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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #7

Neuroscience: the poor cousin of drug discovery

This article was published in a slightly revised form in the February 2019 issue of MedNous

Aging populations everywhere are on the rise creating a need for new medicines to treat neurological disorders. However recent data from the US Food and Drug Administration suggests that this need is not being well met.

The FDA approved 59 new molecular entities in 2018 – higher than any previous year – and topping the previous record of 53 in 1996. Among the 2018 approvals were 16 new drugs for cancers. By comparison only seven new medicines were authorised for diseases affecting the brain, which are estimated by the World Health Organization to affect nearly one in six of the world’s population (1). Among the recently approved drugs are two treatments for the prevention of migraine, – considered by many as a vascular disease rather than a brain disease – two for childhood epilepsies, one for opioid withdrawal symptoms and an oral inhalation formulation of levodopa for Parkinson’s disease. The group also includes Onpattro (patisiran), a small interfering ribonucleic acid (siRNA) therapeutic for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. The list of drugs appears in Table 1. The development portfolios of companies still involved in neuroscience is very thin, especially when compared with the more than 500 new oncology drugs being currently tested in clinical settings.

In this article we examine several reasons why drug development in neuroscience is lagging behind other fields. We also give examples of outliers, or companies that have taken a different approach to treating diseases of the brain which could change the current paradigm.

If it were easy, more people would do it

The brain is a very complex organ. It monitors, triggers and controls the functioning of all other organs, external interactions and interconnections of the human body. The organ itself consists of 85 billion neurons, which are interconnected through 1,000 contacts, and each single neuron triggers 1,000 signals per second. Recent research has shown that the brain has at least 100 billion glial cells, including astrocytes, oligodendrocytes and microglial cells, which control the brain’s immune system, the formation of new synapses and overall brain plasticity, or its ability to change throughout life. To feed this complex system, the body has provided the brain with approximately 400 miles of blood vessels. To function efficiently, this system requires fine tuning, something that cannot easily be analysed from the outside.

Past efforts to understand the healthy brain relied mainly on phrenology, or the study of localised brain function. A relatively new approach is to try and understand the brain’s molecular architecture by studying noncoding regions of the genome. This is being undertaken by a group called the PsychENCODE Consortium (2) which was set up in 2015 by the US National Institute of Mental Health to describe all of the genomic elements within the brain and explain their roles in human development and disease. Thus far, the consortium has produced papers describing the molecular pathways and cell types involved in autism spectrum disorder, schizophrenia and bipolar disorder.

Separately, scientists from the VIB research institute and KU Leuven in Belgium have done further research on the amyloid hypothesis which posits that the accumulation of beta-amyloid is the cause of nerve cell toxicity in Alzheimer’s disease. The Belgian researchers say that an amyloid-beta precursor protein APP, may underlie the neuronal network abnormalities seen in mice with the disease. If so, this would create new opportunities for treating a diverse range of psychological and neurological disorders.

Meanwhile new imaging and digital tools will enable scientists to observe all parts of the brain and navigate it in the same way that Google Earth gives a three-dimensional picture of the Earth. These technologies, emerging from the Blue Brain Project, have been described by Marc-Oliver Gewaltig of the Swiss Federal Institute of Technology in Lausanne.

The single target orthodoxy

As shown by the work of the PsychENCODE Consortium, the molecular architecture of the brain is complex. This means that it may be necessary to look at multiple, rather than single targets in developing new therapies for neurological diseases. Until now the orthodoxy has been to discover ‘selective agents’ that focus just on neuron activity. However, this has not yielded novel, active treatments for schizophrenia, autism, major depressive disorder, epilepsy or Parkinson’s and Alzheimer’s diseases. Billions of dollars have been spent on research to no avail, leading several large pharma companies and many start-ups to abandon the field. Earlier this year, Roche and Sanofi have both announced the discontinuation of ongoing clinical trials of some of their Alzheimer’s disease candidates targeting beta-amyloid.

There are nonetheless exceptions. Here we discuss three examples. Two are French companies developing combination therapies, and the third is a Chinese-Australian team researching natural products.

The first company, Pharnext SAS, was co-founded in 2007 by Daniel Cohen and Ilya Chumakov to explore a network pharmacology approach to drug discovery. They call their paradigm “pelotherapy”. This involves studying genomic data and pathways underlying a given disease to identify molecules that could potentially interact within the network. The researchers then deduce synergistic combinations of compounds which might treat the disease. These are compounds which have already been approved in other indications. The therapeutics are tested and developed at optimal doses in new formulations. Proof-of-concept for this approach was reached in October 2018 when the company reported positive Phase 3 results in a trial of patients with Charcot-Marie-Tooth disease type 1A (CMT1A), an inherited neurological disorder that affects peripheral nerves. The therapy, PXT3003 is a combination of baclofen, a central nervous system depressant; naltrexone, a drug for the management of alcohol and opioid dependence and sorbitol, a laxative. On February 4, Pharnext announced the receiving of US FDA Fast Track designation for an oral solution of PTX3003 for the treatment of CMT1A.

The second company, Theranexus SA, was founded in 2013 by Franck Mouthon and Mathieu Charvériat to improve the efficacy of drugs already approved for neurological diseases. They discovered that combinations of drugs acting simultaneously on neurons and on non-neuronal, or glial cells, could substantially improve the performance of existing treatments. Three such combinations are in early-stage clinical development. THN102, which is in a Phase 2 study for narcolepsy and Parkinson’s disease, combines modafinil and flecainide. Modafinil is a treatment for sleeping disorders while flecainide is an antiarrhythmic drug repositioned to act on glial cells. The second drug, THN201, for the treatment of neurological disorders linked to Alzheimer’s disease, combines donazepil, an Alzheimer’s treatment, with mefloquine, an antimalarial drug. The third candidate, THN101 for neuropathic pain, combines amitriptyline, a drug for mental illness, with mefloquine, an antimalarial.

