by Tiago R. Felix
Simply put, drugs alone are not, and will probably not be, an effective and safe treatment for most cases of nervous system disorders (NSDs). However, both society and the pharmaceutical industry seem to have so far largely overlooked the most promising alternative to drugs in the treatment of NSDs, that is, neurotech devices1. I will shortly introduce these devices, but before that, I would like to walk you through some of the main facts that got us where we are today.
The BIG unmet need
Consider this: globally, two groups of diseases impose the greatest health burdens of all (expressed in terms of the composite indicator Disability-Adjusted Life Years [DALYs]) and one of them corresponds, indubitably, to cardiovascular diseases. But would you have guessed that the group of diseases that poses an equally high health burden corresponds to, yes, NSDs?
As a broad group of diseases, NSDs include mental and substance use disorders, neurological disorders, back and neck pain, and sensorineural hearing loss. Taken together, in the year 2019 they caused 15% of the global health burden, which is an even greater health burden than that of cancer and diabetes combined (13%).
If you found concerning the sheer burden of NSDs, then hold tight, because it gets even more worrisome… As it happens, that burden has been steadily increasing and, according to the latest global estimates, the growth of the health burden of NSDs from the year 2010 to the year 2019 was 15%. The increase in health burden is even more noticeable in the case of sensorineural hearing loss and neurological disorders, which have over the same period grown by 21% and 18% respectively, that is, appreciably faster than cardiovascular diseases did (13%). This alarming rate at which the health burden from NSDs is increasing is considered to be primarily linked to the rapidly ageing world population.
The impact of NSDs on health across the globe is even greater if we exclusively consider disability (health burden is a broader concept that includes both life lost due to ill-health and disability4). NSDs alone were responsible in 2019 for an astonishing 39% of the global disability (expressed in terms of the indicator Years Lived with Disability [YLD], which also takes into account the average level of disability caused by a disease). This amount of disability is more than four times (!) that caused by cardiovascular diseases, diabetes and cancer all combined.
The significantly higher impact of NSDs on global disability can be explained by the fact that cardiovascular diseases and cancer predominantly decrease longevity, whereas NSDs primarily reduce the quality of life. That is a fundamental difference between the impacts of these diseases. Since NSDs overall do not significantly decrease longevity, patients affected by them are likely to require treatment for longer periods of time, which may be seen as an additional economic incentive for developing medical solutions to NSDs.
Big Pharma’s big nightmare
In the light of the growing, devastating impact of NSDs, one could conclude that the global pharmaceutical industry must be stepping up its NSD-related investment in research and development (R&D), right? But this does not seem to be the case. As a matter of fact, the information available suggests that quite the opposite happened in the last decade.
Despite all the unmet medical needs potentially acting as an incentive to develop medical solutions to NSDs, large pharmaceutical companies have slashed their internal investment in NSD drugs and significantly downsized their neuroscience research divisions. The quintessence of that downsizing lies in the fact that this industry has witnessed a drastic reduction in the number of drug discovery and development programmes in neuroscience5.
Some of you may be thinking right now: “But aren’t these cuts in R&D simply part of a bigger trend in the pharmaceutical industry that actually covers not only NSDs but a wide range of therapeutic areas?” Well, while such a trend is factual and clear, it does not explain in itself the sheer level of frustration with the development of new NSD drugs experienced by the pharmaceutical industry in the last decade. I will lay out here some of the reasons why it is so, but first I would like to add a word of caution about the interpretation of the cuts in R&D in neuroscience by mentioning that, despite these cuts, the combined number of R&D projects in neurology and psychiatry still is second only to that in oncology6.
Logically, these sharp cutbacks in R&D in neuroscience raise the question: did large pharmaceutical companies decide to have their financial resources diverted from in-house R&D into outsourcing R&D? Indeed they did. It seems that these companies have decided to “de-risk” NSD drug development by shifting their activities to licensing, partnerships, and mergers and acquisitions. However, once again, you may be surprised to know that over the last decade not only has the total value of deals in neuroscience remained constant, but also the average value of a deal has in fact decreased.
In spite of the fact that the value of funding (venture capital investment and public offerings) in neurology and psychiatry combined is second only to that in oncology,8 the facts mentioned above may portray a grim outlook for the pharmaceutical industry and its aspiration of tackling NSDs. I would like to shine some light on what could be considered to be the direct cause, the indirect cause, and finally the root cause of that perceived grim outlook; obviously the root cause is deemed to be the most concerning and the one that may ultimately set the stage for alternatives to medication.
The direct cause
NSD drugs are considered by many to be the underdog or long shot of drugs. They have earned the unenviable distinction of having the lowest success rate (in clinical trials) among major drug classes, expressed by a mere 3% probability of going from Phase I of clinical development all the way to launch. Compare this to the three-fold greater success rate of anticancer drugs (9%).
