Studies Investigate 2 Doses of Fenfluramine in Dravet Syndrome

Joseph Sullivan, MD

Low-dose fenfluramine, previously known as ZX008, has shown success in its clinical development for Dravet syndrome thus far, and in September, drug manufacturer Zogenix resubmitted its new drug application (NDA) to the FDA for the treatment of seizures associated with the rare epilepsy. The application, which is supported by data from a pair of phase 3 clinical trials and an interim analysis of an ongoing open-label extension study, was previously rejected by the agency in April after it determined that the NDA was not sufficiently complete to permit a substantive review.¹

The pivotal clinical trial program launched with studies 1501 (NCT02682927) and 1502 (NCT02826863), both of which evaluated the efficacy and safety of 2 doses of fenfluramine (0.2 mg/kg/d and 0.8 mg/kg/d) versus placebo as adjunctive therapy in pediatric and young adult patients with Dravet syndrome (FIGURE 1).²

The trials included patients aged 2 to 18 years with a clinical diagnosis of uncontrolled Dravet syndrome. The patients must have had a minimum number of convulsive seizures per 4-week period over the 12 weeks prior to screening, and they had to be on a stable antiepileptic regimen for at least 4 weeks prior to screening.

Individuals were excluded if they had pulmonary arterial hypertension, a current or past history of cardiovascular or cerebrovascular disease or glaucoma, or moderate or severe hepatic impairment, as well as if they were receiving concomitant therapy with centrally acting anorectic agents, monoamine-oxidase inhibitors, serotonin-acting agents, atomoxetine, or other centrally acting noradrenergic agonists, cyproheptadine, and/or CYP 2D6/3A4/2B6 inhibitors/substrates. Treatment with carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin within the last 30 days was merit for exclusion as well.

“Study 1501 was initiated in 2015 as the first of our 3 double-blind, randomized, placebo-controlled trials in Dravet syndrome,” Gail M. Farfel, PhD, executive vice president and chief develop- ment officer, Zogenix, told NeurologyLive®. “Due to slow enrollment, the data from patients who entered the trial by April 2017 were combined with data from an identical trial, Study 1502, and reported as Study 1 on September 30, 2017. The results of Study 1 showed that ZX008 decreased seizures by 63.9% over the placebo treatment, a dramatic improvement.”²

Farfel added that Study 1 also featured a pair of novel end points, which provide evidence of the therapy’s efficacy in Dravet syndrome. “A key secondary end point was the duration of the longest interval of seizure freedom for each patient, [and the results] showed that the median longest seizure-free interval for patients treated with the high dose of ZX008 was 21 days, compared with 9 days on placebo,” she said.

A second phase 3 trial, Study 1504 (NCT02926898), was initiated later in 2016 and included 87 patients (aged 2 to 18 years) who were randomly assigned to receive adjunctive fenfluramine 0.5 mg/kg/d (n = 43) or placebo (n = 44). After completing a 6-week observation period, patients were titrated to their target dose (maximum daily dose 20 mg/kg/d) over 3 weeks and then continued on that fixed dose for 12 weeks. Top-line results reported in July 2018 showed that patients who received the study drug achieved a 54.7% greater reduction in mean monthly convulsive seizures versus placebo (P <.001), with a median reduction in convulsive seizure frequency of 62.7% compared with 1.2% in the placebo group.3 Notably, all patients were on a stable stiripentol regimen during the course of the study.

Additional data are currently being collected from Study 1503 (NCT02823145), which is the open-label extension study available to patients who participated in studies 1501 or 1502 (FIGURE 2). Patients who are eligible for continuous treatment for an extended period of time may enroll in the 36-month study, which also includes a 2-week postdose period. Patients enrolled in the trial will be titrated to an effective dose, with a maximum dose of 30 mg/kg/d.

Interim data from Study 1503that were included in the NDA showed a 66.8% median reduction in monthly convulsive seizure frequency over the treatment period, with 64.4% and 41.2% of patients demonstrating a >50% or >75% reduction in seizure frequency, respectively. Notably, reductions in seizure frequency were recorded at 1 month and continued throughout the treatment period (median duration of treatment, 256 days).⁴

Joseph Sullivan, MD, director of the University of California San Francisco Pediatric Epilepsy Center at Benioff Children’s Hospital, and an investigator in ZX008’s clinical development program, expressed to NeurologyLive® that there is an urgent need for safe, effective, and better-tolerated medicines to control seizures as well as to lower the associated comorbidities. He, along with many of his peers treating these patients, would welcome fenfluramine as an additional option.

