DSF recently announced funding for a Longitudinal Dravet Syndrome Natural History Study led by Dr. Kelly Knupp with The Dravet Lifespan Multidisciplinary Clinic at Children’s Hospital Colorado. Today’s blog explores the importance of understanding the natural history of a disease, ways natural history data are collected, and an overview of some of the past and current efforts to detail the natural history of Dravet syndrome.
The natural history of a disease refers to the symptoms experienced by patients, how those symptoms present or change over time, and the extent to which the symptoms impact the patient. A Natural History Study seeks to gather the information needed to describe the various aspects of the disease.
A clear picture of the natural history of a disease can help to:
- Identify key signs and symptoms of a disease, improving clinical recognition and early diagnosis;
- Understand the long-term outcomes for patients;
- Provide insights into how (or if) available interventions and therapies impact outcomes, which can guide clinical care plans;
- Investigate if certain factors like demographics, genetics, and other factors correlate with patient outcomes;
- Reveal knowledge gaps in understanding of the disease;
- Determine which symptoms are measurable with existing clinical tools, which can impact not only clinical care but also be useful in clinical trials for new therapies;
- Provide data that can serve as an external data source to compare to patients in interventional clinical trials for new therapy development.
There are several ways a Natural History Study can be approached, but there are two main categories: retrospective and prospective.
Retrospective Natural History Studies gather existing data and information, usually from electronic medical records (EMR). This type of study is much less burdensome to patients, generally just requiring signing consents and indicating where records are held. Retrospective studies are generally less costly than prospective studies, although extensive data processing and analysis is necessary to transfer raw information from the EMR into consistent, comparable data. Despite these advantages, there is some drawback to retrospective studies of natural history data. Clinical-level information is not always gathered in a consistent manner, information can be missing, gathered infrequently depending on medical appointments, or recorded differently across institutions making it difficult to compare the data. As an example, you may be able to see a patient with Dravet syndrome started and later discontinued a medication, but you may not know the reasons for discontinuation- it could be for a lack of seizure control, side effects that were not tolerable, or issues with accessibility of a therapy. To try to reduce the impact of some of the missing or inconsistent information, a very large number of participants are required to feel confident in the trends identified from retrospective data.
Prospective Natural History Studies gather information from patients over time in a consistent and standardized manner. Large numbers of patients are still required, particularly if there is variability in how patients’ symptoms present, but because the data is more consistent and controlled, it does not require as many patients as a Retrospective Natural History Study. Participants in a Prospective Natural History enroll and symptoms are measured regularly over time; the longer and more detailed the study, the more insights that may be gained. Data may be collected from visits to medical providers for assessments, as well as surveys or questionnaires that are completed by the medical professional and/or the participant or their caregiver. Patient registries may also be used to collect regular, prospective information from participants, and may be used alone or in combination with a clinical study to gather natural history data.
Several recent efforts are working to build upon what is already known about the natural history of Dravet syndrome.
In a recent example of gathering retrospective natural history data, DSF recently provided funding to the Dravet Genome Study led by researchers at the Children’s Hospital of Philadelphia. This study aims to collect samples from 500 patients with SCN1A-related epilepsy for whole genome sequencing. The researchers are also collecting clinical data from participants’ electronic medical records for comparison to the genetic information. In addition to providing direct insights into the relationship between clinical presentation and genetics, it will also generate a large amount of retrospective natural history data from those medical records that can be used to strengthen our understanding of Dravet syndrome and related epilepsies. [The Dravet Genome Study is still enrolling- you can learn more about the study and how to participate here.]
Companies that are developing therapies which hold the potential to modify the clinical course of Dravet syndrome have also looked to gather insights into the natural history of Dravet syndrome to inform their therapeutic development. Encoded Therapeutics led the ENVISION study, which was a prospective, observational study that followed patients for up to two years with SCN1A mutations and a diagnosis of Dravet syndrome who enrolled at the age of 5 years or younger. Similarly, Stoke Therapeutics led the BUTTERFLY study, which was similar but included participants from 2 to 18 years of age to enroll. The data generated from such studies informed which measurement tools might be most effective to use in clinical studies testing new therapeutics, as well as provided a comparison to participants in early stages of those interventional trials to give insights into potential efficacy. Natural History Studies can be incredibly helpful for regulators, like the US FDA, to make decisions about experimental therapeutics and to assess the data outputs from clinical trials by providing additional context about the typical course of a disease.
Academic and clinician-led efforts to collect natural history data are also underway. With support in-part from DSF, the SCN1A Horizons Study is enrolling up to 400 children and adults with SCN1A-related epilepsies for a Prospective Natural History study that is led by expert healthcare professionals across several centers in the United Kingdom with an initial goal to follow the patients for 3-years. Many of the assessments used in the BUTTERFLY and ENVISION studies are kept consistent with measurements in this study to ensure that data can be compared in the future to form a more comprehensive picture.
To continue to build upon these data sets, DSF elected to fund Dr. Kelly Knupp to begin the Longitudinal Dravet Syndrome Natural History Study. This study will follow children and adults with Dravet syndrome to track symptoms like seizures, behavior, development, sleep, appetite, autonomic symptoms, and motor function. The study will result in a large database of information from standardized clinical, neuropsychological, and parent-reported data on key signs and symptoms to provide insight into Dravet syndrome across the lifetime. The study has been designed to be comparable to the other similar natural history efforts, such as the Horizons study in the UK. The recently established Dravet Lifespan Multidisciplinary Clinic at Children’s Hospital of Colorado is an excellent environment to support this kind of prospective natural history study in a context that also provides the benefit of expert multidisciplinary medical care to the participating patient families.
DSF remains committed to strategically advancing research for Dravet syndrome in ways that will most robustly benefit the broad patient community. Investing in this new effort to further document and build datasets that characterize the natural history of Dravet syndrome aligns with DSF’s strategic priorities and will support the future of research, clinical care, and drug development for Dravet syndrome.
You can learn more about the Longitudinal Dravet Syndrome Natural History Study and other research DSF has funded here.
