Therapeutic areas in focus
Looking to the future of neurology
Pharmafile speaks to Martin Citron at UCB about the challenges facing neurology and how these can be overcome
Pharmafile: Which areas of neurology have the greatest unmet patient needs?
It depends on how you define ‘greatest’. You can look at most severe or you can look at the largest number of patients, or you can look at the product of both.
If you were just to look at the greatest severity, an obvious example would be amyotrophic lateral sclerosis (ALS), which is an area we’ve been looking at, but people are still dying and there’s no real treatment.
On the other hand, you could look at areas that affect greater numbers of people but are not as severe, and then the areas that affect quite large numbers of patients that are also severe, such as Alzheimer’s disease. Of course, Alzheimer’s is very high impact, but there are also diseases that affect smaller populations that are still quite severe.
For example, some that are of particular interest to us are specific childhood epilepsies, such as Dravet Syndrome and Lennox-Gastaut, and some hereditary epilepsies. There are also a number of neurodegenerative diseases that we’re active in, as well as Alzheimer’s and Parkinson’s.
Overall, the unmet need in neurology is huge. This unmet need is one of the major reasons people are still interested in neurology and want to keep doing more in the area, despite the intrinsic difficulties.
UCB has some treatments in the pipeline for stereotypical prolonged seizures. As this would be the first rescue treatment for this condition, what is the extent of the unmet need in this area?
Stereotypical prolonged seizures affect up to 30% of people living with epilepsy.
Due to the unpredictability of these types of seizures and the length of time they last, without on-demand treatment there is a higher risk of long-term neurological impacts and potential for further complications for people living with epilepsy.
We are focused on finding solutions for high unmet need. In our portfolio, we currently have an acute, on-demand treatment for seizures in phase 3 development. Successful treatments for prolonged seizures may not only reduce potential long-term neurological impacts, but also allow people living with epilepsy to the lead the best life they can.
We still have a long journey ahead, but we are driven by our commitment to people living with severe neurological disorders; they inspire our R&D and ensure our expertise, innovation and ambition align with their unmet needs.
How did the pandemic affect neurological patients’ access to treatment?
The pandemic affected everyone and everything. It is significant that some forms of epilepsy can be triggered by stress and anxiety, and the pandemic’s stress-inducing nature may have resulted in an increase in seizures in these individuals.
Without a doubt, the shift in focus of healthcare services almost entirely to COVID-19 had a detrimental impact on patients with neurological disorders. As with other conditions such as cancer, delays
and disruptions due to the pandemic would have directly or indirectly affected specialist consultations, diagnosis, treatment and rehabilitation care.
Reduced healthcare capacity also meant that people with neurological disorders might not have been able to see their doctor for routine appointments, including treatment reviews.
We are very mindful about taking learnings from the pandemic to improve the lives of people living with neurological disorders. In particular, we are continuing to invest in digital health tools that can support patients to better manage their conditions.
For people living with epilepsy, for example, this could mean fewer breakthrough seizures, fewer visits to the hospital and fewer follow-up visits to their specialist.
What role do technologies such as AI and ‘specialised neurons’ play in advancing clinical research into neurological conditions?
They increasingly help the development path, starting with target identification, where we ‒ and probably everyone else ‒ are now experimenting with more AI-based methods, and iPSC-based methods, which are specialised stem cells. We are also trying new technologies, such as substituting or improving animal models like organoids.
There are also advanced technology paradigms when it comes to clinical trials. For example, for both our epilepsy programmes and our movement disorder programmes, we are discussing implementing digital biomarkers that show great promise at improving the quality of clinical trial data.
This also touches on one of the reasons why there’s more excitement in the field now on some of these clinical trials; with these improved biomarkers we will hopefully be able to improve on what’s been done in clinical development in the past.
For example, in Parkinson’s disease, we’re going beyond the classic registrational readouts such as Unified Parkinson’s Disease Rating Scale (UPDRS), with the inclusion of digital biomarkers.
What are the greatest challenges in the development of treatments for neurological disorders?
Some people say the fact that these diseases are not fully understood is the biggest challenge; I don’t agree. The biggest challenge is, at least for some of these indications, testing a hypothesis clinically. It is so expensive and involved that you can’t test many things and you don’t have that many chances. You have to be quite sure about specific areas of biology or of a certain approach, which limits what you can try. I think that also limits venture investment in some of these indications.
For example, oncology has jumped ahead of neuroscience in the past 30 years, because you can do relatively small trials and even possibly see results in phase 1 that tell you if your approach is working.
However, in neurology, with a heterogenous population and slowly progressing disease, you sometimes need quite big studies to find out whether your drug works. The cost for these studies becomes quite prohibitive.
As Head of Neuroscience research, what are your hopes for, and what would you like to see in, the landscape of neurology, over the next decade?
Given that the cost of these proof-of-concept trials is prohibitive, then maybe we can bring the cost down with better biomarker approaches ‒ perhaps with digital biomarkers. Hopefully, we can make the patient population going into the trial more homogenous and therefore reduce patient numbers, which will subsequently reduce trial costs.
Of course, there is a whole lot of new biology being tested. This could build new pathways that have not previously been explored.
There are also new platforms such as gene therapy, which will allow access to some indications and disease situations that were not previously addressable, such as with small molecules and antibodies.
The combination of new mechanisms, new platforms and new biomarker insights will hopefully inspire more success in the field.
We’ve decided to really focus on three areas: epilepsy, neuroinflammation and neurodegeneration. Starting with epilepsy, we realise that the time for new, symptomatic treatment for large populations is over. We’re really trying to address the causes for specific, severe epilepsies that are currently unaddressable. We are also investigating specific patient needs that don’t necessarily involve pharmacology, such as new forms of administration.
In neurodegeneration, we are trying to focus on the fundamental protein misfolding pathologies. We’ve tried to establish a number of different approaches and partner with some major companies (such as Roche for Alzheimer’s disease, and Novartis for Parkinson’s disease) for the proof-of-concept trials in both of these indications.
In neuroinflammation, we have an immediate focus on addressing autoimmune disorders, as well as a number of early-stage programmes.
joined UCB in 2012 as Vice President Neuroscience Research, and is currently SVP and Head of the Neuroscience TA in Early Solutions. In his role, he is responsible for UCB’s neurology early pipeline. He is a member of the Early Solutions Leadership Team reporting to the CSO.
Over the last eight years, Martin’s team has revitalised the neurology early pipeline, added the antibody modality and expanded discovery beyond epilepsy into neurodegeneration, neuroinflammation and gene therapy through internal research, academic partnerships and in-licensing. Martin is an experienced leader in neurology with more than 20 years of experience building groups and directing programmes from earliest discovery stages into clinical proof-of-concept studies. He is an internationally recognised neurodegeneration researcher with more than 28,000 citations, best known for identification and characterisation of beta-secretase, a key enzyme in Alzheimer’s disease.