Alzheimer’s drugs in development and the amyloid hypothesis

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  • It’s been a while since we’ve had good news in the search for new Alzheimer’s drugs.
  • On Wednesday, VTV Therapeutics, a small North Carolina biotech, said its Alzheimer’s drug failed a late-stage trial. 
  • Now, all eyes are on a set of treatments that go after the “amyloid hypothesis,” an approach that has already faced some setbacks.

It’s been a pretty bleak year in the search to find new Alzheimer’s treatments.

In 2018 so far, the CEO of Axovant stepped down after 10 months on the job and a failed Alzheimer’s trial, Merck said it was cancelling a trial looking at Alzheimer’s treatment — a BACE inhibitor — in early stage patients, and now VTV Therapeutics has said that its Alzheimer’s drug failed a late-stage study. 

Alzheimer’s affects more than 5 million Americans, a number that’s expected to balloon to 13.8 million by 2050 . There are only four drugs that have been approved to treat the symptoms of the disease, and the most recent drug approval happened in 2003.

The number of setbacks the field has seen in recent years has people coming back to a theory: We might be trying to treat the neurodegenerative disease at the wrong time, when it’s too late.

Research has determined that years — even decades — before a person might start showing symptoms, amyloid beta deposits in the brain that are characteristic of Alzheimer’s disease can start to accumulate.

Starting earlier could benefit treatments that are targeting beta amyloid deposits in the brain, with the hope that clearing them out could help slow down the rate of cognitive decline. This idea of targeting beta amyloid deposits in the brain to clear them out is known as the “amyloid hypothesis.

But there’s one major drawback to the amyloid-beta approach: In people who have Alzheimer’s, these deposits build up in certain parts of the brain, but it’s still not known whether the plaques cause the disease, or if they’re just a byproduct. What does seem to be well established is that in people with the genetic version of the disease, there is a strong relationship between those mutations and amyloid plaques.

And the hypothesis has already been put to the test and seen a few failures. For one, Merck’s now-failed BACE inhibitor was also acting on the amyloid hypothesis to prevent the protein from forming and keep the disease from progressing. Solanezumab, a drug developed by Eli Lilly that also acts on the amyloid hypothesis, failed some key clinical trials, though the company is still testing it in the pre-clinical stages of the disease. 

Even so, it’s where a number of big drugmakers are exploring in trials that will read out over the next few years. 

Here’s what’s ahead

  • Biogen’s aducanumab, is going after the amyloid hypothesis. It’s expected to have results in 2019 or early 2020.
  • Lanabecestat, AstraZeneca’s BACE inhibitor, is going be reading out in 2019. Like Biogen, it’s going after the amyloid hypothesis.
  • Eli Lilly’s solanezumab failed a phase 3 trial in patients with mild dementia in November 2016, but has plans to keep trying the drug in pre-clinical stages of the disease to see if it works preventatively. Solanezumab is going after the amyloid hypothesis as well. While three trials have been stopped, the fourth in this preventive setting is expected to have results in 2022.
  • Genentech has two Alzheimer’s drugs in late-stage development, despite hitting setbacks. In February, Genentech and its partner AC Immune launched a phase 3 trial for crenezumab, another drug that’s targeting amyloid deposits in the brain. It’s expected to have data in 2020. The other is gantenerumab, a drug also targeting amyloid that failed earlier trials. The hope is that by increasing the dose, it might work. Genentech started a new phase 3 trial for gantenerumab in 2017.



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