CETP I405V: ASSOCIATED WITH LONGEVITY - OR WITH COGNITIVE DECLINE?

In an article published online today by Scientific American, author Gary Stix points to two apparently conflicting scientific studies regarding a specific variant of the gene encoding ‘cholesteryl ester transfer protein’, CETP I405V.  One of these studies, published in early 2011 by researchers at the Albert Einstein College of Medicine, found that individuals who carry two copies of this CETP variant within their DNA appear to have a lower risk of dementia and cognitive decline, and of heart disease.  It could potentially be surmised from this study that CETP I405V contributes in some way to healthy aging and longevity.

However, a more recent study conducted at Rush University Medical Center in Chicago has found that CETP I405V may instead correspond to an increased risk of Alzheimer’s.  In an attempt to replicate results from the Albert Einstein study, the Rush researchers observed a more rapid rate of cognitive decline in study participants having this CETP variant.  Additionally, post-mortem studies of the brains of deceased participants with CETP I405V revealed greater densities of the type of plaque that is characteristic of Alzheimer’s disease.

While startling, these conflicting results are perhaps not surprising, per Mr. Stix:

"Welcome to the wild-and-wooly world of gene-association studies that attempt to tie DNA to disease. Unless the link between a gene and a disease or phenotype is a very strong one, researchers who try to follow up on initial studies often get different results the second or third time around."

Perhaps the differing results in the two CETP I405V studies is due to demographic differences between participants in the two studies, or perhaps these were due to chance rather than genetics.  Alternately, perhaps CETP I405V in and of itself has a relatively weak effect on an individual’s cognitive abilities.  It’s simply impossible to say at this point in time.

A number of CETP inhibitors are currently in clinical trials for use against cardiovascular disease.  Based on the disparate results of the Albert Einstein and Rush studies, one must wonder how these may – or may not – ultimately bear on an individual’s cognitive health.

[Scientific American]

ADVANCES IN INTERPRETING ELECTRICAL SIGNALS WITHIN THE BRAIN

A team of researchers led by Gaute Einevoll of the Norwegian University of Life Sciences has developed a series of detailed mathematical/biophysical models that can be used to correlate nerve cell activity with electrical signals recorded by electrodes within the brain.  While it previously was possible to record such signals, interpreting these in a meaningful way has been challenging due to the incredible volume of signals that are transmitted within even a tiny region of the brain at any given time:

The problem of interpreting electrical signals measured by electrodes in the brain is similar to that of interpreting sound signals measured by a microphone in a crowd of people. Just like people sometimes all talk at once, nerve cells are also sending signals "on top of each other."

In the current study, efforts have focused on measuring and interpreting low frequency signals known as ‘local field potential’ or ‘LFP’, which indicates the activity of the many neurons that are in close proximity to a recording electrode.  The researchers suggest that measuring such signals and modeling their spatial reach, which appears to be dependent on synaptic activity, could be of significant value in diagnosing and treating various neurological and neurodegenerative diseases.

As an example, electrodes could be surgically implanted into epilepsy patients to detect activity that is indicative of an impending seizure, and in turn ‘inject’ an electrical current that would effectively prevent the seizure.  In a similar manner, implanted electrodes are currently used in many individuals suffering from Parkinson’s disease, as a means of preventing trembling.

The researchers are also optimistic that this method could be of use in treating individuals suffering from paralysis due to spinal cord fractures, by monitoring and transmitting signals from certain nerve cells to a ‘robot’ arm or leg.

[ScienceDaily]

WILL ACADEMIC COLLABORATIONS ENHANCE PHARMACEUTICAL PIPELINES?

In an effort to boost lagging pipelines of new drug candidates, it appears that big pharma may be increasingly looking to academia.  While it is far to early to gauge success, it is certainly interesting to consider two of the approaches that are currently being pursued.

