Big pharmaceutical companies are taking lessons from the disappointing performance of experimental drugs aimed at one of the most obvious targets in Alzheimer’s disease—the deposits of a protein called beta-amyloid that appear in the brain when the disabling neurodegenerative disorder is clearly established.
New Brunswick, NJ-based Johnson & Johnson and Indianapolis-based Eli Lilly both saw their antibody drugs against beta-amyloid fail to meet goals in late-stage trials last year. J&J is now diversifying its Alzheimer’s research programs to look at genes and proteins that may be involved in the early onset of the disease, says Guy Seabrook, vice president of neuroscience innovation at the Johnson & Johnson California Innovation Center in Menlo Park, CA.
The innovation center, which formally opened in June to help J&J (NYSE: JNJ) scout for research partners and nourish startups, recently announced a collaboration with Hamburg, Germany-based Evotec, which has a branch in South San Francisco. Evotec (Frankfurt Stock Exchange: EVT) has been studying brain tissue samples to see which genes are turned on or off as the early processes of Alzheimer’s take hold, and has compiled its findings in a proprietary database. J&J, through its division Janssen Pharmaceuticals, will work with Evotec to find the best avenues for thwarting those harmful genes with drugs.
“There are several hundred genes in the database we’ll be exploring as potential candidates,” Seabrook says.
The idea for the collaboration was first hatched in September of 2012 at a meeting in South San Francisco that brought J&J and Evotec experts together, Seabrook says. In February, the FDA issued a call to drug companies to focus on the early stages of Alzheimer’s disease, and offered guidance for developing treatments that might prevent the nerve degeneration that leads to memory loss and dementia.
Scientists have already discovered a few inherited genes believed to cause the rare cases of early onset Alzheimer’s disease, which can strike adults as young as 30. But most cases are diagnosed in patients 60 or older, and no single gene has been identified as the cause. Some genes are known risk factors, however—such as a form of the apolipoprotein E (APOE) gene, APOE ε4. In 2011, a consortium of research centers formed the International Genomics of Alzheimer’s Project (IGAP) to expand knowledge of the genes that raise the risk.
Beyond inherited risks, it’s possible that the activity of normal genes could be disturbed by external factors such as diet, smoking or environmental toxins, according to the NIH’s National Institute on Aging. Each gene carries the code for the manufacture of a particular protein. Academic researchers and companies such as Evotec have been studying the output of proteins to see which genes are more active in protein production in people with Alzheimer’s disease.
The big drug outfits that can afford to conduct sizeable clinical trials in Alzheimer’s disease aren’t abandoning work on beta-amyloid, which forms plaques or clumps in the brain that are suspected of blocking nerve action and triggering destructive immune system reactions. Although Lilly’s (NYSE: LLY) antibody solanezumab fell short of the primary goals set in two Phase 3 trials, the company said in July it will try again with a third trial. J&J, which scuttled work on its antibody bapineuzumab IV, is still pursuing research on beta-amyloid and a protein called tau, whose abnormal forms cause damaging tangles in nerve cells.
“We remain committed to work in the amyloid and tau areas,” Seabrook says.
But the Evotec collaboration, dubbed TargetAD, is an opportunity to dive into “new areas people haven’t really explored before,” Seabrook says.
Evotec’s brain tissue samples come from both healthy people and those with Alzheimer’s disease from the early to late stages. By comparing the normal and diseased brains, the researchers are trying to illuminate the molecular mechanisms that go awry as the disorder begins.
Seabrook says some of the suspect genes have been linked to inflammation, to a metabolic imbalance called oxidative stress, or to the ongoing process by which neurons in the brain form and break connections with each other. Breaking of nerve connections, called synapses, can result in memory loss, a symptom of Alzheimer’s disease.
Some cellular pathways observed in Alzheimer’s disease are also implicated in diabetes and cancer, Seabrook says. It’s possible that drugs shown to work against diabetes or cancer might be repurposed to stave off Alzheimer’s disease, he says.
Under the agreement with Evotec, J&J will have the chance to select disease mechanisms and drug candidates identified through the collaboration, and move them into pre-clinical and clinical testing. The drug giant will reimburse Evotec for as much as $10 million in research costs over a period of at least three years. Evotec would also stand to gain as much as $125 million to $145 million for each drug development program that meets specified milestones.
Seabrook says J&J would prefer to develop small molecule drugs, but the company doesn’t rule out the development of biologic drugs such as antibodies if they would work best against certain disease targets.
Though it may take decades of work, Seabrook says, the ideal outcome of research in Alzheimer’s disease would be to develop early treatments to head off the disorder, as well as early diagnostic tests to identify the patients who need those drugs.
“It would be fantastic if we could accomplish that,” Seabrook says.
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