In recent years, researchers have taken important steps towards understanding how brain diseases develop and why they evolve the way they do. This knowledge may lead to new and improved treatments – which gives renewed hope to patients and their families.
The human brain is one of our most important organs. At the same time, the brain is extremely complex. It consists of more than 100 billion nerve cells, and each individual cell may be connected to as much as 10,000 other nerve cells.
It is a difficult task to develop drugs for brain diseases such as schizophrenia, depression, Alzheimer’s and Parkinson’s disease. A successful drug requires highly specialized competencies, many resources and a long-term, dedicated effort.
According to WHO, the societal burden of brain diseases is just as high as those of heart diseases and cancers combined. Over 700 million people suffer from brain diseases1 and in the EU alone these diseases cost society EUR 350 billion in lost productivity.2 The illnesses have great implications for the patients, whose life expectancy is 10-20 years shorter than for non-sufferers.3
“We know that innovation is the key, when solving the puzzle of the brain and in order to succeed bold decisions have to be made. We seek to develop completely new types of treatment which will enable us to treat brain diseases at an earlier stage of the illness, and also make it possible to treat patients who are currently untreatable,” says Kim Andersen, head of Lundbeck’s research.
Researchers are optimistic, not least due to the last 10 years which have seen considerable scientific breakthrough in the understanding of brain diseases.
Researchers are currently fighting on two fronts. They are trying to refine medications which attack already known neurotransmitters – such as serotonin, dopamine and norepinephrine – in order to make medications more focused and cause fewer side effects. At the same time, they are also trying to identify new approaches which can be used to develop new drugs.
One of the great ambitions is to influence the underlying disease biology and slow down the progression of diseases, which currently can only be treated on the basis of their symptoms.
“The research in neurological diseases such as Alzheimer’s and Parkinson’s disease is where cancer research was 20 years ago. And just like cancer has progressed from being a death sentence to often being treatable and in some cases curable, the next few decades will see far more effective treatments for a variety of neurological diseases,” explains Kim Andersen.
The key to treatment
Researchers have identified a number of specific gene mutations which predispose for Alzheimer’s and Parkinson’s disease, respectively. This insight into some of the underlying causes of the diseases can be used to develop new drugs that influence the underlying disease biology. Furthermore, knowledge of the activities of several specific proteins can lead to new therapeutic angles in the treatment of the two diseases.
“The proteins are both natural and essential, but when you get older, the brain’s capacity to process ‘waste products’ may begin to fail, resulting in the proteins accumulating and spreading into the nervous system. The process begins many years before the disease can be observed in the patients, so an understanding of the proteins may be the key to treating patients earlier and more effectively,” says Kim Andersen.
For more than 100 years, scientists have been aware that patients with Parkinson’s disease develop insoluble lumps consisting of the protein alpha-synuclein in the brain as the disease progresses. And it has long been assumed that by influencing this protein, the progression of the disease may be slowed down. Lundbeck has now identified a number of antibodies which can bind to alpha-synuclein, and one of these antibodies has shown a positive effect on Parkinson’s disease in animal testing.
“By influencing alpha-synuclein with an antibody, we may be able to delay the disease and prevent it from spreading to the nervous system. In this way, we can prevent the emergence of secondary symptoms and at best stop the progression of the disease,” says Kim Andersen.
The project is so innovative that it has attracted both attention and research funding from the Michael J. Fox Foundation, which is one of the world’s leading centers for Parkinson’s research.
Similarly, tau- and beta-amyloid accumulate in the brain of Alzheimer’s patients. These proteins form insoluble compounds over time, which create a poor environment in the brain.
In partnership with one of the world’s leading experts in tau-research, Professor Einar M. Sigurdsson from New York University, the Danish researchers are trying to develop a therapeutic antibody against the tau-protein. As part of this process, they are also working on finding a diagnostic marker, which enables them to evaluate at an early stage whether a given antibody has an effect or not. It will make the otherwise expensive and time-consuming studies more focused and hence shorten the path to a possible treatment.
Researchers are also finding new ways in terms of psychiatric disorders such as depression and schizophrenia. An international research collaboration, which includes Lundbeck, has recently shown that certain variations in the human genome have a direct impact on the brain and are associated with impaired intellect and functional ability in people with these variants.
“In place of the current one-size-fits-all treatment, a sharper biological classification of patients will enable us to increasingly provide tailor-made treatment of specific patient subgroups.”– Kim Andersen
The findings are interesting, because the genetic variations increase the risk that carriers develop the debilitating and life-threatening brain disease schizophrenia. This means that the new research is a breakthrough in the understanding of the causes of developing schizophrenia, and the results have been published in the renowned scientific journal Nature.4
“Our research gives hope that in the future we can develop medications which might reduce some people’s risk of developing schizophrenia, and we can also develop treatments for the so-called cognitive symptoms, which deal with functional capacity and are associated with the disease,” says Kim Andersen.