First, AstraZeneca recently reached agreement with the Medical Research Council in the U.K. to grant academic researchers access to a number of novel compounds that have been developed by AstraZeneca, but which for various reasons have been put on hold by the company.  Even should these compounds never be developed into drugs, they may be of significant value in medical research.  Individual academic researchers can submit proposals, through the MRC, to use these compounds in ‘new areas’.  AstraZeneca will retain rights to the compounds themselves, with any new research findings owned by the researcher’s academic institution. [FierceBiotech]

Second, Pfizer is in the process of establishing a number of ‘Centers for Therapeutic Innovation’ to enable active collaborations between Pfizer and researchers at academic medical centers.  Pfizer provides both funding and research space, and welcomes proposals from researchers, with the goal of identifying new large molecule drug candidates across a broad range of potential therapeutic areas.  As a part of this ‘open-engineering partnering model’, Pfizer promises that participating researchers will be ‘highly incentivized’, with incentives including access to Pfizer’s compound libraries and other research tools.  According to Pfizer, which apparently plans to open numerous such Centers across the U.S. and, ultimately, worldwide:

The CTI collaborative model will effectively and efficiently combine the best ideas, research and expertise of the AMC with Pfizer's resources. The result of this integration will be better testing of clinical hypotheses, increasing the speed with which we establish Proof-of-Mechanism (PoM) and ultimately bring truly differentiated medicines to patients in need.  [Pfizer]

FOX TRIAL FINDER SEEKS TO CONNECT VOLUNTEERS WITH CLINICAL TRIALS

Human clinical trials of novel drug candidates are a necessary step in bringing any new drug to market; observational trials of individuals diagnosed with a particular disease also yield important information that could ultimately be used in the drug development process.  However, recruiting individuals to participate in clinical trials is often quite challenging and takes considerable time.  In an article in the current edition of Neurology Now, Debi Brooks, co-founder and executive vice chairman of the The Michael J. Foundation for Parkinson’s Research (MJFF), indicates that only 10% of all individuals suffering from Parkinson’s disease participate in clinical trials, and that the vast majority of clinical trials take longer than anticipated due to challenges involving recruitment.

In hopes that providing easily accessible, comprehensive information regarding clinical trials will boost participation, MJFF has recently launched the ‘Fox Trial Finder’, a web-based tool that is designed to connect individuals with appropriate clinical trials relating to Parkinson’s disease.  Each interested individual is asked to create a profile, including demographic information, location, medical history, and how long he or she has suffered from Parkinson’s.  This information is then used by Fox Trial Finder to identify any current trials that appear to be a good match, and subsequently to provide alerts regarding any trials that may be initiated in the future.  Should an individual choose not to create a profile, he or she can still browse through the list of current trials and contact the appropriate researchers if interested in participating.  Even healthy individuals are encouraged to take part, as ‘healthy controls’ are often needed for a particular trial.

Approximately 110 clinical trials are currently included in Fox Trial Finder, and over 1,200 individuals have signed on to date, with approximately 2/3 of these having Parkinson’s.

Enabling individuals with Parkinson’s to actively participate in activities that may ultimately result in finding a cure is crucial to MJFF, and by Michael J. Fox himself:

“When I got my diagnosis,” says Fox, “the first thing the doctor did was give me a prescription. Countless PD patients have had this same experience. If that doctor could have also given me a pamphlet describing something I could do to help myself and others over the long term—beyond filling a prescription—that would have meant everything. So that's our vision. That's what we are working toward every day. We want patients and the PD community to receive the message: There is something you can do. In fact, you may be the only one who can do this particular thing.”

The Fox Trial Finder can be accessed at https://foxtrialfinder.michaeljfox.org/.

[Neurology Now]

WHY BIG PHARMA IS MOVING AWAY FROM CNS DRUG DEVELOPMENT

During the past year, a number of large pharmaceutical companies have either shut down or significantly downsized their neuroscience R&D programs.  In view of the today's news that Novartis too plans to close its neuroscience division, it seems worthwhile to explore the reasons why the pharmaceutical industry is currently shunning psychiatric and neurodegenerative diseases.

