In the Code Blog
New Systematic Literature Review Contributes to a Fuller Picture of Dravet Syndrome
Not seeing a video above?
Try adjusting your Cookie settings.
This month, the journal Epilepsy & Behavior published a systematic literature review (SLR)1 of the burden of Dravet syndrome. Encoded Therapeutics, along with experts in epidemiology and health economics and preeminent Dravet syndrome clinicians and key opinion leaders, Dr. Joseph Sullivan, Director of the University of San Francisco Pediatric Epilepsy Center, and Prof. Sameer Zuberi, Consultant Pediatric Neurologist at the Royal Hospital for Children and Honorary Professor in the University of Glasgow, co-authored this paper, which summarized contemporary studies reporting the clinical, humanistic and economic burden of Dravet syndrome. The SLR also identified important gaps that remain despite the increasing number of published manuscripts in the last decade.
Encoded Chief Medical Officer Dr. Salvador Rico discusses the impetus behind this SLR and the insights it reveals about the clinical evolution and burden of Dravet syndrome. He also shares the role these findings are having in the design of the ENDEAVOR first-in-human trial for ETX101, Encoded’s investigational gene regulation therapy for SCN1A+ Dravet syndrome.
Why did you conduct this SLR?
The SLR is part of Encoded’s multipronged strategy to improve our understanding of the burden, progression and unmet medical need of Dravet syndrome to inform design and development of the EXT101 clinical trial. To ensure a thorough understanding of the landscape, we systematically assessed the literature for studies characterizing Dravet syndrome in terms of clinical symptoms, impact on health-related quality of life (HRQoL) for affected people and families, and financial burden to families and healthcare systems. As previous visual representations of the clinical evolution of Dravet syndrome have been based on expert opinion and consensus (rather than data), we developed contemporary, evidence-based visualizations of the evolution of the seizure-related and non-seizure-related manifestations of Dravet syndrome.
This SLR summarizes the contemporary available data to help paint a fuller picture of Dravet syndrome. However, gaps remain, in part because most studies are cross-sectional and lack longitudinal data to understand the impact and its progression over time. Encoded is working with the Dravet syndrome community to bridge those gaps through our ongoing DRAVET ENGAGE initiative, which captures experiences and feedback from the patient community, and ENVISION, our ongoing prospective natural history study of children with Dravet syndrome.
What are the key findings and takeaways from this SLR?
The SLR distilled clinical findings into two schematic diagrams. The first (see Figure A) charts the evolution by age of the seizure-related manifestations of Dravet syndrome as well as all-cause mortality and mortality due to sudden unexpected death in epilepsy (SUDEP). The second (see Figure B) illustrates the evolution of non-seizure-related manifestations, such as developmental delays, impaired speech and communications, and motor and behavioral problems.
The review confirmed the devastating impact and trajectory of Dravet syndrome. This includes the early and high burden of seizures as well as the neurocognitive and developmental impairments, such as early stagnation of communication and motor skills by 2 years of age. We also found that, while likely still underestimated, the reported direct costs of the disease are high, and both patients and their caregivers have substantially impaired quality of life. Mothers, in particular, are seemingly more impacted personally and professionally than fathers.
While likely still underestimated, the reported direct costs of the disease are high, and both patients and their caregivers have substantially impaired quality of life.
The SLR additionally revealed some striking findings. For example, the incidence of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) traits is higher than expected, often beginning before the age of 5 years, and affecting up to two-thirds of people by adulthood. In support of previous anecdotal reports, we also found that developmental delay may sometimes precede seizure onset. Furthermore, the publication highlights the elevated and persistent risk of mortality for people with Dravet syndrome, which continues into adulthood.
The SLR findings align with the initial ENVISION data that were presented by Dr Andreas Brunklaus (Consultant Pediatric Neurologist at the Royal Hospital for Children in Glasgow, United Kingdom) in December at the American Epilepsy Society Annual Meeting. There, he highlighted the early onset of developmental delays before age 3 years, the high seizure burden despite the use of multiple and newer antiseizure medications, and that the quality of life for these children and their families is impacted early and worsens with age.
The quality of life for these children and their families is impacted early and worsens with age.