Even the modest set of successful NSD drugs which made it to the finish line of regulatory approval tells a less impressive story. For instance, in the last two decades, drugs acting on the central nervous system (the main subclass of NSD drugs) not only required on average 20% more time to be developed than other drugs, but also took on average 38% longer to win approval compared to other drugs (data from the United States Food and Drug Administration10). As I will discuss below, there are a number of key factors leading to unsuccessful and demanding clinical trials; understanding these factors will open the door to grasping the root cause of it all.
The indirect cause
Neuroscience is viewed more and more as a burgeoning field of research, as attested by the doubling of core neuroscience journals and a 37% increase in publication figures from the year 2006 to 201511. But remember: all that glitters is not gold… The vast amount of data and information generated by the scientific community so far has not yet been distilled into a substantial amount of useful knowledge — the type of knowledge that would allow us to have more than the generally insufficient understanding of NSDs we currently have.
Limited knowledge about how diseases disturb the nervous system and about the mechanisms of action of NSD drugs means that practically the whole process of discovering and developing an appropriate pharmaceutical drug is highly inefficient, and what is worse, ineffective 12,13. This bleak situation is reflected in the exceptionally great difficulties that have been encountered in the following attempts:
- identifying suitable biomarkers to objectively diagnose conditions, as opposed to making a diagnosis based on symptoms or the patient’s perception;
- choosing objective clinical trial endpoints to unambiguously measure drug effects, instead of resorting to clinical outcome assessments such as self-assessment questionnaires;
- developing drugs that treat the underlying cause of the NSD rather than its symptoms;
- developing target-specific drugs, in place of non-specific medications that act, for instance, on major neurotransmitters or other ubiquitous molecules in the brain.
A major repercussion of subjective clinical endpoints, and of the low specificity underlying the action of NSD drugs in psychopharmacology, neuropharmacology and the pharmacology of pain, is that not only are placebo responses generally high (and even long-lasting for some NSDs14), but also drug responses are relatively low, which results in small treatment effects. Antidepressants, for example, which are used to treat the second leading cause of disability, have an average response rate of 47% — just slightly higher than the corresponding average placebo response rate of 36%. As a consequence, the average treatment effect of antidepressants is as low as approximately 10%.
The aspects mentioned above may help to understand the daunting challenges of NSD drug development; however, they themselves are consequences of a much more fundamental cause.
The root cause
The basic functioning principle of medication in general does not enable NSD drugs to be effective and safe, and the root cause of that lies in the intricacies of neurophysiology. There is one particular feature that sets the nervous system apart from all other organ systems: in addition to the individual properties of nerve cells or neurons, it is the connections between neurons, rather than solely neurons per se, what determines the actual functions neurons perform from a myriad of possibilities.
The relevance of the neural circuitry to the efficacy and safety of NSD drugs lies in the fact that it is exceptionally difficult to deliver medication with a high degree of spatial accuracy so that specific neurons or neuronal connections — and therefore specific neural computations and cognitive processes — can be affected. That is why NSD drugs carry all too often significant side effects, many of which can be very debilitating. Furthermore, medication almost invariably acts exclusively on the chemistry of the body, whereas the nervous system relies heavily on electricity or electrophysiological processes to gather, transmit and process information.
It is unlikely that even the advent of fully-fledged gene therapy and nanomedicine will pave the way to effective and safe drugs against most NSDs considering that medication (alone) of any kind is fundamentally not able to identify the specific set of neurons or neuronal connections on which it needs to act to manipulate a particular neural computation. The functional identity of neurons is essentially concealed in their intricate connections and is to a great extent revealed by spatio-temporal patterns in their electrophysiological activity. Medications are, in essence, oblivious to all of that. But fortunately there is (lots of) hope in a different kind of technology.
Solutions to NSDs in the age of neurotech devices
Just imagine a world where people born deaf could truly hear by means of a device that would directly stimulate their nervous system — a device that would allow them, among other things, to use their cell phones not only to hear phone calls, but also to play music back in their heads (both literally and figuratively speaking) with no sound waves or external vibrations involved. Now imagine that also in that world people severely afflicted with chronic back or leg pain could soothe the pain with the help of a device that not only directly stimulated their spinal cord, but also automatically adjusted the level of stimulation, depending on signals sent by the spinal cord to the brain. Try also to imagine that same world where people, who would otherwise suffer from obstructive sleep apnoea and who would every night face dozens of episodes of abnormal breathing per hour, would instead have significantly fewer of such episodes thanks to a device that directly stimulated a nerve of their body.
How wonderful that world would be! And it would not be very different from our own world because that futuristic and seemingly utopian reality I described above is exactly the world we are already living in.
