Merck Makes A 'Speculative' Step Into Alzheimer's

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Forbes

Although several rivals have recently experienced setbacks with Alzheimer’s compounds, Merck hopes to defy the odds with plans to take a pill into a Phase II/III study with patients who suffer from mild-to-moderate stages of the disease. And while one analyst calls the move speculative, the decision underscores an ongoing willingness to place big bets on tackling Alzheimer’s, a market that may offer the pharmaceutical equivalent of a Powerball payoff.

To be specific, Merck (MRK) will test a beta-amyloid precursor protein site-cleaving enzyme, or BACE, inhibitor, which the drugmaker notes is the first drug with this type of mechanism to advance to this stage of clinical research. The Phase II portion of the new trial will enroll 200 patients and be completed by late 2013. The Phase III segment would then begin with 1,700 patients, and there is speculation that  second Phase III trial might also be attempted with only earlier-stage patients.

The decision comes after Bristol-Myers Squibb halted testing of an Alzheimer’s compound, and Pfizer and Johnson & Johnson gave up on their bapineuzumab compound, which failed to meet two Phase III primary endpoints in patients with mild-to-moderate stages of disease (read here). Eli Lilly, however, is proceeding with its solanezumab compound, which slowed cognitive decline in patients with mild disease, but showed no statistically significant reduction in functional decline (see this).

“Merck is committed to advancing the understanding and treatment of Alzheimer’s disease,” says Darryle Schoepp, a senior vp and head of neuroscience and ophthalmology at Merck Research Laboratories, in a statement. The trial, by the way, will study one of three oral doses of the compound, called MK-8931, which will be administered daily versus a placebo.

The effort underscores that a significant level of interest remains, at least among some researchers and executives, to study compounds in later-stage patients, despite the recent setbacks. For its part, Merck notes that its BACE inhibitor recently demonstrated a reduction in cerebral spinal fluid, or CSF, a biomarker, in a Phase I study. By contrast, Roche recently doubled the size of a trial testing a compound in patients with early-stage disease. And so one analyst, while noting that Merck may give Lilly a ‘run for its money,’ expresses caution.

In a research note, ISI Group analyst Mark Schoenebaum writes that Merck could end up on the same timeline to market as Lilly  if the FDA asks Lilly to do another confirmatory Phase III trial of its compound. If not, though, Merck would be about three years behind. He adds that the Merck drug “appears to prevent (almost entirely) the formation of new amyloid beta plaques in the brain.” The Lilly drug, however, leads to removal of existing plaques.

But while he called the 90 percent reduction in CSF “impressive,” Schoenebaum points out that “the meaning of bio-markers is no longer clear.” Why? The Pfizer and J&J compound had good biomarker data, but no clinical impact, while the Lilly data revealed some clinical impact despite very mixed biomarker data. And he continues, “we do not believe that Merck has any clinical efficacy data at this point upon which it is basing its Phase II/III decision. Thus, one must still view the Phase III as highly speculative.”

Indeed, there is increasing belief that, to be truly effective, a drug will have to combat the disease in its earliest stages, before signs of dementia appear. Although the biomarker data is encouraging, as Schoenebaum points out, this is far from a reliable predictor. Merck obviously needs the data to get to Phase III, but a payout is far from clear. The odds, in fact, may yet wind up resembling a ballooning Powerball kitty.

New evidence links repeat concussions to permanent brain injury

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Examiner

n a study published in the December 3 issue of the journal Brain, researchers from Boston University School of Medicine reported that examination of deceased athletes’ brains showed that most had signs of chronic traumatic encephalopathy (CTE), an Alzheimer’s-like condition, after sustaining repeated head injuries.

The study “extends our knowledge concerning the spectrum of the clinical and pathological abnormalities associated with CTE,” said Ann McKee, MD, lead researcher, professor of neurology and pathology, director, neuropathology core, at Boston University School of Medicine, and co-director of the Center for the Study of Traumatic Encephalopathy, in a December 3 news release.

An accumulation of blows
As reported in the Boston Globe, the study was based on brain samples taken posthumously from 85 donors who had histories of repeated head injuries. This new research adds to the mounting evidence linking CTE to repeated hits to the head in such sports as football and hockey. CTE is a progressive degenerative disease whose symptoms include memory loss, paranoia, confusion, impaired judgment, impulse control issues, depression, and dementia.

Among those in the study, 80 percent – 68 men, ages 17 to 98 and nearly all of whom played sports – showed evidence of CTE. Of the 85 donors, 50 were football players, including such NFL stars as Dave Duerson, Cookie Gilchrist and John Mackey. Also in the group were six high school football players, nine college football players, seven professional boxers and four NHL hockey players.

The four stages of CTE
Researchers interviewed families of the brain donors to learn more about the behaviors they exhibited as the disease progressed. In stage I, CTE victims suffered headaches and had trouble concentrating. In stage II, victims were depressed, had explosive tempers and short-term memory problems. Victims in stage III had cognitive impairment and difficulty with planning, organizing and handling multiple tasks. By final stage IV, full dementia was present.

