- Amgen and Novartis said they are ending early two trials of the experimental Alzheimer's disease drug CNP520 after an interim review revealed "worsening in some measures of cognitive function" among patients enrolled in the studies.
- The trials were conducted in pre-symptomatic patients with a set of genes associated with higher incidence of Alzheimer's, the main avenue of research remaining for agents that seek to reduce accumulation of a neurotoxic protein called beta amyloid.
- Cessation of the CNP520 trials, part of a program called Generation, leaves just three active prevention trials, one of which, called DIAN-TU, is due to yield results within months.
Despite billions of dollars spent on research, Alzheimer's disease has proven incredibly resistant to pharmaceutical intervention.
Reducing the effects of beta amyloid on brain tissue has been the leading avenue of research for years, and yet all the agents that have been tested in humans have failed to delay worsening of patients' cognitive function. At their worst, they fail to help patients while increasing health risks, as with Johnson & Johnson's discontinued atabecestat.
Like atabecestat, CNP520 (umibecestat) is a BACE inhibitor, impeding an enzyme essential to the biological process that creates beta amyloid. And like atabecestat, the drug was being tested in pre-symptomatic patients believed at risk for Alzheimer's disease.
The Generation trials, which were also run by the Banner Alzheimer's Institute, tested the Amgen/Novartis treatment in patients with copies of the APOE4 gene, which puts patients at between two to five times greater risk of developing Alzheimer's than the general population, depending on whether they have one or two copies of the gene.
One of the Generation trials required two copies, while the other allowed patients with one copy to enroll if they showed signs of elevated brain amyloid.
Because amyloid-blocking drugs have failed to show any benefit in symptomatic patients, researchers have shifted their testing to pre-symptomatic, at-risk patients. They've done so under the belief that by the time amyloid begins accumulating in the brain, too much damage has been done to slow or reverse the disease course.
Discontinuation of the Generation trials at a planned interim review casts doubt on even that avenue of research.
Two of the remaining active prevention trials, DIAN-TU at Washington University in St. Louis and API-ADAD at Banner, focus on patients with presenelin mutations, which gives carriers a 50% chance of developing a familial form of early-onset Alzheimer's. API-ADAD focuses on a single extended family in Colombia with this mutation.
One other BACE inhibitor remains in active late-stage development, Eisai and Biogen's elenbecestat, although hopes aren't high there either.
"We believe this is another amyloid-directed dementia program that Biogen should de-fund and abandon," wrote SVB Leerink analyst Geoffrey Porges in a Friday note to clients.
Still, Eisai and Biogen's persistence with the amyloid approach may be one factor helping sustain belief that research should continue in that direction. The companies have initiated Phase 3 studies of both elenbecestat and another amyloid-targeting agent called BAN2401.