Beyond the impact of Dravet syndrome on families, what does this SLR reveal about the impact on society?
The diverse clinical manifestations of Dravet syndrome are intrinsically linked with the economic and health system burden of this disease. Caring for those living with Dravet syndrome requires substantial healthcare resource use, driven by hospitalizations and in-home medical care visits. However, the costs of managing the neurodevelopmental aspects of Dravet syndrome were infrequently reported, including attendance at special schools for children and supportive living/residential community homes for adults. Individuals living with Dravet syndrome may need around-the-clock care, which means one parent may need to sacrifice their career to become a full-time caregiver, leading to a high rate of single-income families in the Dravet syndrome community.
One parent may need to sacrifice their career to become a full-time caregiver, leading to a high rate of single-income families in the Dravet syndrome community.
As such, while the costs reported in the SLR were substantial, they likely underestimate significantly the actual direct and indirect burden on families, healthcare systems and society. The true economic burden of Dravet syndrome is still under-reported, especially for those that survive into adulthood, and is an area that needs further study in future.
How is this SLR informing the ETX101 clinical trial?
Along with the learnings from DRAVET ENGAGE and ENVISION, this SLR underscores the importance of opportune administration of potentially disease-modifying therapies. The onset and impact of neurocognitive and developmental manifestations by the time children are 2-3 years of age support initiating clinical trials of disease-modifying therapies in young children for the greatest potential benefit across the spectrum of Dravet symptoms. Nonetheless, the results also reinforce that the entire Dravet population still has substantial unmet needs that are not addressed with currently available antiseizure medications.
The entire Dravet population still has substantial unmet needs that are not addressed with currently available antiseizure medications.
The results from these initiatives have also reinforced the importance of including clinical trial endpoints related to cognition, communication, motor function, ASD, ADHD and/or other manifestations in addition to seizures. The ENVISION study is helping us determine the appropriate measures to assess those outcomes. Importantly, all three initiatives remind us that Dravet syndrome affects the entire family unit. We need to find endpoints that are meaningful to the whole family, not just the individual. As Lauren, mom to Finn, who is a 7-year-old living with Dravet syndrome, told us, “Dravet syndrome is a whole family syndrome.”
What else is needed to complete the full picture of Dravet syndrome?
DRAVET ENGAGE, ENVISION and this SLR are important pieces of the puzzle. We still need more high-quality, longitudinal data to understand how Dravet syndrome and its manifestations evolve over time, and how it impacts families and healthcare systems. Encoded is part of a broader community dedicated to making strides in these areas. To give just a few examples: an international group of Dravet experts has developed a model2 for predicting the probability of developing Dravet syndrome based on a given SCN1A variant and the age of seizure onset. Additionally, the HORIZONS study (led by Andreas Brunklaus) is planned to follow up with children and adults living with Dravet syndrome in the United Kingdom for 3 years and will further help define the full range and evolution of disease manifestations. Moreover, Encoded and others are working to discover biomarkers that could be used to assess disease progression or the clinical efficacy of new therapies.
We still need more high-quality, longitudinal data to understand how Dravet syndrome and its manifestations evolve over time.
Acknowledgement: Special thanks to our partners at Broadstreet Health Economics & Outcomes Research and SSI Strategy for their support on this publication.
1Sullivan J, Deighton AM, Vila MC, Szabo SM, Maru B, Gofshteyn JS, James ES, Rico S, Zuberi SM. The clinical, economic, and humanistic burden of Dravet syndrome – A systematic literature review. Epilepsy Behav. 2022 Mar 22;130:108661. doi: 10.1016/j.yebeh.2022.108661. Epub ahead of print. PMID: 35334258. https://www.sciencedirect.com/science/article/pii/S152550502200110X?dgcid=coauthor#f0015.
2 Brunklaus A, Pérez-Palma E, Ghanty I, Xinge J, Brilstra E, Ceulemans B, Chemaly N, de Lange I, Depienne C, Guerrini R, Mei D, Møller RS, Nabbout R, Regan BM, Schneider AL, Scheffer IE, Schoonjans AS, Symonds JD, Weckhuysen S, Kattan MW, Zuberi SM, Lal D. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies. Neurology. 2022 Mar 15;98(11):e1163-e1174.