In addition, the study found that damage to the brain was far more extensive in athletes who played professional contact sports and died after the age of 50. These patients were also more prone to severe memory loss and personality changes before they died.

The volume of cases in the study “allows us to see the disease at all stages of severity and how it starts and spreads in the brain, which gives us an idea of the mechanism of the injury,” McKee told the New York Times.

Protecting young football players
The study’s results are sure to renew calls for more restrictions like the Massachusetts concussion law which prohibits young football players who have sustained concussions from returning to a game on the same day of injury.

Robert Cantu, MD, study co-author, clinical professor of neurosurgery at Boston University School of Medicine and co-director of the Center for the Study of Traumatic Encephalopathy, told the Boston Globe he would like to see tackle football replaced by flag football for all children under the age of 14. He also favored high school teams limiting contact practices to once a week during the regular season.

“There’s no talk of setting up formal rules for limiting contact practices,” said Paul Wetzel, spokesperson for the Massachusetts Interscholastic Athletic Association. “But most football coaches will tell you two or three games into the season, they’re limiting contact practices to avoid injuries.”

Can chocolate make you smarter?

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East Side News

The regular warnings about chocolate and their negative impacts on people’s health may all be refuted by this study. A recent paper showed that a regular intake of cocoa (one of the main ingredients of chocolate) can help improve the mental functions in elderly people, and reduce the risks of mild cognitive impairment, a precursor to dementia and other forms of dementia diseases. Other studies revealed that mice and snails who ate chocolate had improved their memory capabilities.

Franz Messerli of Columbia University performed a study in which he counted the number of nobel laureates per 10 million population with the amount of chocolate consumed in that country. The number of nobel prize winners was to be used as a general indicator of the country’s intelligence level.. The P value was 0.0001, which means there is a 1/10,000 probability of the graph showing no correlation. The only country that didn’t quite follow the trend was Sweden because Sweden has a very high number of nobel laureates but consumes much less chocolate. However, because Sweden is the country that donates and evaluates the Nobel Prizes, Messerli has a theory that “‘the Swedes might have a slightly patriotic bias.’”

This study has an extremely high correlation, but as most know, correlation does not necessarily mean causation. Although it seems very likely that chocolate may be an important factor in the number of Nobel Prize winners in a country, more studies must be performed to consider other factors that would probably play a more crucial role in this process.

Psoriasis drug may halt or reverse Alzheimer's disease

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LA Times

A biological medication already widely used to treat plaquepsoriasis may be able to slow the accumulation of amyloid plaques in the brain that are the hallmark of Alzheimer's disease, a new study has found. The same study found that in older mice with established Alzheimer's, this treatment approach, which suppresses the brain's immune reaction to beta amyloid, brought a marked improvement in cognitive function and may even halt or reverse early signs of Alzheimer's.

The new study was published this week in the journal Nature Medicine.

Conducted by researchers in Switzerland and Germany, the study offers a glimmer of hope in the thus-far discouraging search for a therapy that could halt or reverse the inexorable process of neuronal loss and mental decline that affects some 35-million people worldwide. It also strengthens evidence for the long-suspected role of inflammation in the development of Alzheimer's disease.

The authors of the study suggest that researchers should immediately launch clinical trials of ustekinumab — a biologic drug already approved by the Food & Drug Administration for the treatment of plaque psoriasis (and marketed as Stelara) — on patients with mild cognitive impairment or very early Alzheimer's disease. They called agents that shut down specific immune responses — medications tested in auto-immune disorders such as psoriasis, Crohn's disease and multiple sclerosis — "the ideal candidate for the initiation of clinical trials" for Alzheimer's.

"This kind of research is a step forward in identifying potential human targets for drug action," said Dr. Lon Schneider, director of pharmacological research at USC's Alzheimer's Disease Research Center, who was not involved with the current study.

At the same time, Schneider cautioned against drawing too much hope from the latest research. In animal models of Alzheimer's disease, he said, interventions that seem to work for mice "have not translated to humans," he said. And even when an existing drug appears promising, he added, researchers are far from knowing what dose or form of administration will be safe and effective for humans.

"Using the drug off the shelf may not be either" safe or effective, he warned.

The latest research focuses on the role of the immune system in the degenerative process at the heart of Alzheimer's. Looking at the cerebrospinal fluid of 39 human subjects with established Alzheimer's disease and 20 healthy control subjects, the researchers showed that the accumulation of beta-amyloid in the brain may set off an immune reaction — including the release of two proteins known as interleukin-12 and interleukin-23.

These two chemicals, collectively called IL-12/23, send forth a signaling molecule called P40 that increases inflammation across the brain. Past research suggests that in brains where P40 is in plentiful supply, beta-amyloid particles that are circulating form plaques. Those plaques, in turn, disrupt signaling throughout the brain and appear to  cause the decline in memory and mental function so familiar to the loved ones of those with the devastating disease.

Researchers have sought to suppress IL-12/23 by different means. But among the most successful so far have been the injection of antibodies that shut down P40's signal. When the authors of the study injected P40 antibodies and an inactive control substance into young mice who were genetically programmed to develop Alzheimer's disease, they saw a distinct difference: At about middle age, the mice that got the P40 antibodies had 31% less beta-amyloid plaque in their brains than their peers who got the placebo.

