The Johnson & Johnson (J&J) Innovation Center, through J&J unit Janssen Pharmaceuticals Inc., is pledging up to $10 million up front per program, followed by as much as $145 million more for each, in a deal with Evotec AG that aims to find and target the true originators of Alzheimer’s disease (AD).

Guy Seabrook, head of neuroscience at the center, said the pairing will provide “a high-acuity lens for us to look at the molecular mechanisms that underpin the onset of AD.” J&J and Evotec were expected to make the deal public Friday.

It’s the second collaboration arranged through J&J’s Menlo Park, Calif., center. In June, San Bruno, Calif.-based Second Genome Inc. entered a multiyear agreement, with no terms disclosed, to use the firm’s microbiome-modulation platform to discover drugs for ulcerative colitis. (See BioWorld Today, June 6, 2013.)

In the three-year pact with Evotec, of Hamburg, Germany, Janssen, of New Brunswick, N.J., gets the opportunity to internalize selected targets and therapeutic candidates from Evotec’s TargetAD database and move them into preclinical and clinical development.

Janssen is reimbursing up to $10 million in research costs and making preclinical, clinical, regulatory and commercial payments up to a maximum of $125 million to $145 million per program.

TargetAD provides drug targets derived from the analysis of dysregulated genes in what the company called “high-quality and well-characterized human brain tissues, representing all stages of disease progression, as well as control tissues” from brain-healthy subjects.

”It’s clear we need to better understand how the disease process starts, particularly around thinking about prodromal [pre-symptomatic] AD, as it marches into more cognitive impairment and established forms of the disease,” Seabrook said.

”We can learn from some of the examples in the past,” he added. “Studies have been conducted but there hasn’t been very good evidence that the drug or therapeutic in question is engaging the central target,” which has been the cause of at least some of the many AD failures.

“There are ways in which we can address that, of course,” Seabrook said. “One is to monitor the changes in protein levels in cerebrospinal fluid or potentially using imaging tracers to determine whether the therapeutic is reaching the site of action in the central nervous system.”

Casting a Wider Net

Finding new targets is the main thrust of the deal, though, and the companies will use TargetAD as well as genomewide association studies.

“We can interrogate [the database], not just by looking at the genes at risk, which obviously are there throughout the lifetime, but we can collate that with the movement in protein levels and expression of those particular genes at different stages of the disease.”

ApoE3 and ApoE4 genes are involved in AD, but there are others, Seabrook noted. “We also know that individuals who have elevated homocysteine levels in their plasma have a higher risk of dementia,” he said, and having the benefit of not only public-domain information but Evotec’s database can help the firms explore an “unbiased way of looking at the biology” of AD.

“We cannot ignore the fact that amyloid and tau define the disease, and so the expectation is that the targets we think about may impact those downstream, but we’re looking really for the things that are causal to disease onset,” Seabrook said.

Although areas of interest in AD have been identified, Seabrook declined to talk about specifics, other than to say Janssen is “bringing fresh eyes to the table” with “bioinformatics-type approaches,” and would be inspecting “adjacent pathways that may modulate those [known] proteins, such that we can find tractable ways of bringing forward new therapeutics. We probably wouldn’t be going after the traditional secretase-type targets.”

Last year, the Pharmaceutical Research and Manufacturers of America released a report, “Alzheimer’s Research: Setbacks and Stepping Stones,” showing that, between 1998 and 2011, 101 treatments failed to reach patients. In the same period, only three medicines were approved to treat symptoms of the disease. (See BioWorld Insight, Oct. 14, 2013.)

“There’s extremely high attrition in this field, but that’s not to say this is not a very important area we need to work on for society’s benefit,” Seabrook told BioWorld Today. “AD is the sixth leading cause in the U.S., and we have 5 million Americans living with the disease. Estimates from the Alzheimer’s Association are that the current [annual] cost of $203 billion is expected to rise to $1 .2 trillion by 2050, with a tripling of the number of individuals who have AD.”

The amyloid-plaque hypothesis that has long held sway in AD “is really made up of several different flavors,” involving approaches in which amyloid-beta oligomers and/or cleavage of adenosine triphosphate could take center stage, Seabrook noted. “All of those approaches would impact amyloid production in the brain. Each carries a different risk in terms of potential side effect liabilities, but also carries a different risk in terms of the technical probability of success. It depends upon what you believe is the causal factor in the death of neurons and the destruction of synaptic connections in the brain.”

But the net can be cast wider. “There may be other events occurring upstream or downstream of amyloid that may actually be contributing to the disease progression,” Seabrook said. “That’s the area of biology that we need to be exploring more as a field.”