“Disease modification” in epilepsies: key questions answered

Epilepsy research is entering an exciting new chapter, with researchers delving deeper into the concept of “disease modification” - aiming to develop treatments that not only better control symptoms, but also may modify the underlying disease process. 

While the potential of disease modification in epilepsy treatment is promising, several challenges need to be addressed. These include identifying appropriate therapeutic targets, optimizing drug delivery methods, ensuring safety and efficacy, and conducting robust clinical trials to establish the long-term benefits of disease-modifying treatments. 

As we have seen in other therapeutic areas such as Alzheimer’s disease or Parkinson’s disease, as the science advances it will become increasingly important for the pharmaceutical industry, regulators, healthcare professionals, and patient community, to agree on a more accurate definition of what is meant by “disease modification” in any given situation so that the effect and outcomes of any potential new treatments can be accurately measured and interpreted.

While still in the early stages of development, the progress being made in understanding the molecular and genetic basis of epilepsy is bringing us closer to the realization of disease-modifying treatments, offering hope for a brighter future for individuals living with epilepsy.

What do we mean by “disease modification” in epilepsy?

“Disease modification” describes changes that affect the underlying pathophysiology of a disease and have beneficial outcome on the clinical course. In simple terms, this means treating the root cause of disease, rather than addressing individual symptoms. This is a descriptive term, not a single well-defined effect. It requires careful interpretation within a given therapy area and disease, and it may take many forms with several distinct outcomes based on the nature of the epileptic condition. This means that our job in epilepsies is to clarify exactly what kind of disease-modifying effect we are seeking in different types of epilepsy, and how this is best measured.

Where we are now?

To date, treatment of epileptic seizures has been based on addressing symptoms, with medication targeted at raising the threshold to the occurrence of epileptic seizures. While this helps address disruption and potential damage caused by a symptom (seizures), it does not significantly impact comorbidities such as learning and behavior, which are particularly important because epilepsies frequently begin in childhood.

At the other end of the spectrum, a curative treatment is specific to the disease. While symptomatic treatments may work across several diseases with the same symptom(s), curative treatments work to correct underlying pathobiology – the biological root of disease. This approach addresses co-morbidities beyond the primary symptom, with the possible benefit that it may result in a longer-lasting effect than symptom-based treatment.

How are we approaching disease modification in research and development and the clinic?

Research into disease modification and identification of disease-modifying treatment targets is approached from two perspectives:
•    Outside-in: developing our knowledge of the natural history of disease, understanding non-seizure symptoms and outcomes 
•    Inside-out: understanding of biological pathways and identifying targets as close to the root cause of the disease as possible

Through this combination of careful observation of the whole symptom picture and understanding of how epilepsies progress, coupled with research into the pathobiology of disease, we hope to identify suitable targets for disease modification.

What should disease-modification-based treatment goals look like in epilepsies?

Disease-modifying treatments will change how we approach the care of patients with epilepsies, but they will also require new approaches to constructing and measuring the success of clinical trials.

Conventional design for clinical studies can fall short when applied to disease-modifying treatments, due to reliance on narrow, short-term outcome measures, inappropriate efficacy endpoints, and potentially unacceptably high risks to patients with refractory epilepsy, high seizure burdens, and elevated baseline risk of sudden unexplained death in epilepsy patients (SUDEP).  Suitable replacements for traditional endpoints may include markers of developmental achievement, language and communication, sleep, behavior, and motor function.

As we look to evolve our approach to the treatment of epilepsies, another challenge is regulators’ inclination to be specific and pragmatic, which leads us towards defining treatment by “what the drug does.” This has an inherent bias towards a focus on symptoms. However, study design and treatment labelling in oncology and (closer to our neurobiological home) in Alzheimer’s disease and multiple sclerosis have established precedents in terms of defining efficacy through impact on disease progression. While there is no regulatory definition of disease modification for epilepsies, there is plenty of cause for optimism.