Guest Columnist

Menelas N. Pangalos, PHD,
Executive Vice President, Research and Early Development, Innovative Medicines, AstraZeneca PLC

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Cracking the Challenges in Neuroscience Research and Development

Diseases of the central nervous system have one of the heaviest socioeconomic burdens on society and with an ever aging population this burden has the potential to become catastrophic. Alzheimer’s disease alone affects an estimated 25 million people worldwide and neuropsychiatric illnesses such as depression, addiction, schizophrenia and anxiety are amongst the most impactful with regard to social burden. On behalf of patients and the millions of people who have had to watch their loved ones suffer from these diseases, we must do better. We must deliver better tools to help us diagnose the disease, followed by better medicines to help us treat the underlying cause, rather than just the symptoms.

A universal challenge in the search for treatments to diseases of the central nervous system is that we have yet to achieve a solid enough understanding of brain development and disease etiology, making it difficult to establish robust and predictive pre-clinical animal models. These deficiencies in understanding are particularly stark when contrasted to oncology, where we can study tumor biology, genetics and signaling pathways in tissues directly derived from patients. The oncology field has made significant strides in shifting the focus from treating unselected patient populations to identifying stratified patient populations that are the most likely to respond to a given treatment. For example, crizotinib, a recently approved ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor showed tumor responses in 90% of patients carrying ALK fusions. Clearly with this type of patient selection, it becomes much easier to articulate a benefit risk for a medicine. This focus on understanding the underlying pathophysiology of neurological and neuropsychiatric disease as well as the heterogeneity of patient populations is critical to our ability to improve our success rates in the discovery and the development of new medicines.

In this regard the barriers to conducting successful clinical trials in the neuroscience arena remain stifling; Heterogeneous patient populations, late diagnosis of slowly progressing disease, subjective outcome measures, high placebo rates, are but a few of the factors that lead to one of the highest therapy area attrition rates. This uncertainty, even in late stage development, leads to a need for replicative, large and often long trials to achieve statistically significant and clinically meaningful effects that can be approved by regulators and reimbursed by payers.

As a consequence, at a time when socioeconomic issues related to diseases of the central nervous system are dramatically increasing, many companies are pulling out or scaling back their neuroscience research and development. At AstraZeneca we have taken these challenges and risks to heart and are taking a very different approach to drug discovery and development in the neuroscience space. We recently announced that instead of investing in a traditional large internal fixed cost neuroscience group, we will pursue a more flexible, nimble model with a small core of highly experienced neuroscience leaders. This small dedicated group will have the budget, resources and decision making rights to move and build a neuroscience pipeline from target identification to end of Phase 2. They will work with the best available private and public neuroscience partners, sharing risk, cost and reward as appropriate. This approach aims to combine the decision-making speed of biotech with the support and backing of a big pharmaceutical company. Most importantly, it allows us to invest the majority of our research dollars in science and projects instead of more traditional fixed costs (e.g. headcount, bricks and mortar).

There is little doubt that we need new ways of working and that any single organization or group is not going to crack the ‘neuroscience’ challenge in isolation. As an industry we have to work more closely with our peers and with our colleagues in academia and government. Our strategies and priorities should be better aligned, so that private and public sectors can more easily share pre-clinical and clinical data and tools that can help progress the field. In a highly competitive research environment sharing successful data may be more challenging, but given the particularly high attrition rates in the neuroscience arena, sharing data from failed molecules that have helped to de-validate specific mechanism of action could help save hundreds of millions of dollars in futile research and development funding, allowing all groups to focus on projects with a higher probability of success. Importantly, there also needs to be a renewed sense of urgency and public pressure applied to neuroscience research as a whole with the express purpose of making a significant impact on these devastating diseases in a timescale that will make a difference. This has already happened in important areas such HIV research and is happening today in the field of microbial resistance, as demonstrated by the recent announcement by Europe’s Innovative Medicines Initiative to fund antibiotic development with a $286 million stimulus.

In summary, we keenly need a renewed willingness to work together across industry, academia and government with a resolve to unlocking the challenging science behind these brain disorders and delivering better treatments to the patients that so desperately need them.


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