Why is There a Shortage of Neuroscience Drug Approvals for the Market?

    18/01/2015

    Despite a recent upsurge in the number of new drug chemicals (New Molecular Entities or NMEs) approved by the Food and Drug Administration (FDA), there remains a lack of drugs for the treatment of central nervous system and psychiatric diseases, otherwise known as CNS diseases. The most well known CNS diseases currently being targeted for therapy include depression, psychosis, epilepsy and Alzheimer's disease. As of 2014, 41 New Drug Applications have been approved in the US - a major improvement compared with the downward trend of previous years and almost as good as the last approval boom of 1996 (53). However, the number of NMEs designed to treat neurological disorders has been lacking. Why is this? To understand the issue, one needs to look back at the role of the FDA and the regulation of drug development by pharmaceutical companies.

    In 1937 a scandal broke out in which an elixir of sulfanilamide, used to treat bacterial infections, caused the deaths of over 100 patients in 15 states across the US. The drug was dissolved in diethylene glycol which had not been tested for toxicity and was ultimately found to be fatal. In the immediate aftermath the Food and Drug Cosmetic Act was introduced by President Theodore Roosevelt to ensure all manufactured drugs were tested for dangerous effects before being placed on the market. Since then, every drug that has ever been legally sold in the US has gone through a rigorous safety/toxicity testing process and a thorough critical review processes to satisfy FDA approval. Every drug must be tested for a variety of effects in the laboratory, then in animals, then in human patients (Phase I to III clinical trials) and then during postmarketing surveillance. Many potential drug compounds are dropped during these stages of development from which only one may or may not be selected for final review. Similar processes hold true for Europe and Japan, who also have agencies equivalent to the FDA. Over the years this process of drug testing has taken longer and review processes have become increasingly complicated in order to keep up with modern medicine. The entire timeline for developing one single drug usually takes over 10 years, amounting to over $100 million in costs. In recognition of this burden, both the FDA and the pharmaceutical industry have undergone structural reforms to ensure more urgent new drugs can be expedited to the market approval stage. Thus, it is in the interest of companies to develop a drug that will make big financial returns to cover the exorbitant costs of innovation and development, especially before the 20 year patent cliff expires.

    A simplified cartoon of the drug discovery process:

    However, a study last year by Tufts concluded that only 6% of new drugs for CNS disorders entered into Phase I clinical trials are ever able to make it through the pipeline to FDA approval. CNS drugs are 10% less likely to pass from Phase II to the all-important Phase III clinical trials stage compared with a drug that treats other indications such as cancer. The time taken for the FDA to review neurological drug applications also takes up to 5 months longer than for other types of drug. In Europe, the statistics are no better - the number of new active substances approved by the European Medical Agency decreased from 15 between 2004-2008 down to 9 between 2009-2013.

    Study from Tufts shows a lower probability of CNS drugs to advancement through clinical testing and longer time frames for development (from the Regulatory Affairs Professional Society):

    Part of the problem with developing CNS drugs is that pathologies vary so widely and so little is know about measuring their progress objectively. While neuroscience discoveries in these fields have advanced quickly, the translation into clinical treatment is hindered by the lack of solid end-points (ie. at what point should the treatment be stopped) and also by unknown adverse effects (such as the tendency for suicide after a prolonged dose of certain anti-depressants). Furthermore, many brain disorders are triggered by genetic inheritance, epigenetic factors, or as yet unknown causes for which the the mechanisms are not well defined.

    The other issue is simply economics. The number of deaths worldwide that can be attributed to neurological disorders alone (excluding stroke) are less common than the number of deaths due to cardiovascular diseases, respiratory tract disorders and cancer. An estimate by the World Economic Forum in 2011 showed that 30% of deaths worldwide were caused by cardiovascular disease and 13% caused by cancer, while the WHO estimated in 2012 that global deaths due to neurological disorders amount to around 11%. However, of that proportion, only 15% of brain disorder deaths are due to damage other than cerebrovascular disease. Funding for heart disease and cancer research, both in academia and in industry, has traditionally been better than for neuroscience research. On the other hand, compared to all other chronic diseases, neurological and neuropsychiatric illnesses account for up to 6% of financial and years lost by a patient who would otherwise be healthy - that was a cost of over $2.5 trillion as of 2010.

    In order to stimulate a growth in drug approvals for CNS disorders it is up to the pharmaceutical industry and regulatory agencies to shift their emphasis towards long-term impacts of chronic diseases rather than on shorter term diseases that result in high mortality. Furthermore, it appears that smaller biotech, pharma and startup companies would have the edge on pushing neuroscience drugs towards market development compared to large traditional pharmaceutical companies, weighed down by bureaucracy and steak holders demanding profits. In the age of personalized medicine and epigenetic innovations, it should be easy to see a turn around in a few years time for CNS drug treatments to gain more widespread approval. The question now is whether there is a will to do so in industry.