Those wonders of technology represent the broad category of neurotechnological devices, also known by the nickname “neurotech devices”, and their most life-changing realm is arguably where neuroscience and biomedical engineering meet in the form of neuromodulation medical devices. Neurotech devices are closely related to neuroprostheses — though some neurotech devices do not need to be implanted — and are also closely related to electroceuticals — although neurotech devices also include light-based and electromagnetic neuromodulation techniques beyond electrical stimulation.
Neurotech devices boast technology that confers them two remarkable capabilities:
- they can stimulate specific neural circuits and
- they are able to communicate bidirectionally with the nervous system.
The first feature stands in stark contrast with drug delivery alone and is a direct consequence of the intrinsically high spatial resolution of stimulation delivered via a physical device placed in a precise location of the body. The second attribute is in even sharper contrast to medication and can be put into practice by the use of three basic components: built-in sensors that measure neural activity (typically electrical activity), a processing unit which interprets the measured signals, and an output device that delivers the intended stimulation.
These two attributes of neurotech devices, when combined, can be a true game-changer in the treatment of NSDs. High-resolution stimulation means acting on specific neural computations and, in turn, specificity of action leads to fewer side effects and possibly a greater treatment effect size. Similarly, the ability to both sense and stimulate enables an adequate modulation of the nervous system based on objective changes in its activity or on objective responses to its stimulation, thereby also improving the specificity of action and, consequently, reducing side effects as well as increasing treatment effects17.
Recent major efforts to compare diseased to healthy connectomes (set of all neural connections) should further contribute to exploiting the inherently higher specificity of neurotech devices18. Moreover, new developments in monitoring and modulation of neural activity — most notably those making use of artificial intelligence and machine learning 19,20— have the potential to make, for example, the powerful feature of closed-loop neuromodulation become commonplace21. Regardless of when (or if) the pharmaceutical industry resolutely turns to neurotech devices for new medical solutions to NSDs, the age of neurotechnology in the shape of medical devices is most definitely here.
The devices I alluded to in the “just imagine” exercise at the beginning of this section epitomise the great potential of neurotech devices 23,24,25: the first of those devices — the cochlear implant — which is considered (and rightly so) a marvel of technology, has already been received by more than half a million people around the world26 as a means of bypassing the compromised part of the ear and directly stimulating the auditory nerve (by converting sounds into electrical stimuli). This device not only allows the level of stimulation to be adjusted according to the electrophysiological auditory responses to stimuli27, but also offers the possibility to benefit from telehealth/telemedicine capabilities in an excellent example of a fully-fledged digital health solution28. The second device I alluded to corresponds to the Evoke closed-loop spinal cord stimulator (Saluda Medical, Australia) and the third device is the Genio hypoglossal nerve stimulator (Nyxoah S.A., Belgium).
High hopes for the future: hybrids of medical devices and pharma
Moving forward, what if neurotech devices instead of replacing NSD drugs would actually turn out to be the forerunner of a large-scale merger of the pharmaceutical and medical device industries? We have good reasons to believe that this is likely to happen in the foreseeable future. For one thing, we are already seeing this type of fusion of technologies taking place in cochlear implants, as the pharmaceutical company Sensorion and the medical device company Cochlear have announced a collaboration to study combination therapies based on the cochlear implant and a drug29.
Another telling example of a symbiotic relationship between the two industries is the neurotech device company Galvani Bioelectronics, formed through a £540 million partnership between the pharmaceutical company GlaxoSmithKline (GSK) and the healthcare and medical device company Verily Life Sciences30. As these partnerships demonstrate, neurotech devices could be the way to turn a threat into an opportunity.
Considering the fact that the basic framework of the nervous system consists of both electrical and chemical functional elements, it is only natural that the development of therapies acting on those two levels — we could call it the “neurotech 2.0” — ushers in safer and more effective treatments for NSDs. What is more, some prospective applications of neurotech devices fundamentally rely on (bio)pharmaceutical technologies, and the breakthrough biological technique of optogenetics is a case in point. For optogenetic neurotech devices to control neurons by the use of light, it is necessary that those neurons be previously genetically modified to express light-sensitive molecules, which is a feat dependent on the advent of human gene therapy31.
Here, finally, I would like to sound a word of caution for the pharmaceutical industry: the environment that I described of vast and growing unmet medical needs, and of inability to successfully tackle NSDs using the current dominant approach (medication), represents exactly the type of conditions ripe for disruptive companies, products and technologies. Unless this industry embarks on and firmly commits to accelerating the development of neurotech devices, others will eventually be in an unrivalled position to bring to the market significantly better products. One of the worst things the pharmaceutical industry could do to itself perhaps could be to treat that unmet need with a “business-as-usual” attitude or with the kind of contempt that possibly characterised the reactions of executives from Nokia and Kodak to revolutionary technology, an attitude which ultimately led to the monumental failure of once-very-successful corporations. Alternatively, what the pharmaceutical industry could do is to emerge as a major player in neurotech and to welcome a new era, a better era, the era of neurotech devices.
