Drug-Resistant Focal Epilepsy: Clinical Trials and Emerging Therapies. Transforming Patient Care Through Innovation

Date

13th January, 2026

Executive Summary

Drug-resistant epilepsy (DRE) is one of the most significant challenges in modern neurology. Affecting approximately 15-16 million people worldwide—about 30% of all individuals with epilepsy¹—this condition places an immense and continually increasing burden on patients, caregivers, and healthcare systems. Even with optimal pharmacological therapy, patients with DRE experience substantial impacts on safety, independence, cognitive function, and overall survival.

The emergence of novel therapeutic agents with differentiated mechanisms of action offers renewed hope for this vulnerable population. Next-generation potassium channel openers, functionally selective sodium channel modulators, and other innovative modalities are redefining the treatment landscape. However, bringing these transformative therapies to patients requires more than scientific innovation—it demands highly specialized operational expertise to navigate the uniquely complex nature of DRE clinical trials.

This white paper provides an evidence-based overview of the evolving landscape of drug-resistant focal epilepsy, highlighting recent clinical and regulatory milestones, the operational challenges inherent in modern trials, and the ways specialized clinical research organizations (CROs), such as Pivotal, are driving innovation through scientific and operational excellence.

The Evolving Paradigm of Drug-Resistant Epilepsy

From Symptomatic Control to Disease Modification

Drug-resistant epilepsy (DRE) is defined as the failure to achieve sustained seizure freedom after adequate trials of two appropriately selected and tolerated antiseizure medication (ASM) regimens, whether used as monotherapy or in combination¹. Established by the International League Against Epilepsy (ILAE) in 2010, this definition provides a standardized framework for identifying patients who require alternative therapeutic strategies.

The impact of DRE extends far beyond the seizures themselves, triggering a cascade of physical, psychological, and social consequences that profoundly affect quality of life.

The Multidimensional Burden of Drug-Resistant Epilepsy

Physical Risks and Mortality:

Seizure-related injuries affect 28-40% of patients, including fractures, burns, and head trauma²
Mortality rates are elevated 1.6 to 9.3 times compared to the general population³
Sudden unexpected death in epilepsy (SUDEP) remains a devastating outcome, with an incidence of approximately 1.16 per 1,000 person-years among patients with DRE⁴

Neuropsychiatric Comorbidities:

Depression affects 30-50% of patients with DRE⁵.
Anxiety disorders occur in 20-30% of cases⁶.
Cognitive impairments particularly in memory, attention, and executive function are common and often worsen with longer disease duration⁷.

Quality of Life Impact:

Driving restrictions limit independence and employment opportunities.
Educational challenges and reduced career prospects affect long-term socioeconomic outcomes.
Social stigma and isolation contribute to emotional and psychological burden.
The economic burden is substantial encompassing direct medical costs, lost productivity, and caregiver strain⁸.

Identifying At-Risk Patients:

Understanding predictors of drug resistance enables early identification and timely intervention. Key risk factors include⁹:

Early age of epilepsy onset, particularly during infancy.
Symptomatic etiology with identifiable structural brain abnormalities.
High seizure frequency at initial presentation.
History of status epilepticus.
Abnormal findings on neuroimaging.
Failure to achieve seizure control with the first appropriately selected ASM.

The critical insight: The probability of achieving seizure freedom decreases sharply after failure of appropriately selected medications. In newly diagnosed patients, approximately 47% achieve seizure freedom with their first ASM¹⁰. Among those whose first medication fails, the second and third regimens provide only an additional 11.6% and 4.4% likelihood of achieving seizure freedom, respectively¹¹ .

Breakthroughs in Therapeutic Innovation:

Recently Approved Disease-Modifying Therapies

Cenobamate: A Dual-Mechanism Approach

Cenobamate has demonstrated remarkable efficacy through its dual mechanism of action: selective inhibition of persistent sodium current and positive allosteric modulation of GABA_A receptors. Approved by the FDA in 2019 and the EMA in 2021, cenobamate has shown exceptional results in clinical trials involving this highly refractory challenging population¹²:

Seizure freedom rates: Controlled studies reported seizure-freedom rates of up to 28% at 200 mg/day during the 6-week maintenance phase, and up to 21% at 400 mg/day during the 12-week maintenance phase, compared with <10% for placebo.
Median seizure reduction: 55.6% at 200 mg/day compared with placebo.
Responder rates (≥50% reduction): 55.6% at 200 mg/day, 64.2% at 400 mg/day.

