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FEATURE
Neuroscience — The Search Continues
Nick Chia
Senior Director and Clinical Development Strategist, Strategic Drug Development, Quintiles, Asia Pacific

The year 2012 has been a let-down for investigators in the field of neurosciences and for patients with neurological and psychiatric disorders. Suspense has been building up during most of 2012 for the results of the major Phase III Alzheimer’s Disease (AD) clinical trials from Eli Lilly, Elan, Pfizer and J&J. The results have been disappointing. However, despite the failures, set-backs and waning interest in neurosciences from pharmaceutical companies, new thoughts and directions of research are taking us down different paths, away from the traditional and well-trodden road that we are familiar with.

In January of 2012, a trial from Medivation on latrepirdine (Dimebon), backed by Pfizer, failed to show any benefit on AD, but instead cost the company about 750 million USD. In July, bapineuzumab, developed by Irish drug-maker Elan in association with Pfizer and the US multinational Johnson & Johnson, also failed to show an impact on symptoms. In August, Eli Lilly, reported the failure of solanezumab, its second AD drug to disappoint in two years. In 2010, a trial of semagacestat from Eli Lilly not only failed to slow the disease but worsened the symptoms. The setbacks have damaged confidence among pharmaceutical companies in the field of neuroscience, which was already shaky to begin with. The world’s leading pharmaceutical companies are stepping back from the search for new treatments for AD after the failure of a series of high-profile drugs trials.

It also doesn’t help that Europe is engulfed in economic turmoil. According to a report from the European Federation of Pharmaceutical Industries and Associations (EFPIA, 2011), countries like Greece, Italy, Portugal and Spain have ran up a debt of over EU 12.5 billion with the pharmaceutical companies. This in turn has translated into greater pressure on pharmaceutical manufacturers worldwide to cut back on their R&D budget during times of recession. Neuroscience, unfortunately, has been hit rather disproportionately, with AstraZeneca, Pfizer, Merck, Sanofi, Novartis and GlaxoSmithKline all downsizing their research departments in US and Europe.

Craig Ritchie, a leading Alzheimer’s researcher at Imperial College London UK, said: “The companies are streamlining their neuroscience departments and one can understand why. But it is hugely disappointing because there is a massive unmet need. There is a shift to symptomatic treatments instead of disease-modifying ones. There is a lot less energy in the system than there used to be. We need a success story - a catalyst - to make people feel there is something to work towards.”

AD has been on the radar of patients, physicians, care-givers and the politicians in recent years. In 2012, US president Barack Obama signed the National Alzheimer’s disease Act, which will lay out the national strategy to tackle the escalating AD crisis. As a result, US$156 million of government fund has been set aside to fight AD in the US and the Department of Health and Human Sciences releases the first-ever National Alzheimer’s Disease Plan in the US.

AD is the major cause of dementia and the total worldwide cost of dementia is estimated to be about US$604 billion in 2010. The number of people living with dementia worldwide is currently estimated at 35.6 million. This number will double by 2030 and more than triple in 2050. Globally, the total number of new cases of dementia each year stands at nearly 7.7 million, implying that one new case is diagnosed every four seconds. Dementia is seriously disabling for those who have it and is often devastating for their caregivers and families. Dementia doesn’t just affect individuals; it also affects and changes the lives of family members. It is a costly condition and has social, economic, and health impacts on the society. Nearly 60% of the burden of dementia is concentrated in low- and middle-income countries and this is likely to increase in coming years (WHO, 2012).

Major pharmaceutical companies like Eli Lilly, AstraZeneca and GlaxoSmithKline are also backing away from depression research. AstraZeneca and partner Targacept recently revealed the news of failed antidepressant programs, announcing that they are scrapping development of their experimental antidepressant TC-5214. AstraZeneca made the announcement after ditching its own discovery efforts in the depression field after years of frustration. AstraZeneca’s exit from antidepressant discovery comes amid an exodus from the field across the pharmaceutical industry, which has largely turned its attention to safer bets in developing drugs for cancer and rare genetic diseases.

