CNP520 (Umibecestat)

CNP520 (umibecestat) was an oral therapy that Novartis and Amgen were developing along with the Banner Alzheimer’s Institute to delay the start and progression of Alzheimer’s disease.

After mid-study analysis of data from their Phase 2/3 Generation Program studies, Novartis and Amgen decided to discontinue trials of CNP520.

How CNP520 works

The hallmark of Alzheimer’s is an accumulation of toxic amyloid-beta protein in the brain, which is thought to cause brain cell death and cognitive decline. An enzyme called BACE1 paves the way to the accumulation process of this protein by cutting another protein called APP (amyloid precursor protein) into smaller fragments, which then form amyloid-beta plaques.

CNP520 is a BACE1 inhibitor. It was designed to prevent the BACE1 enzyme from cutting up APP, a move that was supposed to curb amyloid-beta accumulation.

Studies in human cells in a laboratory setting and in mice showed that CNP520 could prevent the formation of amyloid-beta plaques. It also did not cause a problem that other BACE1 inhibitors cause — lightened patches of skin, a condition known as hypopigmentation. The reason for this, scientists think, is that CNP520 inhibits the BACE1 enzyme but not the BACE2 enzyme, which is involved in the regulation of skin pigmentation.

CNP520 in clinical trials

A Phase 2 clinical trial (NCT02576639) that ran from August 2015 to March 2016 showed that CNP520 was safe across a range of doses and that patients tolerated it well. In addition to the therapy’s safety, researchers looked at its pharmacokinetics (how it moved through the body) and pharmacodynamics  (how the body processed it).

The study included 124 healthy people older than 60 who received one of four doses of CNP520 a day for three months. Researchers conducted the trial at locations in the U.S., the U.K., the Netherlands, Belgium, and Germany. The results were published in the journal Alzheimer’s & Dementia.

Novartis and the Banner Alzheimer’s Institute started a Phase 2/3 trial (NCT02565511) called Generation S1 in November 2015 to see whether a CNP520 combo therapy could delay the start and progression of Alzheimer’s. The other treatment was the Novartis-developed immunotherapy CAD106. The trial compared the combination of CNP520 and CAD106 with a placebo.

The trial participants consisted of 481 people, ages 60 to 75, with two copies of the APOE4 gene and no signs of cognitive impairment. Scientists consider people with an APOE4 gene at high risk of developing Alzheimer’s.

The treatment group in the Generation S1 trial received a CNP520 pill once a day, plus injections of CAD106 in the first and seventh weeks, and every three months thereafter. Researchers compared their results with that of a placebo group.

Amgen, Novartis, and the Banner Alzheimer’s Institute started the Generation S2 trial (NCT03131453) in November 2017. This trial was designed to compare CNP520 and a placebo’s abilities to slow cognitive decline.

Researchers planned to recruit 2,000 participants, ages 60 to 75, to this trial. Generation S2 was open to people with either one or two copies of the APOE4 gene and elevated levels of amyloid-beta protein in their brains. Participants received one of two doses of CNP520 a day or a placebo.

In July 2019, Amgen, Novartis, and Banner Alzheimer’s Institute announced they no longer would be continuing the Generation S1 and S2 studies after collecting data from 481 and 1,145 participants, respectively. The decision to cancel the programs was based on preliminary data collected from the trials, which showed worsening in some cognitive function scores. The research sponsors felt the possible benefits no longer outweighed the health risks of continued exposure to the drug.


Last updated: August 14, 2019


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