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      Breaking the Lock for Locked-in Syndrome: A new Brain Computer Interface

    10/01/2015

    A short while ago I watched The Diving Bell and the Butterfly, an extraordinary film based on the true story of Jean Dominique Bauby, the French ELLE magazine executive who suffered a stroke at the age of 43, leaving him almost completely paralyzed and a sufferer of Locked-in Syndrome. Locked-in Syndrome is caused by a brain stem stroke that cuts off blood supply to the medulla often resulting in severe quadruplegia and an inability to speak. However, parts of the brain involving cognitive function, proprioception and sometimes extraocular muscles are left intact which means patients can still sense their surroundings, can see and hear people and can sometimes communicate by moving their eyes. Depending on the severity of the stroke and which brain regions are damaged, the resulting levels of paralysis vary greatly in different people - from total Locked-in syndrome, where patients cannot respond to anything and lie in a "sleep paralysis" state, to partial Locked-in syndrome, where patients retain some voluntary control of their head and neck. Jean Dominique Bauby had to rely on Partner Assisted Scanning, a system where a person would recite the alphabet slowly and he would respond by moving his eyes in order to communicate each word he wanted to speak. You can imagine the tedious and laborious process it took for him to communicate on a daily basis, not to mention the process of writing his memoire that inspired the film.

    A recent clinical trial study brings us a step closer to alleviating the suffering of Locked-in patients. A collaboration set up between Harvard and Brown University scientists directly connected paralyzed patients with a computer processor in a system called BrainGate Neural Interface System. This study began 5 years ago when two patients who had suffered brain stem strokes were connected by neurosurgery using intracortical microelectrodes implanted to the arm area of the motor cortex. The electrodes were connected to a 96 channel recording cable that fed into a a decoder for the neural interface computer. The computer was connected to two robotic arm systems which could move in response to the patient's thoughts (the decoder responds to spikes in action potential firing). After nearly 2000 days of training and assessement on the neural interface system, one patient was able to successfully use the robotic arm to lift up a cup of coffee, drink from it and place it down. This was the first time after 14 years the patient drank (almost) unassisted:

     

    In the latest paper, the medical team report that the patient can successfully augment the point-and-click movements of a computer mouse as well as the efficient use of an on-screen keyboard to express words and sentences. They were even able to conduct limited internet Google Chat using the system. The patient was able to do this after 1900 days of training by imagining the physical movement of the mouse, while connected to the BrainGate system. The key to speeding up the typing process was to use an ingenious radial keyboard rather than the traditional QWERTY keyboard:

    The implications of this brain-computer interface are that it solves the problem of slow, laborious communications between the paralyzed patient and the outside world. Such a device could be used to help not only people who suffer from Locked-in Syndrome but also those with spinal cord injuries, amyotrophic lateral sclerosis and any other disorders which cause quadruplegia.

    The ongoing clinical trial, named BrainGate2, can be found here at clinicaltrials.gov.

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      Spinal cord injury treatment by inhibiting scar molecules

    06/12/2014

    Spinal cord injury is a difficult neurological condition to treat, marred by the expansive growth of a glial scar. One class of inhibitory molecules found in the glial scar is chondroitin sulfate proteoglycans (CSPGs) which impact on the ability of damaged spinal tract axons to regenerate and renew their connections. A new study from the Jerry Silver lab just came out in Nature looking at the effects of a new synthetic peptide in the treatment of the disorder. The attraction of damaged axons towards CSPGs lie in a few receptors on the growth cone surface, namely Protein Tyrosine Phosphatase sigma (PTP sigma) and leukocyte common antigen-related (LAR) phosphatase. The Silver lab designed a peptide which mimmics the PTP sigma binding site and applied it to neuronal cultures as well as damaged spinal cords of adult rats. They found striking improvements in axon growth over CSPGs in culture as well as functional improvements in bowel recovery and locomotion in animals after treatment. Such peptides have been the focus of much interest in the regeneration field because of the ease with which they can be potentially applied to the clinic. The new paper has been hailed as another breakthrough from the Silver lab to such an extent that NPR radio featured an entire story about it on their health news section. The Silver lab have an established reputation as they were one of the first groups to characterize CSPGs as inhibitors of nerve regeneration.