The researchers also sought to test the effect of suppressing P40 in rats with established Alzheimer's disease. They implanted mini-pumps that for 60 days infused P40 antibodies directly into the brains of older rats with full-blown Alzheimer's. Another group of such rats got a placebo infusion. The treated mice performed far better than those who got the placebo in tests of memory and cognitive function. And while the treated mice still had amyloid plaques, there was far less beta-amyloid in their brains available to form new ones.

See recent reports of other drugs that have generated hope for Alzheimer's disease:

A hint of success in treating Alzheimer's raises ethical quandary; and

New Alzheimer's pill more likely to cause misery, medical experts say

Top Appropriate Holiday Gifts For Those With Dementia

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PRlog

Christmas,Chanukah and alike are the perfect chance to give gifts that are not only enjoyable but also are beneficial to persons with Alzheimer’s disease or a related dementia. These presents keep on giving long after the holiday season is gone

Over 5.4 million Americans are living with dementia. Is one of them someone you know or work with? Get him/her or anyone with Alzheimer's disease a gift that will keep on giving long after the holiday is gone.

First on the list of gifts is a book by Susan Berg called Adorable Photographs of Our Baby -- Meaningful, Mind-Stimulating Activities and More for the Memory Challenged, Their Loved Ones and Involved Professionals, This book features baby photographs that seniors with dementia love. This book shares a plethora of ideas and resources for you.

Another gift dementia persons will fancy is a holiday classic musical such as: “White Christmas” or “Holiday Inn”,

For those who are Jewish, we have, Debbie Friedman's "Miracles and Wonders: A Hanukkah Musical" and “A Taste of Chanukah”

Next is a sing a long CD or audio cassette of their favorite love songs. There is a series of these called, Old Time Favorites by Nancy Pitkin. Especially for Christmas, Mitch Miller’s sing a long gang has a CD and video for a dementia person’s holiday pleasure.

“Chanukah Favorites”, by award-winning Jewish performer, Judy Caplan Ginsburgh, is a great CD for Jewish people with dementia

You may want to get a sing a long video where your loved one can see and hear performers singing songs they love and are about love. A good one is, Sing-Along with Phil Bernardi: Songs We Know and Love

Here is another idea. Give a friend with dementia some hand lotion. Any kind will do. Just be aware of any allergies or pain issues he/she might have. If he/she can tolerate it, those with a pleasant scent work well. Give him/her a relaxing hand massage talking about how good the hand massage feels, how much you love this person, and a holiday experience you both share from the past.

If you cannot afford or do not have time to get these gifts, give the gift of....read all of Top Appropriate Holiday Gifts For Those With Dementia

Key protein interactions involved in neurodegenerative disease revealed Read more at: http://medicalxpress.com/news/2012-11-key-protein-interactions-involved-neurodegenerative.html#jCp

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Medical Xpress

Medical research Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS)

.The study was published online ahead of print on November 8, 2012, by the journal Structure. The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration. "Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate coresponsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis. All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell's fate. "Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them." 

More information: "Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases," December 5, 2012 print edition of Structure. Journal reference: Structure Provided by Scripps Research Institute 

Remarkable recent discoveries in Alzheimer’s disease

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Examiner

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Medscape Medical News reported on the latest published research in Alzheimer’s disease on November 7, 2012 indicating individuals carrying a mutant gene for Alzheimer’s disease demonstrate markers 20 years before onset of memory changes. In addition to markers in the cerebral spinal fluid, the individuals show structural changes in the brain other than the amyloid plaques and tangles commonly found in patients with the disease.

Dr. Eric M. Reiman, the first author on this recent study, published his results in Lancet Neurology on November 6, 2012. His research group from the Banner Alzheimer’s Institute in Phoenix, Arizona studied about 5000 people who carry the gene mutation that produces Alzheimer’s disease as early as age 45 years in Colombia.

Reiman and colleagues compared carriers of the gene with non-carriers and found structural differences in area of the brain called the hippocampus as well as less grey matter in some parietal lobes in individuals with the Alzheimer’s gene mutation. The parietal lobe resides at the top of the head after the frontal lobe and before the occipital lobe at the back of the head. The researchers used magnetic resonance imaging to uncover the changes in the parietal lobe. These changes occurred 20 years before the onset of memory loss. By knowing these alterations exist early, researchers can study treatments and measure for differences at these sites.

According to the Center for Disease Control and Prevention, Alzheimer’s disease causes the most common form of dementia that produces loss of thought control, memory and language. The disease usually affects men and women over the age of 60 years. The cause of Alzheimer’s disease remains presently unknown. Most scientists think several factors such as genetic, environmental and lifestyle contribute to the development of the disease. The discovery of changes in the parietal lobe and hippocampus add significantly to progress in the research.

The National Institute on Aging describes the importance of clinical research for uncovering causes, treatment modalities and disease prevention in Alzheimer’s disease. Patients or families interested in becoming involved in research trials can go the Clinical Trials.gov website for more information. The research trial website lists trials available in all 50 states and 181 countries.