The central nervous system (CNS) compromises the brain and spinal cord and is the most complex system in the human body; consisting of an estimated 100 billion neurons, each connected to thousands more with various and connected functions. With an ageing global population, the prevalence of CNS disorders such as Parkinson’s disease, Alzheimer’s disease and Dementia are slowly increasing; these disorders have enormous contributions to disability worldwide, substantial economic burden and significantly reduce individuals’ quality of life. Unfortunately, there are no disease modifying therapies (DMT) for the majority of neurodegenerative diseases despite the commercial opportunities presented to pharmaceutical companies; the attempts to discover effective and novel medications to treat CNS disorders have proven so difficult that many companies have retreated from the field. There are several high-profile pharmaceutical companies that have decided to shut down major research activities within the neuroscience area. In December 2011, Novartis announced that the company is closing its main neuroscience facility in Basel, Switzerland, similarly, GlaxoSmithKline (GSK) and AstraZeneca, both based in the United Kingdom, announced the closure of major parts of their neuroscience research divisions globally. Other pharmaceutical companies such as Merck, Pfizer and Sanofi-Aventis have each closed their research facilities also. This is a major concern for the patients suffering from CNS disorders.
The development of new drugs is difficult and a rigorous process; the cost of developing a new drug is estimated at over $2 billion and it takes about 10-15 years to bring a drug to market. With this said, the drug development process for a potential new medicine can fail at any point from preclinical to post-marketing because of concerns related to safety, efficacy, product quality and labelling. According to Tufts University Centre for Drug Development, it took 20% longer to develop CNS drugs and about 36% longer on average to win FDA approval after clinical trials. The same study found that the success rates for CNS drugs, defined as final marketing approval by the FDA, were less than half of the approval rates for non-CNS drugs from 1995 to 2007 (6.2% vs 13.2%, respectively) . Given the combined financial risks and the scientific challenges associated with CNS drug discovery, it is not surprising that leaders within the Pharmaceutical industry are investing in other therapeutic areas such as Cancer. The main scientific challenges are lack of complete understanding of the mechanism behind CNS diseases, lack of predictive animal models and the lack of suitable and appropriate biomarkers.
Mechanism of CNS disease
As stated previously, the human brain is a complex system and cannot be readily studied, except in post-mortem. Furthermore, there are significant amounts of brain cells, organised into various synaptic connections and neural circuits, making it difficult to achieve a complete understanding of the underlying mechanisms of most CNS disorders.
Without understanding the mechanism behind CNS disorders, it is challenging to identify and validate molecular targets or construct a predictive animal model. For example, Alzheimer’s Disease (AD) is characterised by the accumulation of amyloid-B plagues, neurofibrillary tangles and neuroinflammation. AD is an intense research focus for both academia and the pharmaceutical industry and studies have demonstrated that Amyloid B (AB) which is derived from amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of AD. However, no models have been identified that recapitulates all the aspects of AD highlighting the complexity behind the mechanisms of AD. Taking the age onset of AD into consideration, which is usually in adults over 65 years old, this might explain why a ‘potential medicine’ doesn’t translate well into humans. A lot of the data surrounding AD has been obtained from young animals; their immune system is very different from an aged individual, therefore, these animal models might reflect the early stages of AD (before definitive diagnosis has been made) and might explain as to why these clinical trial drugs targeting amyloid plaques are failing. This highlights the need to discover biomarkers to help physicians to identify AD before symptoms are shown and before significant brain cell damage occurs. In 2016, a program called MODEL-AD was established by the National Institute on Ageing, with the intention of developing and distributing better quality predictive mouse models for preclinical screening. Approximately 30 strains have been developed so far.
The complexity of brain disorders is also demonstrated in disorders such as Neuropathic Pain and Major Depressive Disorder and the question arises as to how you can model these complex human behaviours in rodents and how can you measure these endpoints in animals as to better translate into humans.
Multiple Sclerosis is an exception
Multiple Sclerosis (MS) is a chronic inflammatory disease characterised by the demyelination of neuronal cells in the CNS. The disease is grouped into four categories: Relapsing Remitting MS (RRMS), Secondary Progressive MS, Primary Progressive MS and Progressive Relapsing MS. The symptoms and disease course worsen as you go from RRMS to progressive relapsing MS. Research and development for MS has been highly active and rapid, contributing to the approval of numerous of DMTs for patients with RRMS, the most common type of MS (85%). The aim of DMTs is to alter the course of the disease and this more rapid development is due to the fact that there is better understanding of the underlying mechanism behind RRMS. For example, research has shown that vascular cell adhesion molecules (VCAM-1) are expressed on the surface of the blood brain barrier (BBB), controlling its permeability and the transmigration of inflammatory molecules from the peripheral system to the CNS. In MS patients, the BBB becomes permeable and there is an influx of inflammatory molecule such as T cells and dendritic cells which results in the activation of antibodies and microglia in the CNS, consequently, attacking the myelin sheath. Tysabri (Natalizumab), a DMT indicated for RRMS, binds to VCAM-1 and prevents the binding of the α4β1-integrin present on leukocytes and neutrophil, thus, preventing the transmigration of the inflammatory molecule, reducing neuronal inflammation and preventing the formation of lesions. Clinical trial data has shown that natalizumab reduces the mean annualised relapse rate by 68% compared with placebo. By diagnosing RRMS patients in the early stages of the disease and initiating early treatment, it can slow the progression of the disease, increase survival rate and improve individuals’ quality of life.
In this short review, it is easy to see the scientific challenges surrounding CNS drug discovery compared to other therapeutic areas and how this has led to large pharmaceutical companies ramping down their CNS drug discovery programs. However, this has led to the emergence of increased numbers of university-led drug discovery centres. This has its advantages, for example, university-led centres are willing to spend more time looking at specific problems and specific diseases compared to a corporate environment. This short review also highlights the need to adapt our drug discovery approaches in regard to CNS disorders, to solve the biggest health problems facing the world today.
- Tufts Center for the study of Drug Development (2018). Tufts CSDD Impact Reports- CNS drugs take 20% longer to Develop and to Approve Vs. Non-CNS Drugs. Vol 24, No 4.