*Guest blog by Pivotal. For more information on the information in this blog post please contact Ms. Natalia Farr - [email protected]. If you would like to submit a guest blog please email [email protected].
Transforming Patient Care Through Innovation
Executive Summary
Drug-resistant epilepsy (DRE) affects approximately 15–16 million people worldwide1 — roughly 30% of all individuals with epilepsy. Despite optimal pharmacological therapy, patients experience profound impacts on safety, independence, cognitive function, and survival. The emergence of novel therapeutic agents with differentiated mechanisms of action offers renewed hope for this vulnerable population. Yet bringing these therapies to patients demands more than scientific innovation: it requires highly specialised operational expertise to navigate the uniquely complex nature of DRE clinical trials. This article summarises the evolving treatment landscape, the operational challenges these trials present, and the specialised capabilities needed to advance them.
The Burden of Drug-Resistant Epilepsy
DRE is formally defined as the failure to achieve sustained seizure freedom after adequate trials of two appropriately selected antiseizure medication (ASM) regimens — a definition established by the ILAE in 20101. Its impact extends far beyond seizures alone, triggering cascading physical, psychological, and socioeconomic consequences.
- Physical risks: Seizure-related injuries — including fractures, burns, and head trauma — affect 28–40% of patients2. Mortality rates are elevated 1.6 to 9.3 times3 compared to the general population, and SUDEP occurs at approximately 1.16 per 1,000 person-years4 among people with DRE.
- Neuropsychiatric comorbidities: Depression affects 30–50% of patients5; anxiety disorders occur in 20–30%6; and cognitive impairments in memory, attention, and executive function are common and often worsen with longer disease duration7.
- Quality of life and economic burden: Driving restrictions, reduced employment and educational prospects, social stigma, and significant direct and indirect costs8 create a substantial and enduring burden for patients, families, and healthcare systems alike.
A critical clinical insight underscores the urgency of early intervention: approximately 47% of newly diagnosed patients achieve seizure freedom with their first ASM9. Among those whose first regimen fails, only an additional 11.6% achieve freedom with the second, and just 4.4% with the third10. Early identification of resistance and access to emerging therapies are therefore essential.
Breakthroughs in Therapeutic Innovation
Cenobamate: A Recently Approved Dual-Mechanism Agent
Cenobamate (FDA-approved 2019; EMA 2021) acts through selective inhibition of persistent sodium current and positive allosteric modulation of GABA⁁ receptors. In controlled trials involving highly refractory patients, it achieved seizure-freedom rates of up to 28% at 200 mg/day — compared to less than 10% for placebo — with a median 55.6% seizure reduction and responder rates (≥50% reduction) reaching 64.2% at 400 mg/day11.
Therapies in Advanced Development
- XEN1101 (Phase 2b, X-TOLE study): This next-generation KCNQ2/3 potassium channel opener achieved a median 52.8% seizure reduction versus 18.2% with placebo, with a 54.5% responder rate and 13% seizure freedom at the 25 mg dose. Its once-daily dosing with no titration requirement and rapid onset represent meaningful clinical advantages.12
- Vormatrigine / PRAX-628 (Phase 2, RADIANT study): This functionally selective modulator of sodium channel inactivation demonstrated a 56.3% median seizure reduction versus 22% with placebo, with approximately 60% of patients achieving ≥50% reduction. Notably, 54% responded within the first week, and no prolonged titration is required.13
Despite these advances, approximately 30% of patients still experience inadequate seizure control, underscoring the persistent need for innovation across diverse mechanisms of action, improved tolerability profiles, and individualised treatment strategies14.
Operational Challenges in DRE Clinical Trials
DRE trials present operational hurdles that set them apart from most therapeutic areas:
- Patient recruitment: Stringent eligibility requirements — including documented baseline seizure frequency and specific prior ASM failures — drive high screening failure rates. Limited access to specialised epilepsy centres and competition among concurrent trials further compound enrollment challenges.
- Complex data collection: Trials rely on daily seizure diaries, centralised EEG monitoring with expert ILAE-standard classification, and detailed polytherapy histories. Sustained patient and caregiver engagement across extended baseline (8–12 weeks) and treatment periods (12–16+ weeks) is essential.
