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Thursday, December 20, 2012

2012 Year in Review


Dear Readers,

In this final blog of the year, I would like to review some of the highlights of what has happened in the world of Alzheimer’s disease research during 2012, and the new directions that we will likely be heading towards in 2013.

This year ushered in the identification of numerous AD susceptibility genes, as multiple genome wide studies began delivering on the promise that sequencing large numbers of individuals will help identify mutations that increase the risk for AD. The Alzheimer’s Disease Genetics Consortium, reported genetic analysis of more than 11,000 people with Alzheimer’s disease and a nearly equal number of elderly people who have no symptoms of dementia. Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. Until recently, only four genes associated with late-onset Alzheimer's had been confirmed, with the gene for apolipoprotein E-e4, also called APOE4, having the largest effect on risk. The findings here added another five -- MS4A, CD2AP, CD33, ABCA7, and EPHA1, thereby doubling the number of genes known to contribute Alzheimer's disease. Later in the year, an additional susceptibility gene was identified, TREM2, also using genome wide sequencing. The manner in which these genes contribute to AD are being carefully scrutinized, as each may represent a potential therapeutic target.

This year also saw the launch of an unprecedented clinical trial, being run by an international collaboration of researchers in academia and industry to prevent dementia due to AD by treating patients with a drug before any cognitive symptoms appear. The trial, called the Alzheimer's Prevention Initiative (API) is being led by Dr. Eric Reiman at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Dr. Francisco Lopera and his colleagues at the University of Antioquia in Colombia. Over the past two years, these scientists and other colleagues have enrolled members of the world’s largest kindred afflicted with a mutation that leads to early onset AD.

Another notable item from 2012 was the results of the Phase I study of Novartis’ CAD106 vaccine against beta-amyloid. This was only the second vaccine study for AD. The first human vaccination trial in AD, Elan’s AN-1792, which was done almost a decade ago, had too many adverse reactions and was discontinued. However, in contrast, CAD106 was well tolerated, and will hopefully move towards a larger, Phase 2 study.

Perhaps the biggest discovery this year was the identification of a mutation in APP that significantly decreases its cleavage by beta-secretase, leading to 40% less production of beta-amyloid. This mutation also confers resistance to the development of Alzheimer’s disease in patients. That is, people with the mutation make substantially less beta-amyloid and do not get AD. Just to review, all neurons secrete a protein called Amyloid Precursor Protein (APP), and APP is cleaved by two scissor-like proteins, gamma secretase and beta secretase. This leads to the production of beta-amyloid, a toxic protein fragment that accumulates in the brain over time, causing brain cell damage eventually leading to dementia, and deposits into amyloid plaques. Genetic mutations in either APP or either one of the scissor-like secretases that cleave it lead to inherited forms of Early Onset Alzheimer’s disease that strike patients in their 30s and 40s.

As readers will recall, the gene for APP resides on the 21st chromosome, and in people with Down Syndrome, who are born with an extra copy of the 21st chromosome, each of their brain cells produce 50% more APP and subsequently 50% more beta-amyloid and therefore have a much greater incidence of AD. Intriguingly, individuals with Down Syndrome who have an extra-copy of the 21st chromosome, but lacking the segment that includes the APP gene, do not seem to get AD.

Over the summer, there was a flurry of results from multiple Phase 3 trials for AD. The results of two Phase 3 trials of intravenous bapineuzumab, a monoclonal antibody against beta-amyloid, showed that it failed to meet its primary endpoints in patients with mild to moderate Alzheimer’s disease. However, data from Eli Lilly’s solanezumab study, as well as the independent ADCS analysis of the trial, showed that the drug slowed down the rate of cognitive decline in patients with mild AD by about 34%. Moreover, in looking at subjects who had positive amyloid PET scans, there was a statistically significant change in total beta-amyloid in cerebral spinal fluid (CSF). Both of these findings are quite exciting, and indicate that this anti-beta amyloid drug has a statistically significant effect on cognition, and a biomarker of AD; a first in AD research. A Phase 3 study of solanezumab in mild AD is being planned.

The year also saw the end of the gamma-secretase inhibitor, avagacestat, which followed in the footsteps of another drug in the same class, semagacestat. Both were shown to have trends towards worsening cognition as an adverse effect. Meanwhile beta-secretase inhibitors, as well as gamma-secretase ‘modulators’ move forward in the drug pipeline, and are thought to hold great promise.

Finally, the FDA approval of Amyvid as an amyloid imaging tracer for PET scans represents a major milestone in the clinical evaluation of AD. Other tracers are being developed and may be approved this upcoming year.

What does 2013 hold in store for the AD world?