On the natural products front, an Australian-Chinese team led by Dennis Chang of Western Sydney University and Jianxun Liu of the Chinese Academy of Chinese Medical Sciences, are researching a new treatment for vascular dementia (3). Their proposed treatment is Sailuotong (SLT), which consists of specific doses of extracts from Ginkgo biloba, Panax Ginseng and Crocus sativus. This combination of herbs was selected on the basis of their traditional use, clinical and pharmacological evidence and the identification of a number of bioactive components known to act on the central nervous system. Based on bioassay-guided fractionations and pharmacological studies using standard animal models, the fixed formulation of SLT was developed and standardised. Altogether 10 bioactive molecules were quantified and included in the final product. Data reported in 2016 from a Phase 2 clinical study of 325 patients who received SLT over 52 weeks, indicated that the treatment significantly improved cognitive function. This preliminary, evidence-based herbal medicine demonstrates the potential benefits of a well-defined formulation multicomponent product based on herbal extracts which act on more than one target. The concept now needs to be confirmed in a multinational clinical trial.

New players in neurology?

In comparison with practitioners in cardiovascular medicine over the past 50 years, those in neurology have been less keen to adopt technology from other disciplines. There are exceptions though, one of which is a project underway in France and the other, a company in Boston, US.

The project, incubated at the Institut du Cerveau et de la Moëlle (ICM) in Paris, is called ni2o which is short for ‘neuron input to output’ and refers to a device that uses deep brain stimulation to treat neurological disorders. It has been designed for implantation through the nasal cavity for the treatment of conditions such as Parkinson’s disease, though human studies have yet to begin. The device will record brain activity and deliver electrical and optical signals to target areas in the brain. Algorithms will determine the therapeutic response, which can be improved by machine learning. The project was started by Howard Newton, professor of computational neuroscience and neurosurgery at the University of Oxford and founder and director of the Massachusetts Institute of Technology Mind Machine Project.

Akili Interactive Inc, a digital medicine company in Boston, is combining cognitive neuroscience with entertainment technology derived from video game development to invent new medicines. The novel treatments are not pills but video games that can be accessed on a smart phone or tablet. Akili’s products have been designed to deliver sensory and motor stimuli to target and activate specific cognitive neural systems in the brain. The company’s lead candidate, AKL-T01, is a potential prescription treatment for attention deficit hyperactivity disorder that targets and activates the prefrontal cortex of the brain of children.  This is the area that plays a key role in cognitive function. AKL-T01 has been evaluated in a multi-centre, randomised, double-blind, active-controlled clinical trial – similar to trials for small molecule and biologic drugs. It is currently under review by the FDA. Akili also has products in development for autism spectrum disorders, cognitive deficiency in adults with major depressive disorders and multiple sclerosis.

The need for longitudinal studies

The longitudinal study, or a study that involves repeated observations of people over time, is a way of studying long-term trends in health. One of the best known is the Framingham Heart Study which started in 1948 to study the epidemiology of cardiovascular disease among adults in Framingham, Massachusetts, US. In 1975 the organisers extended the analysis to include observations on dementia in 5,205 persons 60 years of age or older. The researchers explored correlations between epoch and age, sex, the presence of the apolipoprotein Ee4 allele and educational attainment. There results, published in The New England Journal of Medicine in February 2016, showed that the incidence of dementia declined over three decades (4). The decline was in the order of 20% per decade. A corresponding decline in Alzheimer’s disease was not significant. This temporal trend and a parallel improvement in cardiovascular health over time were observed only in the cohort of people with the highest level of education. These results strongly corroborate previous studies performed in Europe and the US where statistical significance wasn’t reached.

Conclusion

More studies which involve a long surveillance period and use well-defined diagnostic criteria of a given population need to be performed. This will enable scientists and drug developers to better identify the underlying factors of specific brain diseases. Fortunately, the medical and bioinformatics industries are converging with the result that it is now possible to obtain precise images of the brain and treat some disorders with miniaturised devices and digital medicines. Scientists are also starting to look more closely at glial cells and the brain immune system for clues to future treatments.

References:

1. UN World Health Organization Study, 27 February 2007.

2. Sestan, Nenad, Revealing the brain’s molecular architecture, Science, 14 December 2018.

3. Dennis Chan, Jianxu Liu et al, Herbal Medicine for the treatment of vascular dementia: An overview of scientific Evidence, Evidence-base Complementary and Alternative Medicine, 31 October 2016.

4 Satizabal, Claudia et al, Incidence of dementia over three decades in the Framingham Heart Study, The New England Journal of Medicine, 11 February 2016.

Table 1. FDA drug approvals in neurology in 2018

Drug                                Indication                Developer                  Approval date

Aimovig (erenumab-aooe)              Migraine prevention             Amgen Inc                       May 2018

Emgality (galcanezumab-gnlm)      Migraine prevention         Eli Lilly and Co                      Sept 2018

Epidiolex (cannabidiol)                  Dravet syndrome             GW Pharma               June 2018

Diacomit (stiripentol)                    Dravet syndrome             Biocodex Inc                    Aug 2018

Lucemyra (lofexidine)                   Opiate withdrawal           US WorldMeds                      May 2018

Inbrija (levodopa)                         Parkinson’s disease             Acorda Therapeutics       Dec 2018

Onpattro (patisiran)                     Polyneuropathy from              Alnylam                            Aug 2018

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