In clinical trials for new antidepressant medications, pharmaceutical companies are also struggling to demonstrate the efficacies of their pills to lift patients’ moods any better than placebos. Patients in many cases even feel better after taking sugar pills, showing just how delicate the disorder can be.

Studies have estimated that about 450 million people suffer from a mental or behavioral disorder. According to WHO’s Global Burden of Disease 2001, 33% of the years lived with disability (YLD) are due to psychiatric disorders, a further 2.1% to intentional injuries. Depressive disorders alone can lead to 12.15% of years lived with disability, and rank as the third leading contributor to the global burden of diseases. Four of the six leading causes of years lived with disability are due to psychiatric disorders (depression, alcohol-use disorders, schizophrenia and bipolar disorder). Depression affects around 20% of people at some point in their lives. The World Health Organization (WHO) predicts that by 2020, depression will rival heart disease as the health disorder with the highest global disease burden (WHO, 2001).

On the other hand, there is more positive news for multiple sclerosis research. Newer therapies are appearing on the market and they are targeted at the disease-modifying aspect of the treatment, either through immunomodulation or immunosuppression. These newer medications also have improved formulation over the other drugs. They include the orally administered fingolimod and teriflunomide while the older drugs are given through intravenous, subcutaneous or intramuscular routes. However, there is still a lack of neuroprotective medications which can hopefully arrest the course of the disease and bring about remyelination of the neurons that have been stripped of its myelin sheaths.

It is not all doom and gloom in the world of neuroscience research. Pharmaceutical and biotech companies are going back to the board room and are formulating ways to move forward amidst the failures, set-backs and disappointments. There are signs that we should be looking elsewhere for more fruitful research, which will enable us to conduct research through innovative ways. Perhaps we should be looking at understanding more about the disease and at the same time, employ other newly developed research technologies and discoveries in neurosciences research. Such technologies should include genetics, imaging and even devices, which are slowly catching the limelight in the world of biomedical research.

The latest trials in AD are thought to have failed because the drugs were given to patients too late in the disease process to have an effect, or were unable to pick up subtle changes in cognition over a relatively short period. AD, which is marked by the build-up of sticky protein clumps, amyloid plaques, in the brain, is thought to take at least 15 years to develop and by the time symptoms appear, it is too late to reverse. Existing drugs, such as donepezil (Aricept), have limited benefits. Indeed, Eli Lilly and other pharmaceutical companies are trying to look back at their failed clinical trials to see whether the drugs will have an effect on the condition at the mild stage. Scientists are also about to start studies in 2013 that will test the ability of three drugs (Roche’s gantenerumab, Eli Lilly’s LY2886721 and solanezumad) to arrest the progression to AD in those normal subjects who carry the genetic mutations, but who have no symptoms of the disease.

Imaging techniques have been able to detect the presence of amyloid plagues in the brains of patients and are increasingly being used to diagnose as well as track the progress of the disease with treatments or in clinical trials. For example, Eli Lilly’s Amyvid, developed by Avid Radiopharmaceuticals, which will bind to β -amyloid plaque in subjects diagnosed with probable AD. Piramal Imaging from India also recently bought the imaging molecule florbetaben which will reliably detect β -amyloid plaque in the brain from Bayer. Navidea Biopharmaceuticals, a biopharmaceutical company with a focus on precision diagnostic radiopharmaceuticals, has commenced its Phase II, open-label, safety and efficacy Position Emission Tomography (PET) imaging study of NAV4694 for the detection of cerebral β -amyloid plaque in subjects diagnosed with probable AD.