We eagerly await the results from the Phase 3 clinical trial of IGIV in mild to moderate AD. In addition, the launch of the Down Syndrome Biomarker Initiative (DSBI) will undoubtedly help us better understand how AD develops in Down Syndrome, and perhaps identify novel biomarkers of AD. Additional data from ADNI and the DIAN studies are expected, focusing on identifying the earliest changes seen in the AD brain. Additional clinical trials in AD and prodromal AD are ongoing, with several new compounds being prepared for launch in mid 2013. One of these includes the intranasal insulin study, which has had positive early results and is being conducted by the ADCS.

We look forward to keeping you updated on what is happening in the world of AD research in the upcoming year, and are optimistic that there will be great developments in the field of AD in 2013. Stay tuned.


By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 5:02 PM 0 Comments

Thursday, December 13, 2012

Solanezumab to Undergo Additional Phase 3 Trial, Avagacestat Study Halted


Dear Readers,

Yesterday, Eli Lilly announced that it has decided to study solanezumab in an additional phase 3 study that will be conducted only in patients with Mild Alzheimer's disease (AD). Recall that the previous two phase 2 18-month long studies (EXPEDITION I and II) included subjects with Mild and Moderate Dementia due to AD. Just to review, results from the EXPEDITION 1 study showed that patients with mild AD taking solanezumab experienced a slowing of cognitive decline compared to patients on placebo (42% reduction in decline at the endpoint of the 18-month study). Meanwhile, results from EXPEDITION 2 showed a 20% reduction in cognitive decline in patients with mild AD taking solanezumab. Pooled results from both studies showed a 34% reduction in cognitive decline in patients on solanezumab. I discussed the results after they were first released at the CTAD meeting, and suggested a confirmatory trial would likely be the next step.

It now appears Lilly is prepared to take that next step. This will be an important study, as the compound has already shown some evidence of benefit compared to placebo, and may potentially represent the first disease modifying agent for AD.

On another note, Bristol Myers Squibb halted the phase 2 trial of its gamma-secretase inhibitor drug in prodromal AD, after results showed increased adverse events due to the drug, namely a trend towards worsening of cognition. As readers of this blog will recall, beta-amyloid, the presumed culprit in AD, is produced as a byproduct of the cleavage of a protein called APP. The enzymes that cleave APP, and hence produce beta-amyloid, are called secretases, specifically gamma- and beta- secretase. By inhibiting these enzymes, it is thought that the production of beta-amyloid can be reduced. A major challenge has been to develop drugs that inhibit those enzymes’ cleavage of APP, and not their cleavage of other proteins, that may be necessary for normal biological functioning. This is in stark contrast to the immunotherapy drug mechanism that is aimed at simply removing beta-amyloid from the brain.

Meanwhile, Merck announced last week that it has begun enrolling for the largest clinical trial of a beta-secretase inhibitor in AD. Readers of this blog will recall that earlier this year researchers found a mutation in the gene for APP that significantly decreases its cleavage by beta-secretase, leading to 40% less production of beta-amyloid. This mutation also appears to confer resistance to the development of AD in patients. After an initial Phase 2 study that will assess the tolerability of the drug in 200 people with mild to moderate AD, 1,800 subjects will be followed for 18 months in the Phase 3 EPOCH trial. In this study, AD patients will be randomized into four groups receiving 12, 40, or 60 mg of the oral compound, or a placebo tablet, once a day. In Phase 1 studies, reported last July at the Alzheimer’s Association International Conference in Vancouver, a single 100 mg dose of the drug reduced cerebrospinal fluid (CSF) beta-amyloid by more than 90 percent in healthy volunteers.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 1:52 PM 0 Comments

Wednesday, December 05, 2012

Immunotherapy May Hold Promise for AD Treatment


Dear Readers,

A new study published last week in the journal Nature Medicine shows that immunotherapy involving a pathway distinct from beta-amyloid processing and removal from the brain might hold promise for patients with AD. Researchers at the University of Zurich, in Switzerland, and the Charite University Hospital, Germany, targeted two components of the immune system known to boost inflammation in mice genetically programmed to develop Alzheimer's.

Analyzing cerebrospinal fluid of 39 human subjects with Alzheimer's disease and 20 healthy control subjects, the researchers showed that the beta-amyloid may activate an immune pathway — including the release of two proteins known as interleukin-12 and interleukin-23. These two proteins subsequently activate a signaling molecule called P40 that increases inflammation across the brain.

When the researchers injected antibodies against P40(versus placebo)twice a week into young mice that were genetically programmed to develop Alzheimer's disease, they saw a distinct difference: At about middle age, the mice that received the P40 antibodies had 31% less beta-amyloid plaques in their brains than those who were given placebo. The treated mice also performed far better than those who received placebo in tests of memory and cognitive function.

Most importantly, the drug tested is currently FDA approved for psoriasis and is currently in use in human patients. Studies on the incidence of AD in such patients, or at least biomarkers of AD, would be very informative. Additionally, clinical trials would be warranted given these results.



By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 12:13 PM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.