Bill Holt
Bill Holt
Executive Director, Neurosciences, Scientific Affairs

The average human brain only weighs about three pounds, and is nearly 75% water, and yet it is one of our most important organs—the one that helps us think, reason, and learn new things.

Advances in neuroscience research are helping us better understand how the brain works. We spoke with two of our neuroscience and pain experts to learn more about some of these new discoveries and what they might mean for patients.

What has been most promising for patients in neuroscience drug development in the past year?

HANS: A very promising development has been the fact that researchers have been able to disentangle the analgesic and side-effect-inducing properties of morphine.

Opioids have been around for a long time, but their use is complicated by adverse effects such as addiction and respiratory depression. Morphine and related opioid analgesics act as agonists of the μ-opioid receptor, a G-protein coupled receptor (GPCR) that activates both Gαi- and β-arrestin. The μ-opioid receptor signaling through Gαi is responsible for analgesia, whereas signaling through β-arrestin is thought to mediate the adverse effects. In a recent study researchers succeeded in identifying compounds that displayed Gαi-biased signaling without activating β-arrestin and were able to show long-lasting analgesic effects in an animal model without inducing respiratory depression or addiction-like behaviors (Manglik et al 2016).

Findings such as these could speed up the discovery of new analgesic compounds with a strongly reduced side-effect profile.

BILL: Research was presented during this year’s Alzheimer’s Association International Conference (AAIC) around lifestyle factors which could potentially contribute toward Alzheimer’s Disease (AD). Nine key risk factors were identified which, if avoided, could prevent 1 in 3 cases of AD. Alongside current research in prodromal subjects, this information may be the key to an eventual preventative or curative therapeutic.

Bill Holt, Executive Director, Scientific Affairs, Neurosciences, on neurodegenerative research

Multiple Sclerosis (MS) research has seen several advances in the last few years, what are some of these breakthroughs and what has made them possible?

BILL: Investigation into the root cause of MS continues however data suggest genetics, environmental factors, and potentially even viruses can play a role.

The recent approval of ocrelizumab represents an important breakthrough, the drug significantly reduces new attacks in patients with relapsing remitting MS (RRMS), as well as slow the progression of symptoms caused by primary progressive MS (PPMS), representing a first treatment for this less common form of the disease.

Looking forward, a new cellular mechanism was recently discovered which may contribute to MS, using brain tissue samples, researchers found a protein called Rab32 present in large quantities in the brains of MS patients – but is almost absent in healthy brain cells. Although the cause of influx of Rab32 is unknown researchers believe the defect could originate at the base of the cell. The finding will enable scientists to search for effective treatments that target Rab32.

HANS: There are a number of candidate remyelinating (reversing damage caused by MS) compounds, but there is still a need to clearly identify clinical characteristics of the patients who might benefit from them, as well as the optimal time window for treatment.

A very promising discovery has been the recent finding that regulatory T-cells (Treg) are able to promote oligodendrocyte differentiation and (re)myelination (Dombrowski et al 2017). The mechanism behind this function includes acceleration of oli­godendrocyte differentiation and (re)myelination, via CCN3 which is a growth-regulatory protein with bioactivity in extracel­lular, cytoplasmic and nuclear compartments. Theoretically this could mean that researchers can use this new knowledge to develop an entirely new class of drugs which will boost these particular cells and effectively lead to remyelinisation.

How might new insights on biomarkers and genetics provide new targets and pathways for neuroscience drugs?

HANS: Within the field of psychiatry diagnosis is clinically determined by subjective and behavioral criteria. For example, if a biomarker for anxiety was available, a patient with clinical symptoms whom lacked a positive biomarker would still be given treatment. However, if a patient didn’t display enough symptoms to point toward an anxiety diagnosis but did have a positive biomarker then they would likely not be receiving treatment. That said, a refined use of biomarkers could potentially aid physicians in prescribing with certainty, avoidance of unpleasant side effects for the patients and in turn, improved patient adherence.

Considering pain studies, we are beginning to understand that genetic variations in several genes are affecting clinical and experimental pain-related phenotypes. In families in which there is congenital insensitivity to pain (CIP) were found to have well-identifiable genetic abnormities, which can subsequently be used as a target for the development of new analgesic drugs (Chen et al 2015). In the meantime, a variety of genetic polymorphisms has been identified that may predict the risk for drug intolerance or drug-drug interactions.

Thus, in the treatment of pain we could be at the brink of 1) a personalized medicine approach by identifying genetic polymorphisms that may predict the type of subject that responds to a drug as well as the propensity for the development of adverse events, and 2) the development of new analgesic compounds based upon selective targeting of known biological processes in signal transduction mechanisms.

Specific to schizophrenia treatments, what new promising medications are in the pipeline to help patients and how might these address current unmet medical needs?

HANS: There is general agreement among clinicians that there is a need to develop drugs for the following domains: cognition, negative symptoms (e.g. lethargy, apathy, and social withdrawal), treatment-resistant patients, safer drugs and increasing compliance. Several new drug candidates are currently under investigation with new targets, such as the serotonin (5-HT)6 receptor antagonism as a means to overcome the cognitive impairments in schizophrenia (e.g. AVN-211 from Avineuro Pharmaceuticals). Other potential new drug candidates are ITI-007 (a 5-HT2A receptor antagonist from Intra-Cellular Therapies), Lu AF35700 (a D1, 5-HT2A and 5-HT6 receptor antagonist from Lundbeck), MIN-101 (a 5-HT2A and sigma-2 receptor antagonist from Minerva). Some of these are used as add-on strategies during ongoing treatment with antipsychotics.

Another potential drug for treatment resistant schizophrenia will be NaBen (sodium benzoate) from SyneuRx International [Taiwan] Corp.) NaBen is a D-amino acid oxidase inhibitor that was granted orphan drug status for the treatment of schizophrenia patients with refractory disease in combination with clozapine

The problem with ongoing research in schizophrenia is that there are not many new hypotheses that have led to promising new pharmacological approaches; most ongoing trials are investigating medicines that are based upon biological principles that have been formulated a long time ago.

Frederick Lewis, Vice President, Scientific Affairs, Neuroscience, on the future of psychiatric drug development

Depression is rightly recognized today as much more than low mood; how can neuroimaging studies of the brain (structure) help us to further understand the condition and eventually provide innovative therapies and treatment?

HANS: Usually in clinical psychiatric practice PET and MRI are hardly ever used because there is no direct consequence for treatment approaches. However, in antidepressant drug development, neuroimaging can play an important role. PET can play a role in Proof of Neurobiology studies (association of target with disease), Proof of concept (drug distribution and target engagement), Drug dosing studies (clinical effect and side-effects) and Mechanism of action studies (e.g. duration of target engagement; interaction with other biological targets). Neuroimaging is also of value in clinical situations in which decisions have to be taken regarding dose-increases.

With the availability of combined hybrid PET/MRI machines, we will be able to get more information on the human brain in states of health and disease. This combined imaging machine will give us more insight into brain mechanisms involved in e.g. depression and other CNS diseases, as we will be able to combine Receptor Occupancy (RO) studies (PET) with structural imaging and functional imaging using cognitive or emotional tasks in one session. In addition we also have the possibility to gain more information about brain metabolism using FDG-PET (metabolic connectivity mapping; Riedl 2014, 2016), which can lead to new insights into the pathogenesis of Parkinson’s disease and Alzheimer’s disease, especially in the very early stages. In addition, drug development can also profit form this new technology as these combined measurements can be used as a pharmacodynamic marker of the functional, neurochemical and anatomical consequences of drug target engagement.