- Retention: Frequent study visits, extensive assessments, and caregiver burden increase dropout risk. Effective retention requires proactively balancing trial demands with participants’ daily realities.
- Safety monitoring: Complex pharmacokinetic and pharmacodynamic drug–drug interactions, combined with the need for continuous surveillance of cognitive, psychiatric, and behavioural adverse effects, require specialist neurological oversight throughout.
Pivotal’s Specialised Approach
At Pivotal, we go beyond trial management to design and execute fully integrated DRE development programmes — from protocol concept and clinical development through data management, medical monitoring, and medical writing. Our model is built on four interconnected pillars:
- Physician-led scientific rigour: Board-certified neurologists and epileptologists shape every stage of development — designing operationally feasible protocols, providing expert medical monitoring, and anticipating site and patient burden before trials begin.
- Precision recruitment: Our curated network of high-performing epilepsy centres across Europe provides access to well-characterised patient populations. Our proprietary Danah® analytics platform enables predictive, evidence-based site selection and real-time performance monitoring.
- Data and operational mastery: We serve as central integrator across EEG core labs, eCOA seizure diary platforms, and neurocognitive assessment vendors, ensuring data quality, ILAE classification adherence, and seamless system harmonisation.
- Future-ready capabilities: We support complex combination therapy trials, equitable access initiatives across diverse European populations, and post-approval real-world evidence generation through registry programmes.
Conclusion
The field of drug-resistant epilepsy stands at an inflection point. Emerging therapies offer meaningful improvements in seizure control for patients who have historically had few options. Realising their full potential, however, requires not only scientific innovation but also specialised operational excellence — rigorous trial design, expert recruitment, robust data infrastructure, and deep therapeutic area knowledge. Pivotal’s integrated model is designed to meet precisely these demands, and our commitment to both scientific rigour and patient-centred execution remains unwavering.
This is an abridged version of a full white paper. To access the complete article, including detailed clinical data, references, and an in-depth overview of Pivotal’s capabilities, visit pivotalcr.com/drug-resistant-focal-epilepsy/.
References
1. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug-resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069–1077. [Link]
2. Lawn ND, Bamlet WR, Radhakrishnan K, O’Brien PC, So EL. Injuries due to seizures in persons with epilepsy: a population-based study. Neurology. 2004;63(9):1565–1570. [Link]
3. Thurman DJ, Logroscino G, Beghi E, et al. The burden of premature mortality of epilepsy in high-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia. 2017;58(1):17–26.[Link]
4. Sveinsson O, Andersson T, Carlsson S, Tomson T. The incidence of SUDEP: A nationwide population-based cohort study. Neurology. 2017;89(2):170–177. [Link]
5. Scott AJ, Sharpe L, Hunt C, Gandy M. Anxiety and depressive disorders in people with epilepsy: A meta-analysis. Epilepsia. 2017;58(6):973–982. [Link]
6. Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol. 2016;12(2):106–116. [Link]
7. Helmstaedter C, Elger CE. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease? Brain. 2009;132(Pt 10):2822–2830.[Link]
8. Strzelczyk A, Reese JP, Dodel R, Hamer HM. Cost of epilepsy: a systematic review. Pharmacoeconomics. 2008;26(6):463–476. [Link]
9. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548–1554. [Link]
10. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279–286.[Link]
11. Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19(1):38–48. [Link]
12. French JA, Porter RJ, Perucca E, et al. Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults with Focal Epilepsy: A Phase 2b Randomized Clinical Trial. JAMA Neurol. 2023;80(11):1145–1154. doi:10.1001/jamaneurol.2023.3542. [Link]
13. Praxis Precision Medicines. Praxis Announces Positive Results from RADIANT Phase 2 Study of Vormatrigine (PRAX-628) in Drug-Resistant Focal Epilepsy. Press Release. August 4, 2025. [Link]
14. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279–286. [Link]
MEDIA CONTACT
Ms. Natalia Farr | [email protected]