    Silver

     

    The paper was published on December 3rd, this week:

    Nature

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      Google Invests in Neurobiology Startup Companies

    21/09/2014

    Recently while I was browsing through the FierceBiotech website, a hub for hot and trendy biotech and pharmaceutical news, I came upon an article about Google's stealthy new investment in a startup company called Calico. Calico, as it turns out, has just signed its first license for clinical testing in a neuroprotective drug called P7C3. This comound was discovered by a team at UT SouthWestern in Dallas. The discoverers of this chemical, Andrew Pieper, Joseph Ready and Steven McNight, claim that P7C3 have broad therapeutic potentials in treating brain disorders, ranging from Alzheimer's Disease to traumatic brain injury, stroke and ALS. Their papers also cite potential in neurogenesis in the damaged hippocampus of animal models. Their recent publication in Cell Reports suggest that P7C3 acts on nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme involved in making NAD, thus augmenting its effects on neuronal survival and neurogenesis in mice. Read their review article here:

    This is not the first time Google has sponsored a neuroscience company, because it bought an artificial intelligence company earlier this year in the UK. However, it is the first example I have seen where Google have shown an early interest in developing treatments for neurodegenerative diseases. Their decision to hire Genentech CEO Arthur Levinson and other Genentech executives speaks to the seriousness of their goal. Calico is set to build its new biotech laboratories in Silicon Valley, close to Google headquarters, where it will join up with other life science companies like Abbvie.

    Life science and health care startup companies are sprouting up everywhere these days, with many of them backed by venture capitalists from rich Silicon Valley tech companies. Just take a look at this Startup Health website to get a sense of how many of them there are!

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      p-Hacking, Retractions and the Dark Side of Research

    07/09/2014

    Science is a noble human endeavor, but like all human endeavors it is subject to human error and vice. While most of us try to maintain the strictest standards in experimental design, statistical data analysis and a rigorous peer review process before papers are published, some will inevitably game the system in order to get their papers out faster and rise through the academic or corporate ladder. The lack of requirement by certain journals when it comes to reviewing raw data and the large amount of papers submitted for publication in the top Nature, Cell and Science magazines serve to exacerbate a growing trend in data falsifications.

    A study by the University of Pennsylvania in 2012 highlighted the problem of "p-hacking" in research. P-value is seen as the standard measure for statistical significance, required as a minimum by all journals to show that data between experimental and control groups really differ strongly. However, when researchers do not see a clear difference, they sometimes manipulate the data by cherry picking experimental samples which happen to differ more from control samples. The resulting p-value would decrease and the difference becomes significant.

    Listen to NPR's story about p-Hacking

    Re-analyzing data if no significant difference can be found is valid in certain cases (for example re-defining the paradigm when counting the shapes of different neurons in a big assay). But the nefarious practice of personally changing data is misleading and its prevalence in the world of academic publications is troubling. What makes it sad is that this has been happening for many years, as shown by a famous reformer, John Ioannidis from Stanford University, who published a paper called "Why Most Published Research Findings Are False" in Plos Medicine in 2005.

    Of course when fraudulent data is found and papers get retracted, serious consequences can result. The suicides of Yoshiki Sasai (RIKEN institute) this year and Yu-yi Lin (formerly of Johns Hopkins) last year embody the worst examples of how scientists fall from grace. In their cases, it was not merely a case of p-Hacking but a series of fraudulent figures and images that led to the retractions.

    Yoshiki Sasai, professor of regenerative medicine at the Riken Institute. (Picture from Nature Magazine).

    This year alone, I recount a whole slew of stem cell research papers that have been retracted from top tier journals, suggestive of systemic problems with the lack of standards in this field. In fact, an entire industry has erupted to follow a growing number of retractions in academic journals, with websites like retractionwatch.com leading the charge. Even the White House is taking notice of the lack of reproducibility in published scientific data.

    Publishing false data to fan the flames of your novel idea is not new and is not restricted solely to academia. Indeed such acts in other sectors, such as clinical research trials or business analysis, can be far more harmful to the world at large rather than to the reputation of few professors. But as scientists, if we are to move forward with publicly funded programs and generous philanthropic donations it is our duty and responsibility to uphold the utmost sincerity when it comes to publishing true data.

    Retraction Watch website:

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Retiring the Mouse Model Gold Standard

Brexit Britain I weep for you

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Seven Years in Visaland

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Start Talking Science

A Journey into my Genome

Patent Law IX, The Limits of Biotech Patents

Patent Law IX, The Longest Patent Extension Battle

Patent Law VIII, Invasion of Patent Trolls into Biotech

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Patent Law VI, Supreme Court and Laws of Nature

Patent Law V, The Dark Web

Patent Law IV, Gaming the Hatch-Waxman Act

Patent Law III, The Brave New World of Biosimilars

Patent Law II, The Everlasting Patent

Patent Law I, CRISPR-Cas9

FDA Law Intro

The Big Idea

Accountability for Retractions

Neuroscience Drugs

Locked-in Syndrome

SCI scar Inhibitor

Google-Calico

p-Hacking

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Neuropathic Pruritus

Mitochondrial Disease, 3 parent baby

Multiple Sclerosis and Axon Injury

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