PhRMA RELEASES REPORTS REGARDING ALZHEIMER'S DRUG DEVELOPMENT

Two recently-released reports by the Pharmaceutical Research and Manufacturers of America (PhRMA) provide a compelling snapshot regarding the development of drugs for use against Alzheimer’s disease.  The first of these reports, “Alzheimer’s Research: Setbacks and Stepping Stones”, indicates that only three drugs for use in treating the symptoms of Alzheimer’s were approved between 1998-2011, while the development of 101 Alzheimer’s drugs was halted or abandoned during the same period of time – a staggering 34:1 ratio of failures vs. successes.  However, even given these bleak statistics, PhRMA takes the optimistic position that these setbacks – though discouraging – contribute to a body of Alzheimer’s knowledge that may ultimately redirect research efforts toward an eventual breakthrough.

The biopharmaceutical industry is clearly continuing to focus on the development of Alzheimer’s drugs, as detailed in the second of PhRMA’s reports, entitled “Medicines in Development for Alzheimer’s Disease”.  This report cites a total of 93 novel drugs that are currently under review by the FDA or in clinical trials for use against Alzheimer’s or other dementias; these include a diversity of approaches including various routes of administration, gene therapy, and potential vaccines.

The need for a successful drug is emphasized in this report, which states that over 5 million Americans are currently suffering from Alzheimer’s, at a cost of $200 billion per year for the U.S. healthcare system.  Without a new drug that will prevent, delay or halt the progression of Alzheimer’s, PhRMA anticipates that 13.5 million Americans will be afflicted with the disease by 2050, with costs of care increasing to over $1 trillion per year in the U.S. alone.  Even if a new drug is capable only of delaying the onset of Alzheimer’s by five years, PhRMA projects that this would result in a decrease of 43% in the number of individuals with Alzheimer’s, and a $447 billion decrease in corresponding healthcare costs, by 2050.

[FierceBiotech]

RESEARCHERS IDENTIFY POTENTIAL TARGET FOR TREATMENT OF PARKINSON'S

Parkinson’s disease is characterized by the loss of neurons within a section of the midbrain, which in turn results in a lack of dopamine within the central nervous system.  Now, a team of researchers led by Jan-Ake Gustaffson of the University of Houston has learned that the nuclear receptor liver X receptor beta (‘LXRbeta’) may play an important role in preventing and/or treating Parkinson’s.  Through administering the potent neurotoxin MPTP to laboratory mice – which is an accepted model for simulating Parkinson’s disease – it was observed that the harmful effects of MPTP were greater in the absence of LXRbeta.  Conversely, the effects of MPTP were found to be preventable via the administration of a drug that activates LXRbeta receptors – indicating to the researchers that LXRbeta receptor activation could represent a mechanism for protecting against neurodegeneration. 

“LXRbeta is not expressed in the dopamine-producing neurons, but instead in the microglia surrounding the neurons,” Gustafsson said. “Microglia are the police of the brain, keeping things in order. In Parkinson’s disease the microglia are overactive and begin to destroy the healthy neurons in the neighborhood of those neurons damaged by MPTP. LXRbeta calms down the microglia and prevents collateral damage. Thus, we have discovered a novel therapeutic target for treatment of Parkinson’s disease.”

[University of Houston]

FLUORESCENT PROBES MAY ENABLE DIFFERENTIAL DIAGNOSIS OF NEURODEGENERATIVE DISEASES

A series of novel fluorescent probes that bind to amyloid plaques has been designed by a team of researchers led by Jerry Yang and Emmanuel Theodorakis of the University of California, San Diego.  As the accumulation of amyloid plaques is characteristic of certain neurodegenerative diseases, including Alzheimer’s and Parkinson’s, it is hoped that these probes may ultimately be of use in diagnosing such diseases. 

While PET scans are currently used to detect the presence of amyloid in the brain, such scans do not differentiate between different types of amyloid, which in turn are associated with different neurodegenerative disorders.  The fluorescent probes developed by the UCSD researchers appear to overcome this challenge: 

“The key trick here is that the small differences in the proteins that make up different forms of amyloid interact differently with our fluorescent probes to result in measurably different colors of the emitted light,” said Jerry Yang.  “We think that our approach represents a significant step towards developing diagnostics to distinguish between different, but closely related diseases where symptoms and pathological characteristics show may similarities.”

Enabling the differential diagnosis of specific neurodegenerative disorders would in and of itself be a significant step forward.  In addition, as amyloid accumulates in the eye as well as in the brain, the researchers are optimistic that the probes could ultimately enable the diagnosis of neurodegenerative diseases through the eye – for example, via the application of eye drops followed by a simple eye exam.

[University of California, San Diego]

NOVEL WASTE PRODUCT REMOVAL SYSTEM DISCOVERED IN BRAIN

Using two-photon microscopy to visualize the movement of various fluids within the brains of living mice, a team of researchers led by Maiken Nedergaard of the University of Rochester Medical Center has discovered a novel conduit-like system surrounding the blood vessels within the brain.  Termed the “glymphatic system”, this system serves to drain waste products from the brain in a highly organized, rapid manner.  While it was previously known that cerebrospinal fluid functions in cleansing waste products from the brain via diffusion, the glymphatic system appears to be far more efficient, actually pumping large volumes of cerebrospinal fluid through the brain under pressure and draining away waste. 