According to a study conducted earlier this year by The Tufts Center for the Study of Drug Development, there certainly appears to be a significant unmet need – and therefore a significant market opportunity – for drugs that would effectively treat such diseases.  However, the costs associated with developing such drugs, and the risks inherent in doing so, are equally significant – and, in fact, considerably higher than those associated with the development of drugs in other therapeutic arenas.  For example:

• CNS drugs spend an average of 8.1 years in human trials, which is more than two years longer than the average for all drugs;
• Regulatory approvals for CNS drugs take an average of 1.9 years, while 1.2 years is the average for all drugs;
• Taking a new CNS drug from the bench to the market takes almost 18 years, including preclinical studies;
• Only 8.2% of all CNS drugs that enter into human clinical trials ultimately receive marketing approval, as compared with 15% for all drug candidates; and
• 46% of all CNS drugs succeed in late-stage clinical trials, as compared with 66% for all late-stage candidates.

One complicating factor in successfully bringing a new CNS drug to market is the difficulty in accurately assessing whether it really works – and whether it will be both safe and effective for long-term use.  This is particularly crucial as many psychiatric and neurodegenerative diseases can last many years, if not an entire lifetime.

It is disappointing, but perhaps not surprising, that big pharma does not wish to take on what appears to be a very risky proposition – albeit one with a potentially great reward for those that ultimately succeed.

[Scientific American]

NOVARTIS TO SHUTTER NEUROSCIENCE DIVISION

According to a report in this week’s issue of the journal Nature, the pharmaceutical giant Novartis plans to close its Basel, Switzerland neuroscience division.  This announcement comes on the heels of similar announcements by GlaxoSmithKline and AstraZeneca; significant cutbacks in neuroscience research programs have also occurred within Pfizer, Merck, and Sanofi.

While it is moving away from its ‘traditional’ programs in neuroscience drug R&D, Novartis instead plans to focus efforts toward understanding the genetics of brain disorders, in the hope that this will ultimately translate into novel therapeutic strategies.  According to Mark Fishman, President of Research for the Novartis Institutes of BioMedical Research:

“Progress based on neurotransmitters has become small and incremental.  Genetic analysis will provide a real scientific opportunity in psychiatric and cognitive disorders, even if new drugs only arrive in the distant future.”

Novartis will apparently continue to develop the five candidate CNS therapeutics that are currently in its pipeline.

[Nature]

NEW REPORT PAINTS DISMAL PICTURE OF PHARMACEUTICAL INDUSTRY

A new report issued by the consulting firm Oliver Wyman indicates that the situation is “worse than we thought” for the pharmaceutical industry.  In addition to ongoing patent expirations and significant industry consolidation, the report cites a 40% drop in the average number of new drugs approved each year by the FDA since the so-called golden era of 1996-2004, accompanied by a drop in the average economic value created by each drug of approximately 15%.  Perhaps most notably, overall sales per year have dropped by a staggering 49%, while R&D expenditures per year have almost doubled.

In preparing its report, Oliver Wyman considered twenty top pharmaceutical companies.  Of these, only three – Novo Nordisk, Bristol-Myers Squibb, and Johnson & Johnson – did not experience a decline in productivity during the ‘scarce years’ of 2005-2010.  The firm believes that, in order to succeed going forward, pharmaceutical companies must focus on specific disease areas and pursue collaborations as appropriate, while also refining internal R&D capabilities.  While big pharma still has the potential to restructure and grow, the road ahead may be very challenging and will require significant changes to traditional R&D strategies:

The breadth of the decline is important. This is an industry that is endlessly benchmarked, where there is a relentless sharing of “best practice,” and where laggards look to the leaders to chart the way. But in R&D, no company has broken away from the pack. That tells us that we need to be more aggressive and to question the fundamental approaches to pharma R&D for solutions to the productivity challenge.

[Pharmalot] [Oliver Wyman]

DISTINGUISHING BETWEEN ALZHEIMER'S AND FRONTOTEMPORAL LOBAR DEGENERATION

At present there is no definitive diagnostic test for Alzheimer’s disease other than at autopsy.  The symptoms of Alzheimer’s can be quite similar to other forms of dementia, making it difficult for physicians to determine an appropriate course of treatment for individuals experiencing such symptoms. 

