) recruited more than 2,100 patients with mild Alzheimer’s dementia — a number that would be enough to prove the drug’s effectiveness.

After 18 months, however, results were only slightly leaning toward a favorable effect of solanezumab — not enough for a new drug to be marketed. The primary study goal —  a slowed cognitive decline — was statistically no different in solanezumab-treated patients compared to those receiving placebo. The same was true for secondary measures, including a loss of the ability to perform daily tasks.

“The results of the solanezumab EXPEDITION3 trial were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease,” said John C. Lechleiter, PhD, chairman, president and chief executive officer, Lilly, said in a news release.

Solanezumab is still being tested in people with early signs of Alzheimer’s disease (NCT02760602), an inherited likelihood of the illness (NCT01760005), or those with no memory loss but with evidence of amyloid-beta buildup in the brain (NCT02008357). At this time, Lilly has not determined how to proceed with the remaining trials.

According to an article by Alison Abbott and Elie Dolgin, recently published in Nature, many of the scientists involved in the studies have not given up on the amyloid hypothesis, in spite of the setback with solanezumab. The particular characteristics of solanezumab are being blamed for the drug’s failure — not the amyloid hypothesis as a whole.

Highlighting the divide in the research community, the article mentioned an opinion that the intervention with solanezumab might have come too late in the progression of the disease, as amyloid brain changes are likely to start at least a decade before any memory problems become apparent. Others pointed to the fact that it is not even certain that solanezumab did what it was supposed to do.

Christian Haass, head of the Munich branch of the German Centre for Neurodegenerative Diseases, told Abbott and Dolgin that since the antibody targets soluble amyloid, it “could be trapped in the blood without ever reaching the actual target in the brain in sufficient quantities.”

The many critics of the hypothesis are not convinced, however, and emerging data show that Alzheimer’s risk may be far more complex than simply the presence of amyloid. Meanwhile, studies show that environmental factors, including diet, exercise, and metabolic health, may add more to the risk of the disease than simply the presence of amyloid-beta.

Yet, solanezumab was by no means the last drug being tested that might prove the amyloid hypothesis.

Biogen’s aducanumab — a treatment that builds on natural brain immunity against amyloid-beta — is currently recruiting participants for two Phase 3 clinical trials (NCT02484547 and NCT02477800) in people with early Alzheimer’s disease.

In addition, so-called BACE inhibitors, which lower the production of amyloid-beta, are under development by several companies. Some, such as Merck’s verubecestat (NCT01953601 and NCT01739348), and Janssen’s JNJ-54861911 (NCT02569398), have now reached Phase 3 trials.

One study (NCT01953601) is focusing on people with mild memory impairment, while another (NCT01739348) has enrolled patients with mild to moderate Alzheimer’s disease.

So, the final word on the amyloid theory’s validity is not yet out — and will likely not be determined until more trials have concluded.

3 comments

  1. Timothy Daly says:

    I see that people are still holding onto the amyloid-hypothesis, but in the Nature article, beside the particularities of this perhaps poorly-designed drug trial, there are no actual reasons given for retaining the hypothesis.

    My question to its defenders would be this: what evidence WOULD be enough of a reason to give up this hypothesis?

    Personally, 27 years of research from pretty much every Big Pharma company on the planet on a disease that is not entirely genetically determined in 19 cases out of 20 merits a change in direction. How long will we ignore the epidemiology of modifiable risk factors and start to take them seriously instead of trying to interpret everything in terms of amyloid (or tau)? Forgive me, but I just don’t get it.

  2. The problem is that you cannot proof good science using bad science. Analysis of the past immunotherapeutic studies on Alzheimer’s show that they were based on the wrong assumptions. A result of trying to use without too much thought the knowledge acquired from infectious and cancer immunotherapy to Alzheimer’s, a quite different situation. A number of publications have exposed the errors made in those studies, a result of using incomplete and sometimes misleading information. Yet, few mention those problems, perhaps an indication of not mentioning the rope in the house of the hanged man. To complicate the issue many scientists and the press insist in considering the plaque the villain in Alzheimer’s, despite the evidence that plaque may be protective and that many mentally sound older people have plaque in their brains. Besides, amyloid does not exist in a vacuum, but it interacts with other compounds, thus the whole picture is much more complex. Trying to get rid of the amyloid hypothesis would not help until the past errors are recognized and experimental protocols are designed taking into account those problems. Failure to do so must be considered an exercise of intellectual masochism.

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