Competing interests and disclaimer
I am an employee of Cochlear Ltd. However, the opinions and positions expressed in this article are my own and do not necessarily reflect those of Cochlear.
Many thanks to Giovanna Piazzese for the enlightening and thought-provoking discussions around the health impact of NSDs compared to that of cardiovascular diseases and cancer.
About the author
Tiago R. Felix is a biotechnology engineer, a neurotechnology researcher and a communicator who works for the global leader in implantable hearing solutions. Felix is a PhD in Neuroscience from the universities of Freiburg (Germany), Strasbourg (France) and Basel (Switzerland), and a MSc in Biological Engineering from Instituto Superior Tecnico (Portugal) who also carried out a research project on brain–computer interfaces at the University of Twente (the Netherlands). He is strongly committed to improving human well-being through the development and adoption of neurotechnology to treat NSDs. www.tiagorfelix.com
- Neurotech devices are a class of devices that can directly monitor, modulate and/or stimulate the human nervous system.
- Deafness in cochlear and auditory nerve disorders(2015) Handbook of Clinical Neurology
- Global Burden of Disease Study 2019(2020) The Lancet
- Measuring the Health of Populations: Explaining Composite Indicators(2012) Journal of Public Health Research
- Medicines for the Mind: Policy-Based “Pull” Incentives for Creating Breakthrough CNS Drugs(2014) Neuron
- The Biopharmaceutical Pipeline:Innovative Therapies in Clinical Development(2017) Analysis Group
- How Biopharma Companies Are Bolstering R&D Pipelines through Deal-Making (2017) Deloitte Insights
- Trends in Neuroscience Dealmaking(2018) Biopharma Dealmakers
- Trends in Clinical Success Rates and Therapeutic Focus(2019) Nature Reviews Drug Discovery
- Tufts CSDD Impact Report(2018) Tufts Center for the Study of Drug Development
- The Changing Landscape of Neuroscience Research, 2006–2015: A Bibliometric Study(2017) Frontiers in Neuroscience
- Improving and Accelerating Drug Development for Nervous System Disorders(2014) Neuron
- The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes(2017) Neuropharmacology
- The Persistence of the Placebo Response in Antidepressant Clinical Trials(2008) Journal of Psychiatric Research
- Magnitude of Placebo Response and Drug-Placebo Differences across Psychiatric Disorders(2005) Psychological Medicine
- Has the Rising Placebo Response Impacted Antidepressant Clinical Trial Outcome? Data from the US Food and Drug Administration 1987-2013(2017) World Psychiatry
- Closed-Loop Neuromodulation in Physiological and Translational Research(2019) Cold Spring Harbor Perspectives in Medicine
- The Potential of the Human Connectome as a Biomarker of Brain Disease(2013) Frontiers in Human Neuroscience
- A Translational Platform for Prototyping Closed-Loop Neuromodulation Systems(2013) Frontiers in Neural Circuits
- Explainable Artificial Intelligence for Neuroscience: Behavioral Neurostimulation(2019) Frontiers in Neuroscience
- Closed-Loop Electrical Neurostimulation: Challenges and Opportunities(2018) Current Opinion in Biomedical Engineering
- Medical Gallery of Blausen Medical 2014(2014) WikiJournal of Medicine
- Unilateral Cochlear Implants for Severe, Profound, or Moderate Sloping to Profound Bilateral Sensorineural Hearing Loss(2020) JAMA Otolaryngology—Head & Neck Surgery
- Long-Term Safety and Efficacy of Closed-Loop Spinal Cord Stimulation to Treat Chronic Back and Leg Pain (Evoke): a Double-Blind, Randomised, Controlled Trial(2020) The Lancet Neurology
- Implantation of the Nyxoah Bilateral Hypoglossal Nerve Stimulator for Obstructive Sleep Apnea(2019) Laryngoscope Investigative Otolaryngology
- Enhanced Pitch Discrimination for Cochlear Implant Users with a New Haptic Neuroprosthetic(2020) Scientific Reports
- Efficacy of Using NRT Thresholds in Cochlear Implants Fitting, in Prelingual Pediatric Patients(2019) Journal of Otology
- Cochlear Implant Mapping Through Telemedicine-A Feasibility Study(2020) Otology & Neurotology
- Sensorion and Cochlear Announce Collaboration to Study Combination Therapies for Cochlear Implant Patients (2017) Press release from Cochlear
- GSK and Verily to Establish Galvani Bioelectronics – a New Company Dedicated to the Development of Bioelectronic Medicines(2016) Press release from GSK
- Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans(2020) Frontiers in Neural Circuits
15 October 2013, by Julia Skripka-Serry, Fall 2013