After receiving a refusal to file letter and undergoing a Type A meeting with the FDA, Zogenix has announced that it plans to resubmit an NDA for fenfluramine (Fintepla) for the treatment of seizures associated with Dravet syndrome in Q3 of 2019.
Stephen J. Farr, PhD
Zogenix announced that it has received the final minutes from the FDA following a Type A meeting on its investigational treatment for Dravet syndrome, fenfluramine (Fintepla), and has reported that it intends to resubmit its new drug application to the agency in the third quarter of 2019.1
The meeting followed a refusal to file letter which the FDA sent to Zogenix regarding fenfluramine (also known as ZX008) in which 2 issues were identified—the lack of non-clinical data on the chronic administration of the treatment and an incorrect dataset included in the application. Zogenix president and CEO Stephen J. Farr, PhD, expressed his satisfaction with the meeting in a company statement.
“After discussion with the FDA, the agency has let us know that they do not require additional chronic toxicity studies as part of the resubmission of our NDA for FINTEPLA for the treatment of seizures associated with Dravet syndrome,” Farr told NeurologyLive®
. “Rather, they have agreed to our plan to re-submit with all data from our drug development program, along with clinical and non-clinical literature related to fenfluramine. The resubmitted NDA will include some scientific literature that was not part of our original NDA submission.”
The resubmission will also feature additional data from the available literature which was not originally included, and Zogenix noted that a discussion between it and the FDA narrowed down the root cause regarding the inclusion of the incorrect dataset.
“If approved, FINTEPLA could provide profound seizure reduction that does not wane over time in Dravet syndrome patients, many of whose seizures remain uncontrolled even on multiple existing anti-epileptic drugs,” Farr said. “Dravet syndrome is a rare, difficult to treat, and often catastrophic disease that is associated with frequent and prolonged seizures and significant intellectual and motor disabilities. Patients living with Dravet syndrome require constant care, causing tremendous negative impacts on the entire family’s quality of life. We’re very excited to be advancing FINTEPLA as a potential new treatment option for these patients.”
Previously, fenfluramine was granted a breakthrough therapy designation, which has since been rescinded due to the recent approval of 2 therapies for the treatment of Dravet syndrome. Zogenix stated that it “does not expect the rescission of breakthrough therapy designation to limit the potential for priority review status (6-month review) for the Company’s resubmitted NDA.”
One of those therapies, stiripentol, was studied alongside fenfluramine in the Zogenix clinical development program, in which patients who received both therapies in an add-on regimen experienced a 54.7% greater reduction in mean monthly convulsive seizure frequency compared to patients adding placebo (P
<.001). With the second of those therapies, cannabidiol (CBD), there were no comparisons available.
The original NDA, submitted in February 2019, was backed by data from 2 phase 3 trials in Dravet syndrome as well as an interim analysis from a still ongoing open-label extension study. The extension included 232 patients who were treated for up to 21 months with fenfluramine.
In the study with stiripentol, 87 participants were randomly assigned to receive 0.5 mg/kg per day of ZX008 (n = 43) with a maximum dose of 20 mg titrated for 3 weeks or placebo (n = 44) after 6 months of observation. All participants were receiving stable background treatment with stiripentol in addition to other antiepileptic drugs. The investigators reported that fenfluramine demonstrated a median reduction of 62.7% in monthly convulsive seizures compared with a 1.2% reduction with placebo.2
There also improvements reported in the secondary end points, including reductions in convulsive seizures of ≥50% and ≥75%. In all, 53.5% (P
<.001) of participants treated with the Zogenix product reported a reduction in monthly convulsive seizures of ≥50%, while 6.8% reported the same finding with placebo. A ≥75% reduction was experienced by 32.6% (P
=.004) of participants in the fenfluramine arm compared with 2.3% in the placebo arm. Researchers reported that the longest seizure-free interval was 22 days (P
<.005) with fenfluramine and 13 days with placebo.
“Our clinical data has demonstrated profound reductions in convulsive seizures in Dravet syndrome patients who have been refractory to anti-epileptic medications,” Farr told NeurologyLive®
. “And, unlike most other anti-epileptic drugs (AEDs), our long-term data has found that the loss of effect over time does not happen with FINTEPLA. Moreover, fenfluramine is well-tolerated in these children and young adults with minimal drug-drug interactions (which can be quite burdensome for most other anticonvulsant medications).”
Additionally, the therapy was well-tolerated, and no participants experienced cardiac valvopathy or pulmonary hypertension. The rate of serious adverse events (AEs) was similar in both the treatment and placebo arms (14% and 15.9%, respectively). It was reported that 2 participants discontinued treatment due to AEs in the fenfluramine arm.
1. Zogenix Announces FDA Agreement to Proceed with Resubmission of FINTEPLA® NDA [press release]. Emeryville, CA: Zogenix, Inc; Published June 27, 2018. globenewswire.com/news-release/2019/06/27/1875226/0/en/Zogenix-Announces-FDA-Agreement-to-Proceed-with-Resubmission-of-FINTEPLA-NDA.html. Accessed June 29, 2019.
2. Zogenix Announces Positive Top-line Results from Second Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome [press release]. Emeryville, CA: Zogenix, Inc; Published July 12, 2018. globenewswire.com/news-release/2018/07/12/1536420/0/en/Zogenix-Announces-Positive-Top-line-Results-from-Second-Pivotal-Phase-3-Clinical-Trial-of-ZX008-in-Dravet-Syndrome.html. Accessed July 1, 2019.