Therapies in Advanced Development

XEN1101: Next-Generation Potassium Channel Opener

XEN1101, a novel KCNQ2/3 (Kv7.2/7.3) potassium channel opener, has demonstrated compelling results in the Phase 2b X-TOLE study¹³:

Median seizure reduction: 52.8% at 25 mg dose versus 18.2% with placebo (p<0.001).
Responder rates (≥50% reduction): 54.5% at 25 mg versus 14.9% with placebo.
Seizure freedom: Achieved in 13% of patients receiving the 25 mg dose.

Notably, XEN1101 offers once-daily dosing with no titration requirements and demonstrates a rapid onset of action—significant practical advantages for both patients and clinicians.

PRAX-628 (Vormatrigine) a functionally selective modulator of sodium channel targeting the hyperexcitable state

PRAX-628, a functionally designed selective modulator of sodium channel inactivation, has demonstrated promising top-line results in the Phase 2 RADIANT study¹⁴:

Median seizure reduction: 56.3% in the treatment group versus 22% with placebo
Responder rates: Approximately 60% of patients achieved ≥50% reduction in seizures during the study, with 54% responding within the first week
Rapid therapeutic effect: Significant seizure reductions were observed within the first month
The development program is designed to enable rapid attainment of therapeutic concentrations without the need for prolonged titration, addressing a major limitation of many current ASMs.

The Persistent Unmet Need

Despite these recent therapeutic advances, approximately 30% of patients with epilepsy continue to experience inadequate seizure control¹⁵. This enduring treatment gap underscores several critical realities:

Mechanistic Diversity: The heterogeneous pathophysiology the underlying focal epilepsy requires therapeutic approaches that extend beyond the current targets. Patients may respond to differently to various mechanisms of action, hence, continued innovation across multiple pathways remains essential.
Individual Variability: Substatial inter-patient variability in drug response highlights the need for personalized treatment strategies and a diverse and robust pipeline of therapeutic options.
Tolerability Challenges: Even effective ASMs can be constrained by adverse effects that impair and compromise quality of life and reduce treatment adherence, highlighting the importance of developing better-tolerated alternatives.
Disease Progression: In some patients, epilepsy represents a progressive course with evolving mechanisms of pharmacoresistance, requiring ongoing therapeutic innovation.

Operational Challenges in Modern Drug-Resistant Epilepsy Trials

Unique Complexities in Contemporary DRE Studies

Modern DRE trials face substantial operational hurdles that set them apart from trails in many other therapeutic areas:

1. Patient Recruitment Complexity

Stringent eligibility criteria: Enrollment in these trials typically requires documented baseline seizure frequency (often 3-8 focal seizures per month) and specific prior treatment failures (usually ≥2 ASMs).
High screening failure rates: A significant proportion of screened patients fail to meet eligibility criteria requirements due to inadequate seizure documentation, exclusionary comorbidities, or medication history requirements.
Geographic barriers: Limited access to specialized epilepsy centers with sufficient patient volume, thus reducing recruitment reach.
Competition for patients: Multiple concurrent trials often targeting the same well-characterized patient population, intensifying recruitment challenges.

2. Complex Data Collection Requirements

Daily seizure diaries: The trials require consistent patient and caregiver engagement to maintain accurate seizure diaries throughout an extended baseline (typically 8-12 weeks) and treatment periods (12-16 weeks or longer).
Centralized EEG monitoring: Expert interpretation is essential to ensure accurate seizure classification according to ILAE standards.
Complex medication histories: Detailed tracking of polytherapy regimens, including drug names, doses, timing, and concomitant medications is critical for accurate eligibility assessment and safety monitoring.

3. Extended Trial Durations and Retention Challenges

Long observation periods: Prolonged baseline assessments are needed to establish reliable seizure frequency followed by lengthy treatment phases to adequately evaluate efficacy.
High patient burden: Frequent study visits, extensive clinical assessments, and daily diary completion contribute to participants´ fatigue and dropout risk.
Retention strategies: Sponsors and sites must carefully balance study demand with patients’ daily responsibilities, including work, family obligations and transportation limitations, in order to support long-term engagement.

4. Safety Monitoring Complexity

Drug-drug interactions: Careful management of complex pharmacokinetic and pharmacodynamic interactions is essential in patients receiving multiple concurrent ASMs Adverse effect surveillance: Continuous vigilance is required to identify cognitive, psychiatric, and behavioral side effects that may emerge during treatment.
Specialized medical oversight: Ongoing monitoring by neurologists with epilepsy expertise is critical to ensure patient safety and appropriate clinical decision-making.

