Joseph Sullivan, MD

“In the study, there were a significant higher number of patients that reported very much improved. We feel as though that this is a more of a global assessment of things that are beyond just seizures.”

 annual meeting of the American Epilepsy Society (AES), which took place December 6-10, 2019, in Baltimore, Maryland, Zogenix revealed additional data from their phase 3 clinical trial of fenfluramine, demonstrating a significant reduction in convulsive seizure frequency and improvement in everyday executive function in patients with Dravet syndrome. The FDA had previously accepted the NDA for fenfluramine in November 2019 for the treatment of Dravet syndrome.

The rare, catastrophic form of epilepsy is associated with a significant amount of seizure burden on patients and caregivers, which can have a direct effect on the patient’s quality of life. As one of the lead investigators in the fenfluramine clinical trial program, Joseph Sullivan MD, professor of neurology and pediatrics, and director of the University of California, San Francisco Pediatric Epilepsy Center at Benioff Children’s Hospital, understands the direct impact that fenfluramine, if approved, can have on patients with Dravet syndrome.

 at AES to discuss how fenfluramine can reduce seizure frequency and improve quality of life for patients with Dravet syndrome.

Videos

The professor of neurology and pediatrics and director of the Pediatric Epilepsy Center at the University of California, San Francisco, discussed his personal experience with fenfluramine and the advantages that the drug may present when treating patients with Dravet syndrome.

Joseph Sullivan, MD: The Benefits of Fenfluramine Treatment in Dravet Syndrome  

“A lot of the focus is obviously on seizure reduction because that’s what gets you regulatory approval, but we’re looking at a lot of other secondary measures—the non-seizure related outcomes.”

Fenfluramine HCI oral solution, otherwise known as ZX008, is currently being investigated for the adjunctive treatment of seizures associated with Dravet syndrome. Data from Study, 1, a phase 3 clinical trial of the therapy, was recently reported at the American Epilepsy Society’s annual meeting in New Orleans, Louisiana, which showed a reduction in seizure frequency.

Additionally, an open-label extension study was conducted which showed these benefits extend over the long-term. For Joseph Sullivan, MD, the director of the Pediatric Epilepsy Center at UCSF Benioff Children’s Hospital, these results are incredibly positive, but a “pleasant surprise” for him was the additional finding that some patients experienced an improvement in executive function. 

Although this may be attributable to the reduction in seizures, Sullivan posited that it could also be due to fenfluramine’s mechanism of action. To discuss the findings and the importance of discovering more about mechanisms of action, he sat with NeurologyLive in an interview. 

The director of the Pediatric Epilepsy Center at UCSF Benioff Children’s Hospital discussed the findings and the importance of discovering more about mechanisms of action.

Joseph Sullivan, MD: Fenfluramine's Effect on Executive Function in Dravet Syndrome

“Forty-four was kind of the magic number, so you needed to have a seizure reduction of 44% or greater in order to have a high likelihood of giving that score of 1 or 2.” 

At the American Epilepsy Society’s annual meeting held in New Orleans, Louisiana, Joseph Sullivan, MD, a pediatric epileptologist and Director of the Pediatric Epilepsy Center at UCSF Benioff Children’s Hospital, spoke with 

about a secondary analysis that was conducted to scientifically determine a clinically meaningful change in seizure frequency through data from a phase 3 clinical trial (Study 1) of fenfluramine HCI oral solution (ZX008) for adjunctive treatment of seizures associated with Dravet syndrome. Researchers examined the percentage change in seizure frequency as well as caregiver and investigator ratings of Clinical Global Impression of Improvement (CGI-I).

Participants with Dravet syndrome (N=119) were enrolled in Study 1 and randomized 1:1:1 to placebo, 0.2 mg/kg/day of ZX008, or 0.8 mg/kg/day ZX008, and entered a 2-week titration phase followed by a 12-week maintenance period. The study met its primary endpoint which included participants in the 0.8 mg/kg/day ZX008 arm demonstrating a 63.9% greater reduction in seizure frequency versus placebo. After the 14-week period, caregivers and investigators rated the change in clinical status from baseline using the CGI-I scale where scores of 1 (very much improved) or 2 (much improved) were considered to have achieved a clinically meaningful response, and a score of 3 (minimally improved) was not considered meaningful.

The analysis of the association between percentage change in seizure frequency and CGI-I rated by caregivers or investigators suggests that a 44% reduction from baseline can be considered a clinically meaningful response in patients with Dravet syndrome. Based on these data, 75%, 46%, and 12.5% of participants in the 0.8 mg/kg/day ZX008, 0.2 mg/kg/day ZX008, and placebo groups, respectively, achieved a clinically meaningful reduction in seizure frequency in Study 1. Higher levels of seizure reduction (60%—68%) were associated with ratings of “very much improved.”

Sullivan explained that a 44% reduction reinforces the notion that a 50% reduction in seizures is a clinically meaningful endpoint.

The Director of the Pediatric Epilepsy Center at UCSF Benioff Children's Hospital spoke about what defines a "clinically meaningful change in seizure frequency" using data from a phase 3 clinical trial of ZX008 for the adjunctive treatment of seizures associated with Dravet syndrome.

Joseph Sullivan, MD

Articles

Joseph Sullivan, MD: The Benefits of Fenfluramine Treatment in Dravet Syndrome

Joseph Sullivan, MD: Fenfluramine's Effect on Executive Function in Dravet Syndrome

Joseph Sullivan, MD: Scientifically Determining a Clinically Meaningful Change in Seizure Frequency