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Genentech Takes Personalized Medicine Approach in Pursuing Amyloid Hypothesis for Alzheimer's Drug

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Originally published May 22.

Genentech is planning to study whether the investigational drug crenezumab can prevent Alzheimer's in a patient population genetically predisposed to get the degenerative disease.

Moreover, by investigating the drug in a genetically homogeneous group, Roche subsidiary Genentech is hoping to test the theory that amyloid beta molecules – the major component comprising plaque deposits in the brains of Alzheimer's patients – cause the disease.

"This is the ultimate test of whether A-beta is the toxic substance that causes the disease," Richard Scheller, executive VP of research and early development at Genentech, said in a video presentation about the crenezumab development program. "Up to this point this is still a hypothesis which has still not been proven."

Genentech, in collaboration with Banner Alzheimer's Institute and the National Institutes of Health, will conduct a Phase II trial in Medellin, Colombia, and surrounding mountainous regions, where approximately 5,000 residents share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50.

"It's the reverse of what happens in the sporadic [form of Alzheimer's], where children end up taking care of their elderly parents with the disease," Scheller observed, characterizing the group of patients in Colombia as a "very rare human resource."

"Here you have the parents taking care of their children with the disease, which has just devastated parts of the community," he said. By studying patients who are destined to develop Alzheimer's, "we will attempt to prevent the buildup of the plaque in the brains of patients and therefore hopefully prevent the cognitive decline that accompanies the disease."

Study investigators will begin recruiting patients for the $100 million randomized, blinded trial in 2013. The five-year study will involve approximately 300 participants, of whom approximately 100 mutation carriers will receive crenezumab and another 100 mutation carriers will receive a placebo. In a third arm, approximately 100 participants who don't carry the mutations will receive a placebo.

"The participants will not know their genetic test results unless they ask to be tested independent of the trial and none will know whether they are receiving crenezumab or the placebo," a Genentech spokesperson told PGx Reporter. According to Genentech, most study participants do not want to know their mutation status.

This study "allows us to treat them before they show any signs of cognitive decline, and to compare patients treated and untreated to prevent the disease," Scheller said.

The association between presenelin 1 and early-onset Alzheimer's disease was first discovered in 1995. Presenelin 1 mutations are the most commonly mutated gene in early-onset Alzheimer's, comprising approximately 6 percent of early onset familial cases of the disease. To date, there have been 164 presenelin 1 mutations associated with early-onset Alzheimer's disease discovered in 364 families, Genentech said.

According to the company, the specific protocols of the Colombian crenezumab study are still in development. The company will perform an interim analysis after all the study participants have received crenezumab for two years. "At that time we would evaluate continuation of the trial to support an application for approval," the Genentech spokesperson said.

Although the specific indication Genentech would seek for the drug will be determined after discussions with regulatory authorities, the drug developers "would like crenezumab to be as broadly available to patients who may be eligible," the spokesperson added.

Genentech exclusively licensed crenezumab from AC Immune in 2006. While the company is taking a personalized medicine approach by studying crenezumab in a genetically defined patient subset, the drug may not have an indication restricted to that population. Crenezumab is a monocloncal antibody that targets A-beta, the peptide in plaque found in the brains of all Alzheimer's patients. The drug works by binding to A-beta in the brain and preventing the formation of plaque by clearing A-beta in cerebral fluid.

"If this treatment proves effective among people who have the most aggressive form of amyloid accumulation and are struck early in life, there is reason to think that it also might be worthwhile for people at risk for the more common late-onset Alzheimer’s," the Genentech spokesperson said.

Still, Genentech is studying whether patients with specific biomarkers have a differential response to crenezumab. "If the study is able to show that biomarker changes predict the clinical benefit seen in initial participants, we think it would then be possible to test the same treatment and other anti-amyloid treatments in people at risk for developing Alzheimer’s at older ages (e.g., those who carry the common APOE4 gene and those who have biomarker evidence of amyloid accumulation)," the spokesperson said via e-mail.

