New Alzheimer’s Drugs Tested on People Who Don’t Have the Disease (Yet)

Novartis AG thinks its best bet for testing two new Alzheimer's drugs is on people who don't actually have Alzheimer's.

The Swiss drug giant is looking for people whose genes put them at high risk of developing Alzheimer's, but who haven't yet fallen victim to the mind-robbing disease. It hopes such early treatment proves more successful than past efforts to tackle the disease once it has taken hold.

The history of Alzheimer's research is marked by disappointment. In November, a high-profile Eli Lilly & Co. drug called solanezumab was the latest to fail a late-stage clinical trial. That drug aimed to clear clumps of a protein called beta amyloid in the brain, which are closely linked with Alzheimer's. So far, no company has produced a drug that can delay the progression of Alzheimer's.

One of the new Novartis drugs, known as CAD106, is designed to boost the immune system's ability to clear beta amyloid from the blood. The other, which Novartis is developing with Amgen Inc. and is called CNP520, aims to stop its formation in the first place.

"If an anti-amyloid strategy is going to work, the best way to do so is with prevention," said Steven Arnold, a neurologist at Massachusetts General Hospital in Boston.

Recruiting patients to receive treatment for a disease they don't have -- and may never develop -- is riven with logistical and ethical challenges.

The company is looking for people with two copies of a gene called APOE4 to participate in its study. Having two copies of the gene doesn't inevitably lead to Alzheimer's, but the roughly 2% of people who fit this profile are around three times as likely to develop dementia as the general population, according to a recent analysis in the scientific journal PLOS Medicine.

The Banner Alzheimer's Institute, a Phoenix nonprofit, is helping Novartis find eligible participants with a campaign launched at the end of 2015 to test people for the APOE4 gene. The institute places television and newspaper ads, does mass mailings and runs events in clinics to publicize the program, called Genematch.

So far, around 35,000 people have signed up, agreeing to send swabs of their cheek cells for testing. "We seem to have tapped into a very motivated group of people," said Pierre Tariot, director of Banner. "Not surprisingly, a lot of them have a family history of Alzheimer's."

Margaret, a 71-year-old from Virginia, discovered two weeks ago that she has two copies of the APOE4 gene. She signed up for the Genematch program earlier this year after hearing about it through the hospital that is caring for her older sister, who has Alzheimer's.

"It is shocking," said Margaret, who declined to give her last name because she hasn't yet told her family. But "if this works and can prevent or slow it down, then obviously I'd like to participate. That part of it is a no-brainer."

Only a fraction those who sign up will be eligible for the trial. As well as having two copies of the APOE4 gene, participants in the Novartis study must be healthy, between the ages of 60 and 75, and have no outward signs of Alzheimer's, such as cognitive decline. Fewer than 10% of the roughly 1,300 participants needed for the trial have been recruited so far, Dr. Tariot said.

The Genematch staff doesn't know any individual participant's genetic results. Instead, a computer program provides a list of names -- only some of whom are genetic matches -- for them to call. On that call, Genematch will tell the person they might be eligible for a trial and tell them about nearby participating hospitals.

Participants are informed of their genetic profile -- usually by a genetic counselor -- only after a lengthy assessment by staff at the clinical-trial site to determine that they are eligible for, and willing to enroll in, the study.

"The critical thing is that this is done in a highly ethical way," said Vas Narasimhan, global head of drug development at Novartis. "If a patient is not selected for the study, we are not intervening to help them so there is no reason to provide them with this information."

Later this year, Novartis plans to start a further trial that will be open to people who have just one copy of the APOE4 gene, Dr. Narasimhan said. Around a quarter of the population is thought to fit this profile, and they are about 1 1/2 times as likely to develop mild cognitive impairment or dementia as the general population.

After the string of high-profile failures in amyloid-busting drugs, experts are divided over whether they are the right approach to tackling Alzheimer's. "The field is very pessimistic right now," said Murali Doraiswamy, director of the neurocognitive disorders program at Duke University Health System in Durham, N.C.

But the Novartis study was among a small group of trials that could still vindicate this approach, Dr. Doraiswamy said. "We've learned a lot from previous [failed] trials," he said, adding that the "elegant" design of the Novartis study -- in focusing on a narrow band of people known to have heightened risk of Alzheimer's -- makes it a "near-perfect model to test the amyloid thesis."