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Forging a path forward in neurological disorders

Published on 03/07/17 at 12:10pm

The development of innovative treatments for neurological disorders such as dementia has stagnated over the past decade despite being an area of huge medical and social significance. However, this could be set to change as our biological understanding of these ailments deepens, Matt Fellows discovers. 

Neurological diseases are among the most impactful and mystifying areas in pharmaceutical R&D. The disorders stem from dysfunction in the nervous system – both central and peripheral. The manifestation of symptoms and damage can extend to the spinal column, muscles, the neuromuscular junction, and the brain, leading to a range of alarming ailments including migraines, epilepsy, cerebrovascular diseases such as stroke, multiple sclerosis, Parkinson’s disease, and dementias like Alzheimer’s. They can also be caused by head trauma, malnutrition, neurodegeneration as a result of hereditation, or a range of other lesser-known external factors. Bacterial, viral, fungal or parasitic infection can trigger neurological damage as well, either directly or due to the body’s immune response to the infection. Data from WHO suggests that hundreds of millions of people across the world suffer from these diseases – 47.5 million are affected by dementia alone, and this figure is growing at a rate of 7.7 million per year.

Yet, despite the prevalence of these diseases and the ravaging effects they wreak on sufferers and their families, the life sciences industry has been apprehensive to commit time and resources to the development of new, innovative and effective treatment solutions. While groundwork has certainly been laid down, progress in this area has slowed considerably over the past years. There are many speculated reasons for this, and it has led to such disorders tumbling down the pecking order when it has come to prioritisation by researchers and the firms and organisations which employ them.

Will Reese, Co-President and Chief Innovation Officer at analytic firm Cadient, asserts that “emerging scientific approaches bearing new opportunities” are a primary driver for the forward momentum in the sector, alongside two other key factors: “the US healthcare system demanding more efficacious and economically sound solutions, and an aging population driving the costs for care.”

Medical writer Rebecca Mayer Knutsen agrees with Reese, noting that new breakthroughs in our biological understanding are turning the situation around:

“Following a nearly decade-long sluggish period during which investment from big pharma dwindled considerably, a profound understanding of the biology behind neurological conditions is lending a refreshed air to drug development,” she explains. “Notably, scientists are knocking on the door of degenerative brain disorders, though sellable answers to their questions remain years away.

“In the wake of diagnostic innovations and a spike in the understanding of genetic sequencing, drug developers have inched closer to discovering disease-modifying therapies for Alzheimer's disease and other neurological conditions. New approaches bring with them the promises of early detection, personalised medicine, and disease modification.”

These developments lay down the prospect of a bright future after a dismal slog, and one of the most exciting and crucial areas of this evolution is that of dementia research and treatment. This field in particular is close to the hearts of many; the effects of dementia do not just destroy physical freedoms and debilitate on a personal level, but it also ravages on a social scale by stripping away independence. In many cases, families are often burdened with the care and support they must offer their ailing relatives. This is doubly important when one considers the economic implications, with many having to rely on dedicated social carers, while medical care must be intensive and highly-specialised – much like cancer, the area is a highly-charged, emotive and imperative one.

So what is being done internally and externally to ensure patients in need are receiving the care and support they desperately need? Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, spoke to Pharmafocus on the topic and explained that the recent lag in sizeable gains within dementia research is principally due to the high failure rate within the field. As a consequence of this, pharmaceutical companies which fund and drive progress could see the area as high risk and shift their focus to more lucrative regions of R&D, resulting in the stagnation we have witnessed over the past decade or more.

This is, of course, a sad reflection of the economically-fuelled heart of the life sciences and healthcare industries, but according to Reynolds, there are reasons to celebrate, as the situation looks to be improving.

“Dementia research is in a better position today than it ever has been before, but we still have a long way to go,” he says. “Following the Prime Minister’s Challenge on Dementia in 2012, government spending on dementia research in the UK has doubled, and in 2015 stood at £66 million, up from £33 million in 2012. In a report we published this year, we found that these spending increases, along with our own, have translated through to increases in the number of dementia researchers – the number of dementia scientists has doubled over six years.“

This is welcome news, and surely representative of the new-found confidence that pharma firms and clinical trial sponsors have begun to exhibit in light of the latest leaps in understanding of the disease. However, despite this growth, public perception of the disease, and many other neurological disorders, has made the fight a difficult one to win from the very beginning. In relative terms, society has only recently begun to understand such ailments on a functional and personal level, thanks in part to the great work of charitable organisations and awareness campaigns which have elevated them to a level comparable to other diseases like HIV and cancer in the public consciousness.

“Conditions such as dementia are often misunderstood, and the stigma surrounding dementia has contributed to it being overlooked in the past,” Dr Reynolds adds. “Increasing awareness of the condition and the impact it has on people’s lives is changing this, and is helping to boost funding for research.”

The parallel drawn between dementia and cancer – two diseases linked by their emotive power and impact as much as their severity – is also particularly significant as a marker of progress when investigating the strides in research that are being made in the two fields, and the resources dedicated to this end. As Dr Reynolds details, “For every one researcher working on dementia, there are four working in cancer.”

This divide puts the current situation into perspective, and somewhat dampens the otherwise promising state of affairs. Dementia research is still proportionately under the line when it comes to investment; however, as Dr Reynolds outlines, research, support and advocacy groups in this area are working hard to bring these commitments up to the standard they should and need to be at.

“Large initiatives such as the UK Dementia Research Institute are bringing the size and scale we need to rise to the challenge of dementia, and will help to build capacity. The UK has also seen a doubling in the number of clinical trials for dementia compared with three years ago, helped in part by Join Dementia Research, meaning there is a willing pool of volunteers for new studies.