Pivotal’s Specialized Approach: Advancing DRE Programs with Scientific Excellence

At Pivotal, we do more than simply manage epilepsy trials—we design and execute fully integrated development programs built for success from initial protocol concept, clinical development, data management through to data analysis and medical monitoring and writing. Our approach is based on four interconnected pillars:

1. Strategic Protocol Design and Medical Leadership

Physician-Led Scientific Rigor

Our internal team of board-certified neurologists and epileptologists play an active role throughout every stage of the clinical development process:

Protocol Design Excellence: Drawing on our extensive frontline clinical experience, we develop scientifically rigorous and operationally feasible protocols. From the outset, we incorporate meaningful endpoints, rational inclusion and exclusion criteria, and efficient biomarker strategies that reflect real-world epilepsy management.
Expert Medical Monitoring: Our specialized medical team provides comprehensive oversight during trial execution, ensuring accurate seizure classification, effective management of complex polytherapy regimens, and careful assessment of adverse events in patients with neurologic and psychiatric comorbidities.
Anticipatory Problem-Solving: Through smart study design, we proactively identify and mitigate potential site and patient burdens enhancing both recruitment potential and retention rates before trials even begin.

2. Precision in Patient Identification and Recruitment

Overcoming the Primary Bottleneck

Patient recruitment represents often the defining challenge in epilepsy clinical trials. Pivotal has developed a multi-faceted recruitment engine specifically tailored to the complexity of neurological disorders:

Curated Network Excellence: Our carefully validated network of high-performing epilepsy centers across Europe provides access to well-characterized, eligible patient populations. These centers offer the infrastructure, patient databases, and clinical expertise essential for reliable and timely patients enrollment.
Data-Driven Site Selection: Using predictive analytics through our proprietary Danah® platform, we model site performance to optimize enrollment strategies—moving beyond traditional feasibility approaches to truly evidence-based site selection.
Proactive Site Engagement: Our continuous site support and real-time performance monitoring keep recruitment on track, reduce costly delays and allow early identification of issues requiring intervention.
Patient-Centric Design: We collaborate with epilepsy patient advocacy groups to align trial designs with patient and community needs, enhance awareness of ongoing trials, and promote equitable representation across diverse populations.

3. Mastery of Complex Data Partnerships and Logistics

Seamless Integration of Specialized Components

The complexity of epilepsy trials requires the coordination of multiple specialized vendors and technologies. Pivotal serves as the central integrator to ensure operational and data excellence:

Expert Vendor Management: We oversee critical partnerships including centralized EEG and imaging core labs, leading eCOA providers for seizure diary data capture, and specialized neurocognitive assessment platforms. Our involvement extends beyond coordination. We actively ensure data quality, harmonization and seamless synchronization across all systems.
Seizure Classification Rigor: We maintain strict adherence to ILAE seizure classification standards across all sites and raters, a cornerstone of endpoint reliability and regulatory acceptance and confidence.
Advanced Data Infrastructure: Our proprietary Danah® platform enables centralized, risk-based monitoring of critical and essential study data—from adverse events and laboratory results to protocol deviation trends. This proactive analytics-driven approach safeguards data integrity and promote real-time patient safety oversight.

Shaping the Future of Epilepsy Research

Pivotal is driving the next-generation of epilepsy research by enabling:

Advanced Therapeutic Strategies: We are equipped to support highly complex clinical trials, including combination therapies targeting multiple mechanistic pathways and innovative device-drug combination approaches.
Equitable Access Initiatives: We are committed to strengthening representation across Europe by implementing strategies that promote equitable access to clinical trials and inclusive participation among diverse patient populations.
Real-World Evidence Generation: We provide comprehensive support for post-approval studies and registry programs that capture long-term outcomes, treatment patterns, and quality-of-life data in real world clinical practice.

Conclusion

The evolution of drug-resistant epilepsy research reflects both a remarkable scientific advance and a significant operational challenge. While emerging therapies offer modest but meaningful improvements in seizure control, their real-world impact must be evaluated within the context of feasibility, cost, and long-term safety. Achieving success in this new era requires close collaboration among all stakeholders, robust clinical and technological infrastructure, and specialized expertise.

Pivotal’s integrated model— bringing together board-certified neurologists and epileptologists, standardized assessment protocols and methodologies, advanced data platforms, and strong partnerships with high-performing sites—positions us to lead this transformative effort and journey. Whether supporting the development of next-generation channel modulators or advancing precision medicine approaches, Pivotal remains committed to delivering the scientific rigor and operational excellence essential for achieving meaningful progress in drug-resistant epilepsy research and development.

References