Perhaps genetics can predict the likelihood to develop certain neurological and psychiatric diseases. When someone is deemed to be more likely to develop a certain disease, pharmacogenetics may help to allocate a personalized treatment to prevent the disease from developing or at least to slow down the progression of the disease. We already know that genotyping can be used to understand the patients’ risk for developing psychiatric conditions such as schizophrenia and bipolar disorder. It is also known that genetic variability for certain genes such as IMPA-2, INPP-1 and glycogen synthase kinase (GSK)-3ß can increase the risk of suicidal behavior in bipolar patients (Jimenez, 2012). If the person has developed the disease and is being treated, pharmacogenomics can then be used to monitor the response of the individual’s disease to the treatment. While there are many antidepressants on the market, including top sellers such as fluoxetine (Prozac) and paroxetine (Seroxat), many of these antidepressants work in only half of patients half of the time. Recently, a team from Italy managed to identify two types of biomarkers - ones which could predict response to antidepressants, called “predictors”, and the other ones, which change over the course of treatment, are called “targets”. By examining the “predictors” and “targets” over time, psychiatrist can prescribe the most appropriate antidepressant for a particular patient (Cattaneo, 2012).

Devices are also slowly being used by more clinicians for the treatment of neurological and psychiatric diseases. Deep brain stimulation is already being used for conditions such as Parkinson’s disease, depression and chronic pain. There are also more companies which are targeting neurological and psychiatric diseases with devices. For example, cerbomed, a privately-held company in Germany, has developed a non-invasive neurostimulation device for the treatment of epilepsy, depression and pain. Other companies like St. Jude Medical, also has neurostimulators for patients with intractable chronic migraine. Perhaps devices could have its application in other neurological and psychiatric diseases.

As the US and Europe continue to be stuck in the humdrum of the economic crisis, which further decreases the pool of investment in pharmaceutical industry, we should turn to other continents such as Asia, where governments are putting in more research grants to stimulate basic science research and clinical trials. For instance, the South Korean government has initiated a BioVision 2016 plan to build the platform for biotech industry and to develop and commercialize innovative medicines (Hyeon, 2008). Singapore government has also the Agency for Science and Technology Research (A*STAR) for the advancement of science and technology. It has built several research institutes within the country and is also providing scholarships for aspiring students in the field of science and technology. (A*STAR, 2012). The Singapore Health Ministry also recently announced a new clinical trial grant of S$80 million which aims to support innovative and high-impact clinical trials.

As the partnership between the government, academia and pharmaceutical companies are slowly taking shape in this part of the world, Asia could be the right place for this kind collaborative establishment. To move forward in biomedical research during the times of economic hardship and various clinical trial failures, such interaction and exchange of ideas are needed for the advancement in the treatment of diseases, especially in neuroscience.

The future for neurosciences research calls for endeavors into new domains and we need to adopt modern technologies and tools to help us further our search for better treatments. This could include the innovative use of genetics, devices, and imaging tools as well as to conduct research in continents such as Asia, where the environment is becoming more favorable towards basic science research and clinical trials.

References

  • Annual Review of 2011 and Outlook for 2012. EFPIA, 2011.
  • A*STAR Commemorative report. A*STAR, 2012.
  • Cattaneo A, Gennarelli, M, Uher R et al. Neuropsychopharmacology. 1 - 9, 2012.
  • Dementia: A Public Health Priority. WHO, 2012.
  • Global Burden of Disease 2001. WHO, 2001.
  • Hyeon B-H, Kim H-Y, Moon S-H et al. Biotechnology Journal. 3:5:591 - 600, 2008.
  • Jimenez E. ECNP poster, 2012.

About the Author

Dr Nick Chia is Senior Director and Clinical Development Strategist, at the Strategic Drug Development Unit of Quintiles, Asia Pacific, based in Singapore where the team guides clinical and regulatory strategies for clients wanting to develop their medicines in Asia. Previously, he held senior positions in GSK Global and LCG Bioscience in Cambridge. He obtained his degree in medicine from the University of Leicester in the United Kingdom and did his internal medicine training at the Cambridge University Addenbrooke’s Hospital. He completed a four-year post-doctoral fellowship in molecular genetics at the University of Michigan, Ann Arbor, USA.  Nick is also a Fellow of the Royal College of Physicians of Edinburgh.

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