It is hoped that this finding may have implications for Alzheimer’s and other conditions involving the brain, including other neurodegenerative diseases as well as traumatic brain injury and stroke.  There appears to be reason for optimism, particularly given the researchers’ observation that the majority of amyloid beta that is removed from mouse brain under normal conditions appears to be removed via the glymphatic system.  As stated by the study’s first author, researcher Jeffrey Iliff:

"If the glymphatic system fails to cleanse the brain as it is meant to, either as a consequence of normal aging, or in response to brain injury, waste may begin to accumulate in the brain. This may be what is happening with amyloid deposits in Alzheimer's disease.  Perhaps increasing the activity of the glymphatic system might help prevent amyloid deposition from building up or could offer a new way to clean out buildups of the material in established Alzheimer's disease."

[ScienceDaily]

FINDINGS SUGGEST POTENTIAL BLOOD TEST FOR ALZHEIMER'S

At present, the diagnosis of Alzheimer’s generally relies on the symptoms exhibited by an individual, and on the use of PET brain imaging and/or cerebrospinal fluid analysis.  A reliable blood test would be far less expensive and less painful, and would have the potential of enabling a definitive diagnosis at an earlier stage of the disease. 

A team of researchers led by William Hu of Emory University School of Medicine has identified a panel of four markers that could ultimately represent the basis for a sensitive and low-cost blood test for Alzheimer’s disease.  Initially testing 190 potential markers, the researchers identified 17 that have properties that are significantly different in individuals with Alzheimer’s or with mild cognitive impairment (‘MCI’) – which is generally considered to be a significant risk factor for the development of Alzheimer’s – than in healthy subjects.  Further testing led to the finding that the properties of four of the 17 markers appear to be consistent among individuals having MCI or Alzheimer’s.  It was also observed that changes in the levels of these four markers - apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide – mirrored changes in beta amyloid protein levels within the cerebrospinal fluid of these same individuals.  Further testing will enable researchers to determine whether these markers are, in fact, unique to Alzheimer’s and could therefore be used as the basis for a reliable blood test. [Medical News Today]

Unfortunately -- while a simple blood test for Alzheimer’s would clearly be of value, there are still no therapeutic agents that are capable of slowing or preventing the progression of the disease.  The only remaining drug candidate that has reached late-stage clinical trials is Lilly’s solanezumab, a monoclonal antibody that targets beta amyloid protein.  The recent failure of Phase III clinical trials for Pfizer/Johnson & Johnson’s bapineuzumab – another antibody against beta amyloid – has led some to believe that targeting beta amyloid plaque may not, in fact, represent an effective mechanism for slowing Alzheimer’s.  The picture may become more clear when Lilly releases Phase III study results for solanezumab within the next few weeks, and when additional data regarding the failure of bapineuzumab is made available.  [FierceBiotech]

U.S. BIOPHARMACEUTICAL VENTURE INVESTING DOWN SIGNIFICANTLY FROM 2011 LEVELS

As reported by Dow Jones, U.S.-based biopharmaceutical companies raised a total of $570 million via 54 venture capital deals during the second quarter of 2012 - a decline of 22% in deals and a decline of 43% in capital invested as compared with the second quarter of 2011.  Across all sectors, the number of deals and capital invested fell by 9% and 3%, respectively. 

While certain sectors appear to be somewhat healthy, the outlook for healthcare / biopharmaceutical venture investment remains somewhat bleak: 

“IT and Internet investment has been steady but interest in capital-intense industries like healthcare and energy is fading,” said Brendan Hughes, director of information analysis for Dow Jones VentureSource. “The unpredictable environment for IPOs – the traditional exit for biopharmaceuticals companies – has entrepreneurs and investors struggling to find new business models.”

Investment in medical device and healthcare companies declined during second quarter 2012 as well.  The only healthcare-related sector that appeared to fare well was healthcare IT, which recorded a 45% increase in deals and a 33% increase in the amount of capital raised.

[Dow Jones]

DIABETES DRUG EXHIBITS PRONEUROGENIC ACTIVITY WITHIN BRAIN

A team of researchers led by Freda Miller of the Hospital for Sick Children Research Institute in Toronto has found that metformin – a drug commonly used to treat type 2 diabetes – appears to be capable of triggering the growth of new brain cells.  While it has previously been observed that patients having both diabetes and Alzheimer’s exhibited improvements in Alzheimer’s symptoms when taking metformin, it was hypothesized that this was an indirect result of improving the individual’s health via treating their diabetes.  It now appears, however, that this improvement in Alzheimer’s symptoms may be directly due to the metformin itself, via its activation of a specific pathway within the brain.

As reported by the researchers in an article published yesterday in the journal Cell Stem Cell: 

“The findings presented here demonstrate that the widely used diabetes drug metformin is sufficient to activate the aPKC-CBP pathway in neural precursors and to thereby enhance neurogenesis and raise the possibility that metformin could provide the basis for a therapeutic strategy for the human nervous system.” 