Separate from the Colombian study, Genentech last year launched two Phase II studies involving crenezumab in the US, Canada, and Europe. These studies so far involve nearly 500 patients with mild to moderate Alzheimer's. One study is investigating whether the drug reduces cognitive decline in patients. A second study is investigating whether the drug decreases amyloid accumulation and impacts other disease-related biomarkers.

The Amyloid Hypothesis

One of the main aims of the Colombian study is to prove the "amyloid hypothesis," which holds that A-beta causes Alzheimer's.

Crenezumab "would target beta amyloid peptide and beta amyloid in any form of Alzheimer's, all of which have beta amyloid deposition," Ralph Nixon, psychiatry and cell biology professor at New York University's Langone Medical Center, told PGx Reporter. Nixon is not a collaborator on the Genentech study.

The Colombian Alzheimer's population "was chosen because they can be positively identified as destined to develop [the illness] before they have symptoms, thereby enabling investigators to test whether the drug can prevent, rather than reverse, the disease," he said.

Although the amyloid hypothesis dominates Alzheimer's research and most major pharmaceutical companies are developing drugs targeting A-beta, there is data suggesting that flushing A-beta from the brain may harm patients by depleting molecules that aren't associated with disease pathology.

Research led by Inna Slutsky of Tel Aviv University and published in Nature Neuroscience in 2009 showed that A-beta proteins are a critical component of how nerve cell networks in the brain transfer information. As such, Slutsky and her team have hypothesized that removing the protein from the brain could impair a person's cognitive functions and speed up accumulation of amyloid in the brain.

Research exploring the role of presenelin 1 mutations in Alzheimer's offer an alternative drug development pathway to the A-beta strategy.

A team of researchers led by Nixon discovered that presenelin 1 helps lysosome organelles in cells digest unwanted proteins from the brain. However, in a study published in Cell in 2010, Nixon and his colleagues demonstrated that when there are mutations in the gene, this protein clearance process is compromised, resulting in the accumulation of toxic proteins and neuronal cell death causing Alzheimer's.

"Presenelin is part of the enzyme complex that generates beta amyloid peptide by cleaving it from a larger protein," Nixon explained. However, his research suggests that presenelin 1 mutation-associated impairments to neural cells don't seem to be dependent on A-beta. Nixon believes his findings about the role of presenelin 1 mutations in Alzheimer's open the door to developing Alzheimer's drugs that target markers and pathways other than amyloid.

"Many of the major drug companies are working on developing programs to target the clearance mechanism disrupted [by presenelin 1 mutations] in Alzheimer's and several other neurodegenerative diseases," Nixon said. "Some are specifically looking at the lysosome that was described as dysfunctional in our Cell paper."

Nixon said he is continuing to further explore the role of presenelin 1 in Alzheimer's and is working with some drug firms in this regard.

Allen Roses, director of Duke University's Dean Drug Discovery Institute and CEO at Zinfandel Pharmaceuticals, has long held that A-beta is not the right target for Alzheimer's drug development. Roses' laboratory at Duke discovered in 1993 that carriers of the APOE4 allele have up to a 30 times greater risk of developing late-onset Alzheimer's than non-carriers.

In recent years, Roses and his research team have discovered that varying lengths of the TOMM40 rs10524523 poly-T polymorphism are associated with age of Alzheimer's disease onset and have developed a three-allele risk prediction system for gauging those who are likely to develop early-onset or late-onset Alzheimer's disease (PGx Reporter 7/14/2010).

Zinfandel and Takeda Pharmaceutical are collaborating on a study investigating whether Takeda's diabetes drug Actos can delay Alzheimer's onset in people with a high risk of the disease based on age and genetic factors (PGx Reporter 1/12/2011).

Investigators in this study will test patients with a TOMM40 assay to gauge their risk of getting Alzheimer's in the next five years, and based on their risk, randomize patients to receiving either Actos or a placebo. Actos is an inhibitor of peroxisome proliferator-activated receptor gamma, or PPARg, a receptor that controls genes involved in the metabolism of glucose and lipid in the body, levels of which are abnormal in Alzheimer's patients.

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