Precision medicine is rapidly advancing in the treatment of rare genetic epilepsies, with early trials of antisense oligonucleotide (ASO) therapies showing promising results. These personalized treatments aim to address the underlying genetic causes of epilepsy, offering potential for disease modification and improved seizure control. However, the high cost of these therapies presents a significant hurdle to widespread adoption.
ASO Trials Demonstrate Efficacy
Several ASO trials are underway, targeting specific genetic mutations responsible for various forms of epilepsy. Stoke Therapeutics announced results from a Phase 1/2a trial involving 19 clinically evaluable patients with Dravet syndrome. The data revealed that patients receiving a single 70 mg dose of the ASO experienced a median reduction in convulsive seizure frequency of 43% at three months and 57% at six months. Furthermore, patients who received two or three doses at 70 mg showed an even more substantial median reduction of 85% at three months and 74% at six months. The FDA has cleared the use of three 70 mg doses followed by ongoing dosing at 45 mg.
Another ASO, PRAX-222, developed by Praxis Precision Medicine, targets early-onset SCN2A developmental and epileptic encephalopathy, which is caused by a gain-of-function mutation in the SCN2A gene. Early results presented at the 2023 American Epilepsy Society meeting showed that four patients treated intrathecally with PRAX-222 once a month for four months experienced a 43% median reduction in seizures from baseline and a 48% increase in seizure-free days, with no serious adverse events. Praxis Precision Medicine plans to expand the trial to enroll 60 patients.
The Challenge of Cost and Accessibility
Despite the encouraging results, the exorbitant cost of ASO treatments, estimated at no less than a million euros per patient, raises concerns about accessibility. Pasquale Striano, MD, professor of pediatric neurology at the University of Genoa and Gaslini Children's Hospital, emphasized the financial burden, stating, "We are speaking about treatments that cost no less than a million euros per patient... I don't think the public is prepared to afford this cost."
To maximize benefits and mitigate the costs associated with standard treatments, experts advocate for genetic screening at birth to identify patients early in the disease process. Renzo Guerrini, MD, professor and chair of child neurology and psychiatry at the University of Florence in Italy, believes that personalized genetic treatments are more promising than the traditional one-size-fits-all approach, stating, "Producing a drug for epilepsy that is going to be prescribed to millions of people around the world is an illusion... Now my attitude is very positive, because we are pursuing the opposite: personalized medicine that targets a precise genetic mutation."
Preparing for the Future of Precision Epilepsy Treatment
Medical centers are proactively preparing for the integration of ASO therapies into clinical practice. Juliet K. Knowles, MD, assistant professor of neurology at Stanford University, noted, "We're working hard at Stanford to get our infrastructure ready to handle these patients... There is a lot of careful monitoring you have to do with them. The whole medical team has to be knowledgeable about how they work."
Neurologists are encouraged to consider genetic testing early in the diagnostic process, especially in children with epilepsy. Daniel Friedman, MD, professor of neurology at New York University Grossman School of Medicine, advises, "Neurologists should have a very, very low threshold for suspecting a genetic cause of epilepsy, especially in children... Some people think that genetic testing would be the option of last resort. That's driven by the idea that there's not much you can do about these disorders—a view that will grow only more outdated with time."
While genetic testing and N-of-1 studies hold immense promise, potential pitfalls exist, such as variants of unknown significance. Careful interpretation and functional characterization are crucial to ensure appropriate treatment decisions. As the field advances, ongoing research and collaboration will be essential to optimize the use of ASO therapies and improve outcomes for patients with genetic epilepsies.