To date, this proneurogenic effect of metformin has been demonstrated in rodent and human neurons in culture, and within the brains of adult mice.  Miller and colleagues also observed that metformin appears to enhance spatial memory function in adult mice, together with increasing the number of ‘newly born’ neurons within the hippocampus, as demonstrated via performance of a water maze task.  The researchers are therefore optimistic that the proneurogenic activity of metformin could potentially be effective in mitigating at least some of the neurological damage caused by Alzheimer’s or other neurodegenerative diseases.  Clinical trials to explore this further are currently being planned.

[Cell Stem Cell]

LEVODOPA/CARBIDOPA INTESTINAL GEL REDUCES "OFF TIME" IN PARKINSON'S PATIENTS

Individuals suffering from Parkinson’s disease are often prescribed oral medications containing the drugs levodopa and carbidopa.  Levodopa helps to alleviate Parkinson’s symptoms such as tremors, stiffness, and difficulties in movement, while carbidopa works to prevent the nausea and vomiting that are commonly associated with levodopa.  While these ‘dual-drug’ medications are generally quite effective over a period of several years, their effectiveness in alleviating symptoms over the course of an entire 24-hour period often decreases after five to ten years.  This daily period of ineffectiveness may last for six hours or more, and is generally referred to as “off time”.

A team of researchers led by C. Warren Olanow of Mount Sinai School of Medicine has learned that a patient’s “off time” could be reduced by an average of two hours per day by administering levodopa/carbidopa continuously as an intestinal gel rather than as an oral formulation.  The levodopa/carbidopa gel, or "LCIG", is administered via continuous infusion directly into the intestine, through an implanted tube that is connected with a portable pump.  In addition to reducing “off time”, the researchers found that a patient’s “on time” was improved in terms of symptom reduction.

"Maintaining a response to oral therapy is a challenge in Parkinson's disease patients, and there is a significant unmet need for a treatment that provides the benefits of the drug without off time or dyskinesia," said Dr. Olanow. "Since it is administered continuously through a pump, LCIG is a promising development that improves outcomes and quality of life in patients with advanced disease."

While as yet there is no cure for Parkinson’s, it certainly appears that these findings may well represent a means by which quality of life could be improved for those suffering from this disease. 

[Mount Sinai Medical Center]

PATENT CLIFF CONTINUES TO DRIVE DOWN PHARMACEUTICAL SALES

According to the "World Preview 2018" report released this week by EvaluatePharma, the patent cliff will continue to drive pharmaceutical sales down over the next several years, as patents expire and generic competition continues to grow.  As reported by FiercePharma, 2012 will see a decrease of $67 billion in global drug sales due to patent expirations.  While a decrease of 'only' $29 billion is anticipated for 2013, losses of $40 billion and $56 billion in sales are projected for 2014 and 2015, respectively.  Between 2012-2018, it is anticipated that more than $290 billion in sales will be lost due to patent expirations.

Casting a somewhat more optimistic light, EvaluatePharma’s report predicts that branded drug sales will increase over the same period of time, from $709 billion in 2012 to $793 billion in 2015.  It is also anticipated that pharmaceutical R&D spending will increase by approximately 1.5% per year, reaching a total of $149 billion by 2018.

[FiercePharma]

ERNST & YOUNG RELEASES 26th ANNUAL GLOBAL BIOTECH INDUSTRY REPORT

Ernst & Young’s Global Biotechnology Report 2012, “Beyond Borders”, paints a somewhat optimistic picture of the biotechnology industry:

“The aggregate financial performance of publicly traded biotechnology companies in the four established clusters — the United States, Europe, Canada and Australia — was encouraging in 2011, as the industry built on the recovery that had started a year earlier.”

After adjusting for the fact that three major U.S.-based biotech companies – Genzyme, Cephalon, and Talecris – were acquired by non-biotech companies, revenues across publicly traded biotechs grew by 10% in 2011, up from 8% in both 2009 and 2010.  Growth in R&D expenses reached 9% on a normalized basis in 2011, with R&D spending increasing across 62% of publicly traded companies.  In comparison, R&D spending rose by only 2% in 2010 – with even this modest level of growth differing markedly from the 21% cut in R&D spending across the industry in 2009.  Within the U.S., biotech industry revenues increased by 12% in 2011, after accounting for the acquisitions of Genzyme, Cephalon and Talecris, while U.S. R&D expenses increased by 9%. 

Pharma-biotech and biotech-biotech M&A activity appears to be quite robust.  However, even as the pharmaceutical industry seeks to externalize more of its R&D activities, it appears that pharmaceutical companies are being quite selective in terms of strategic alliances formed with biotech companies, as reflected by the decreasing volume and value of such alliances in 2011.

The entire report can be accessed via the Ernst & Young website, at http://www.ey.com/Publication/vwLUAssets/Beyond_borders_2012./$FILE/Beyond%20borders_2012.pdf.  

[Ernst & Young]