The research team behind the findings have been joined as part of the comprehensive European Innovative Medicines Initiative (IMI) – NEWMEDS cooperation, where universities and pharmaceutical companies are working together to provide a greater understanding of depression and schizophrenia. Without this unique collaboration, the new knowledge would never have been generated.
Lundbeck has for several years been doing research into the importance of gene variations in schizophrenia and have in this context for example developed mice with these genome variations. Hence, these mice have the same basic biology as humans suffering from schizophrenia, and are therefore very useful in studies of the disease.
“Within the foreseeable future, the diagnosis of brain diseases will be defined on the basis of biological characteristics. A sharper biological classification of patients will enable us to increasingly provide tailor-made treatment of specific patient subgroups,” says Kim Andersen.
Anaesthetic against depression
Existing treatments of depression are effective by influencing so-called neurotransmitters in the brain. More than 50 years of research has resulted in great progress, but it remains a challenge that around one third of patients do not respond to their given treatment. Helping this patient population requires alternative thinking.
Research has shown that ketamine, which is a known anaesthetic, has a remarkably efficient and rapid effect on severely depressed patients. The use of ketamine has many adverse side effects, such as hallucinations, agitation, nausea and possible addiction. Hence, there is a need to develop new drugs with the same effect, but without the adverse side effects.
Ketamine works through the neurotransmitter, glutamate, which is one of the key neurotransmitters in the brain. With a better understanding of how this signaling agent is imbalanced in depressed patients, the goal is to develop new treatments for both depression and anxiety.
In recent years, researchers have also found that depression is associated with neuroinflammation, which is an ‘inflammatory condition’ in the brain involving the so-called microglial cells. The normal function of microglial cells is that they are activated by brain injury such as stroke or trauma, where they contribute to eliminate dead cells and infectious microorganisms.
In various disease-induced imbalances, the activity of microglial cells is not correctly regulated, and it can worsen the medical condition. Studies have shown that patients suffering from depression have an upward regulation of inflammatory components in both the brain and body. Early-stage research projects are trying to determine whether patients, who cannot be treated with conventional antidepressants, are suffering from such inflammatory conditions, and whether influencing these can lead to a new type of treatment.
Big questions necessitate cooperation
Due to the great complexity of the brain, scientists all over the world have realized that it requires new ways of cooperation, if we are to achieve results in brain research. Just 10-15 years ago, the industry guarded its research activities and results with absolute secrecy. But this attitude led to a waste of resources and hindered innovations.
It was unthinkable to share knowledge with each other, and different research teams were at risk of reproducing the same negative result over and over again. At the same time, the researchers’ questions only managed to build on their own core competencies.
It made it difficult to ask fundamental questions about the biology of brain diseases such as: Is schizophrenia one single disease? Or does it consist of several diseases? In order to find such answers, researchers need to integrate a wide variety of disciplines such as genetics, chemistry, molecular pharmacology and clinical psychiatry.
To increase the understanding of the biology behind these diseases and develop new effective drugs, Lundbeck’s researchers cooperate with universities at the basic research level and enter strong industrial partnerships.
“Some questions are so comprehensive that they cannot be asked separately, and the answers cannot be found by individual players alone. Cooperation is necessary,” concludes Kim Andersen.
- http://www.who.int/mediacentre/factsheets/fs220/en/index.html, http://www.who.int/features/qa/55/en/index.html
- Gustavsson et al. Cost of disorders of the brain in Europe, 2010. European Neuropharmacalogy, 2011. Wittchen, H.U. et al. The size and burden of mental disorders and other disorders of the brain in Europe, 2011.
R&D at Lundbeck
• More than 1,200 employees work in Lundbeck's R&D units. In 2013, approximately 20 percent of Lundbeck’s revenue was invested in research and development.
• It takes 12-15 years from the researchers get a great idea until a finished drug is ready.
• The average cost of developing a new drug is DKK 10 billion.
• Lundbeck’s partners come from many different parts of the global scientific community:
• Academic partners: King’s College (UK), New York University (US), Mayo Clinic (US) and Heidelberg University (Germany) among others
• Foundations: The Michael J. Fox Foundation (US), The Danish National Advanced Technology Foundation (DK) among others
• Biotech companies: Vernalis plc. (UK), Genmab A/S (DK), Ossianix, Inc. (US) among others
• Pharmaceutical companies: Otsuka Pharmaceutical Co., Ltd. (JP), Takeda Pharmaceutical Company Limited (JP), Merck & Co., Ltd. (US) among others