“However, even with this welcome growth, dementia is still playing catch-up and we must increase the pace if we are going to make the discoveries and find the treatments we so urgently need.”

Removing barriers

As Dr Reynolds points out, there is still much more to be done, and Alzheimer’s Research UK is among those organisations working on the front lines to tackle the real problems which hold the field back and deny patients the novel, innovative therapies they desperately need.

“Our mission is to bring about a life-changing treatment for dementia by 2025 and improve the lives of people living with the condition,” he outlines. As with any disease area, the obstacles between the patient and adequate treatment are multitudinous and varied, not least of which is the necessary degree of R&D investment at the earliest stages. This input has become galvanised in recent times, but an innovative, life-changing therapy is rendered inert if it never makes its way into the hands of the patients who need them.

“It is important that when new treatments are discovered, that patients have access to them,” Dr Reynolds continues. “We have identified some of the challenges that a disease-modifying treatment could face in reaching patients, such as the way a treatment’s potential impact on social care might be valued, and our health system being able to adapt promptly to innovations. We are working with government, industry and regulators now to look at access pathways in dementia, to ensure we ready the system so that future treatments can be delivered to the people who need them without delay.”

Knowledge is power

While this hard work is an ongoing effort from many different parties, the core of the neurological disorders sector lies squarely in R&D, and one example of the many exciting breakthroughs in the region was made just months ago. A topic of much discussion and contention between researchers in the field has been the function of an immune system protein known as triggering receptor expressed on myeloid cells 2, or TREM2. The protein has been known to play a key role in the development of Alzheimer’s, but scientists were at a loss as to exactly how. TREM2 functions by calling defensive immune cells as a response to the build-up of toxic amyloid plaques in the brain – a phenomenon that is the result of misfolded proteins which are thought to be the root cause of the neurodegeneration observed in Alzheimer’s patients.

This defence mechanism has divided observations within the laboratory, as it appears to produce both positive and negative effects, seemingly dependent on the observer.

Lead study author Taylor Jay, a graduate student at the Department of Neurosciences at Case Western Reserve University School of Medicine in Cleveland, Ohio, reported: “Our lab and others had previously published conflicting results about how TREM2 affected pathology in Alzheimer's mouse models. One group published data showing Alzheimer's mice lacking TREM2 had more amyloid plaques. We previously found the opposite, that getting rid of TREM2 improved amyloid pathology. We didn't know why we weren't getting the same answers. That was just the first question we wanted to ask, before we moved onto questions about exactly how TREM2 was influencing pathology.”

Jay’s study found that the key to this confusion lay in the timeframes within which the protein acts. In early stages of disease progression, the removal of TREM2 helped to eliminate amyloid plaques in the brains of the lab mice, but in the late stages, absence of TREM2 resulted in the plaques becoming enlarged.

The study ultimately gave birth to an updated model of the disease, which can be utilised in further investigations. The revelation that the effects of the proteins in the brain are time-dependent could have a resonating impact on treatment designations for patients subject to their stage of disease progression. Key findings like this, however small, are helping to fill in the puzzle of neurological disorders piece by piece as the scientific community’s understanding of the complex biology behind it continues to grow.

Interestingly, when [Pharmafocus] asked Dr Reynolds what he considered to be the greatest steps forward in the development of new treatments and broader understanding, he did not initially gravitate towards the mechanisms of these disorders, but rather the specificity of those who suffer from it.

“Recent failures of late phase clinical trials have revealed that one of our greatest challenges lies in identifying the right study populations, which itself is hampered by difficulties in providing people with an accurate and early diagnosis,” he explains. “With the diseases processes that lead to neurodegeneration being initiated around a decade before symptoms become apparent, understanding the earliest changes and being able to detect them is another key strand of dementia research.

“Advances in imaging techniques have had some of the greatest impacts on improving diagnostic accuracy, with the follow-on effect that study recruitment is improving,” he continued. “Many trials are now requiring positive amyloid-PET scans prior to study enrolment into anti-amyloid therapy studies, and this, as well as biomarker testing, is helping to reduce heterogeneity in trial cohorts. As a field, we also need to be alert to the importance of showing disease-relevance of targets earlier in the development process, to avoid later-stage failures. An increased focus on performing target validation in human tissue should help to overcome this hurdle. Devising more accurate models of human conditions will also improve the early stages of target validation and drug discovery, enhancing efforts in this area.”

Illuminating the road ahead

Perhaps more than any other therapy area, neurological disorders concern themselves with some of the most complex and delicate parts of the human biology, but the committed work of organisations and researchers are shedding light on was once a dark path. There is still a long way to go, but there is a definite sense of progress and excitement in the field.

Studies like those conducted by Jay and her contemporaries are beginning to unlock the significance of treatment timelines in effectively tackling Alzheimer’s, and Dr Reynolds believes that this knowledge could be key in revolutionising the way we approach the disease and perhaps wider conditions beneath the neurological umbrella in the future. Certainly, some of the biggest revelations in our understanding are still to come.

“The next few years will see the output from large studies such as Dominantly Inherited Alzheimer Network (DIAN) and its associated treatment trials, which could have a big impact on the field, with the potential to shift perceptions around the biology of Alzheimer’s disease. While recent failures of anti-amyloid therapies have seen many write off the amyloid cascade hypothesis, we still may have not been properly testing it. By the time people start showing symptoms, amyloid has been building up in the brain for a number of years.

“DIAN is one study that could really help to answer the amyloid question – by treating people with genetic forms of Alzheimer’s with anti-amyloid treatments before they show any symptoms, can we stop amyloid aggregation and neurodegeneration? Up to this point we have been treating people at a relatively late stage in the disease process, but by treating people we know are going to develop the disease, we can really see whether or not these treatments work and gain insight into how early we may need to start treating people in future.”

Matt Fellows

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