Industry Insight

Konrad Werhahn from UCB discusses how disease-modifying solutions may introduce a new era in treatment for epilepsies

Historically, the treatment of epilepsies has focused on seizure control. Yet despite considerable progress, particularly with the introduction of a greater number of chronic anti-seizure medications in recent years, the reality remains that around 30% of patients are not seizure-free.1,2 Uncontrolled seizures can lead to physical complications and psychological difficulties, and there is an increased risk of seizures progressing to potentially life-threatening epileptic emergencies.1,2,3 To address the significant unmet need, epilepsy research is now entering an exciting new chapter with researchers seeking to develop treatments that can modify underlying disease processes.

Disease modification to change the clinical course of epilepsies

At UCB, we know that more needs to be done to improve the lives and prognosis of patients with epilepsy. Our strong research capabilities are allowing us to open the door to new innovative solutions, delving deeper into the concept of ‘disease modification’ to treat the root cause of epilepsies rather than addressing individual symptoms such as seizures. Our research is approached from two perspectives: 

• Outside-in: developing knowledge of the natural history of disease, understanding non-seizure symptoms and outcomes 

• Inside-out: understanding biological pathways and identifying targets as close to the root cause of the disease as possible. 

To support this approach, we are building a molecular taxonomy of epilepsies. This ranges from the discovery of unknown disease mechanisms, to the identification of the genetic root causes of single gene epilepsies, to research into the pathobiology of epilepsies caused by the characteristics of the brain structure. Once the genetic root cause of an epilepsy has been identified, there’s the potential to target causal mechanisms directly through the development of new therapies. 

However, in difficult-to-treat epilepsies in low-prevalence patient populations, such as rare syndromes, the situation is more intricate. Here, disease mechanisms are often less well understood, so we need to rely on gene expression profiling to identify universal or common denominators of disease mechanisms across all epilepsies. Combining patient pathophysiology with genomics helps our researchers to find disease relevant targets and investigate potential therapeutic entry points for disease modification. By harnessing the power of computational design and artificial intelligence (AI), we can accelerate the discovery of new therapies. The exploration of the genetic root cause of the disease is paving the way for new therapeutic modalities, such as gene therapies, as targeted treatment options for different types of epilepsies. 

Although the potential of disease modification is promising, several challenges still need to be overcome to successfully alter the clinical course of epilepsies. These challenges include obstacles in identifying appropriate therapeutic targets, optimising drug delivery methods and ensuring the safety and efficacy of investigational therapies. In addition, the conventional design of clinical studies often falls short when applied to disease-modifying treatments, due to their reliance on narrow, short-term outcome measures with high clinical variance of disease expression, inappropriate traditional efficacy endpoints, short trial duration with only limited observations and potentially unacceptably high patient risks. 

Working alongside leading neurology organisations and institutes, UCB supports research collaborations focused on advancing the science behind epilepsy research. For example, our work with EPICLUSTER, a collaborative research framework established by the European Brain Research Area, ensures that data, resources, study results and expertise are shared across Europe.4 Focused on coordinating priorities for epilepsy research, EPICLUSTER seeks to accelerate drug discovery through new partnerships and programmes of scale, which in turn help UCB to achieve our long-term innovation goal to create a holistic epilepsy portfolio of targeted, precision medicines. We have already made significant progress towards identifying ‘master regulators’ that could work across multiple epilepsies and have several research projects underway in the preclinical phase, including small molecules and gene therapies for drug-resistant structural and monogenetic epilepsies.5 

Disease-modifying treatments could transform the way we approach the care of people living with epilepsies in the future, moving from symptomatic relief to addressing the underlying causes of these complex neurological disorders. Although still in the early stages of development, the progress being made in understanding the molecular and genetic bases of epilepsies is bringing us ever closer to realising disease modification. The work is far from complete, but we remain committed to finding new solutions, striving for seizure freedom and better outcomes for patients today, as well as the anti-epileptogenic options of tomorrow. 

References

1. Pina-Garza JE, et al. Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group. Epileptic Disorders. 2024; May 30
2. Sultana B, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96(17):805–17
3. Kortland LM, et al. Socioeconomic Outcome and Quality of Life in Adults after Status Epilepticus: A Multicenter, Longitudinal, Matched Case-Control Analysis from Germany. Front Neurol. 2017;8:507
4. Visit: ebra.eu/epicluster/
5. François L, et al. Identification of gene regulatory networks affected across drug-resistant epilepsies. Nat Commun. 2024;15(1):2180