A team of researchers led by Gil Rabinovici of UC San Francisco has now developed a type of PET scan that is capable of distinguishing between Alzheimer’s and another form of dementia called frontotemporal lobar degeneration (‘FTLD’), and is more accurate than the ‘FDG PET scan’ that is currently used for this purpose.  Specifically, the scan utilizes a marker called PIB which is capable of detecting amyloid plaque within the brain AT an accuracy of approximately 90%.  This plaque is characteristic of Alzheimer’s disease but not of FTLD.

While the PIB PET scan in and of itself does not appear to be amenable to widespread clinical use, Dr. Rabinovici notes:

"Similar amyloid markers are being developed for clinical use, and these findings support a role for amyloid imaging in correctly diagnosing Alzheimer's disease vs. FTLD."

[U.S. News & World Report]

PLEA FOR PARTICIPANTS: ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE

In a posting on the Alzheimer’s Association website, Michael W. Weiner, M.D., Director of the Center for Imaging of Neurodegenerative Diseases at the San Francisco Veteran’s Affairs Medical Center, has issued a plea for more individuals to volunteer to participate in clinical trials relating to Alzheimer’s Disease.  Weiner, who received the 2011 Ronald and Nancy Reagan Research Award from the Alzheimer’s Association, heads the huge multi-center Alzheimer’s Disease Neuroimaging Initiative (‘ADNI’), which seeks to identify the earliest signs of Alzheimer’s with the goal of ultimately developing therapeutics that will slow the progression of the disease.  As stated by Dr. Weiner: 

I encourage you to lend your voice to this issue and raise awareness of the importance of clinical trials in the fight against Alzheimer’s. Better yet, consider participating in the ADNI trial. We are seeking normal persons, patients with Alzheimer’s disease and individuals with mild cognitive impairment to better understand the breadth and progression of the disease. The age range is 55 to 90. 

Additional information regarding the ADNI trial, including how to participate, can be found at http://www.adni-info.org/. 

[Alzheimer's Association]

NEW FINDINGS REGARDING MOLECULAR MECHANISMS OF ANTIPSYCHOTIC DRUGS

Schizophrenia is a severe, debilitating brain disorder that afflicts approximately 1% of the world’s population, with over 2 million adults suffering from the disease within the U.S. alone.  Individuals with schizophrenia may hear voices that others do not hear, experience hallucinations, or believe that others are reading their thoughts or controlling their minds.  While it appears that genetics may play a role in the development of schizophrenia, the specific cause of the disease, which is thought to be characterized by abnormal brain structure and chemistry, is not yet well understood.  There currently is no known cure for schizophrenia, though various antipsychotic medications are commonly prescribed for the management of symptoms.  [National Alliance on Mental Illness]

The molecular mechanisms employed by these medications has remained unknown to date.  However, new findings generated by researchers led by Javier Gonzalez-Maeso of Mount Sinai School of Medicine and Diomedes Logothetis of Virginia Commonwealth University appear to shed significant light on these mechanisms.  Specifically, the researchers have shown that the administration of antipsychotic drugs results in specific patterns of cell signaling involving two brain receptors that are linked to schizophrenia - increasing the level of activity in the glutamate mGlu2 receptor while decreasing activity in the serotonin 5-HT2A receptor.  Administering hallucinogens has the opposite effect on the activity of these two receptors, which are thought to work together as a complex ‘switch’.  While the optimal ratio of activity is not yet known, it appears that the balance of activity between these two brain receptors differs considerably between healthy individuals and those suffering from schizophrenia.  The researchers are therefore confident that knowledge may hold the key for developing novel treatments against schizophrenia and other mental disorders. 

"Now that we know how current drugs affect the ratio of activity in this glutamate-serotonin receptor complex, we can try to identify or develop more effective treatments for schizophrenia that result in a healthier signaling ratio," said Dr. Gonzalez-Maeso.

[FierceBiotech]