“Based on available data, we have seen the potential for fenflu- ramine to reduce seizures in patients with severe epilepsies,” Sullivan said. “As a result, we are encouraged by the clinical data supporting Fintepla. More importantly, the medical community and physicians will have access to more treatment options so they can find what works best for each individual patient.”

Farfel added that in addition to what’s been shown thus far in fenfuramine’s clinical development, data presented at the 2019 Child Neurology Society (CNS) Annual Meeting, in Charlotte, North Carolina, showed additional notable improvements in other measures, suggesting a potential independent drug effect on self-regulation.⁵

“[As presented] in CNS poster 36, the Brief Inventory of Executive Function scale was administered in Study 1 to assess the effect of ZX008 on cognition,” Farfel said. “Improvement in seizures was associated with improvements in physical, social, school, and psychosocial functioning, which is important during development.”

Also presented at CNS 2019 were data on fenfluramine’s effect on tonic-clonic (TC) seizures in this patient population, which has been similarly successful.⁶ Those data included 206 patients and evaluated 3 different doses: a low dose of 0.2 mg/kg (n = 39), a medium dose of 0.5 mg/kg (n = 43), and a high dose of 0.8 mg/kg (n = 40), compared with placebo (n = 84). Fenfluramine was administered as adjunctive treatment to current antiepileptic drug regimens.

The median baseline monthly frequency of generalized TC seizures ranged from 8.0 to 12.3/month in the 4 dose groups. The frequency decreased by 80%, 64%, and 48% in the fenfluramine 0.8, 0.5, and 0.2 mg/kg/d groups, respectively, compared with 10% in the placebo group. Focal-to-bilateral TC seizures were experienced by fewer patients, with a median baseline frequency of 2.0 to 4.7 per month. As with generalized TC seizures, focal-to-bilateral TC seizure frequency was reduced by 97%, 33%, and 69% in the fenflu- ramine 0.8, 0.5, and 0.2 mg/kg/d groups, respectively, compared with a 39% reduction in the placebo group.⁶

“The magnitude, consistency, and durability of seizure reduction that Fintepla has shown in the pivotal phase 3 trials and ongoing open-label extension study highlights it as a promising potential new treatment option,” Sullivan said. “Both pivotal trials have demonstrated that Fintepla is safe, effective, and well tolerated, with a significant reduction in monthly convulsive seizure frequency compared with placebo seen in a majority of patients. These findings further support the potential of Fintepla to transform the treatment paradigm for Dravet syndrome patients and their families.”

REFERENCES

1. Zogenix resubmits New Drug Application for FINTEPLA for the treatment of Dravet syndrome to U.S. Food and Drug Administration [news release]. Emeryville, CA: Zogenix, Inc; September 26, 2019. globenewswire.com/news-release/2019/09/26/1921144/0/en/Zogenix-Resubmits-New- Drug-Application-for-FINTEPLA-for-the-Treatment-of-Dravet-Syndrome-to-U-S-Food-and-Drug- Administration.html. Accessed November 10, 2019.

2. Zogenix announces positive top-line results from pivotal phase 3 clinical trial of ZX008 in Dravet syndrome [news release]. Emeryville, CA: Zogenix, Inc. September 29, 2017. zogenixinc.gcs-web. com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-pivot- al-phase-3. Accessed November 19, 2019.

3. Zogenix announces positive top-line results from second pivotal phase 3 clinical trial of ZX008 in Dravet syndrome [news release]. Emeryville, CA: Zogenix, Inc. July 12, 2018. zogenixinc.gcs-web. com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-second-piv- otal-phase. Accessed November 10, 2019.

4. Zogenix Announces Positive Phase 3 Trial Results on the Efficacy and Safety of FINTEPLA (ZX008) in Dravet Syndrome [news release]. Emeryville, CA: Zogenix, Inc. December 3, 2018. zogenixinc. gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-phase-3-trial-re- sults-efficacy-and. Accessed November 19, 2019.

5. Bishop KI, Gioia GA, Isquith PK, Morrison G. Relationships between self-regulation and quality of life: results from a phase 3 study of ZX008 (fenfluramine HCl oral solution) in children and young adults with Dravet syndrome. Presented at: 48th Annual Meeting of the Child Neurology Society; October 23-25, 2019; Charlotte, NC. Poster 36.

6. Devinsky O, Cross JH, Gil-Nagel A, et al. ZX008 significantly reduces frequency of generalized tonic- clonic seizures in Dravet syndrome: pooled analysis from two phase 3 clinical trials. Presented at: 48th Annual Meeting of the Child Neurology Society; October 23-25, 2019; Charlotte, NC. Poster 41.