CNP520 is an oral therapy that Novartis and Amgen are developing to delay the start and progression of Alzheimer’s disease.

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 is designed to prevent the BACE1 enzyme from cutting up APP, a move that should curb amyloid beta accumulation.

Studies in human cells in a laboratory setting and in mice have shown that CNP520 can prevent the formation of amyloid beta plaque. It also does not cause a problem that other BACE1 inhibitors cause — lightened patches of skin, a condition known as hypopigmentation. The reason for this, scientists believe, 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, or how it moved through the body and pharmacodynamics, or how the body processed it.

The study covered 124 healthy people older than 60. They 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 appeared in the journal Alzheimer’s & Dementia.

Novartis and the Banner Alzheimer’s Institute started a Phase 2/3 trial (NCT02565511) 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 ongoing trial is comparing the combo with a placebo.

The trial participants consist of 1,340 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. It will compare CNP520 and a placebo’s ability to slow cognitive decline.

Researchers plan to recruit 2,000 participants, aged 60 to 75 years. Generation S2 is open to people with either one or two copies of the APOE4 gene and elevated levels of amyloid beta protein in their brain. Participants will receive one of two doses of CNP520 a day or a placebo.

Both the Generation S1 and S2 trials are part of the Alzheimer’s Prevention Initiative Generation Program. Each will run for five to eight years, with both scheduled to be completed in 2024. Researchers continue to recruit participants for the studies at locations around the world.

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