Following the receipt of a refusal to file letter from the FDA, Zogenix has resubmitted its application for fenfluramine hydrochloride (Fintepla), seeking approval for the treatment of seizures associated with Dravet syndrome.
Stephen J. Farr, PhD
After receiving a refusal to file letter from the FDA in April, Zogenix has resubmitted its new drug application (NDA) to the agency for its fenfluramine hydrochloride (Fintepla) agent, also known as ZX008, for the treatment of seizures associated with Dravet syndrome.1
The NDA is supported by 2 phase 3 clinical trials, as well as an interim analysis from an ongoing open-label extension study of 232 patients who have been treated for up to 2 years.
“We believe that Fintepla, if approved, could become an important new treatment option for patients and families living with Dravet syndrome,” said Stephen J. Farr, PhD, President and CEO of Zogenix. “We appreciate the FDA’s guidance through the resubmission process and look forward to continuing to work closely with the Agency during their review of our application.”
While it was under preliminary review, the FDA deemed the NDA to be insufficiently to permit a substantive review, citing 2 reasons for the decision. The first, that certain nonclinical studies were not submitted to allow assessment of the chronic administration of fenfluramine, and the second, that the application contained an incorrect version of a clinical dataset that prevented the completion of the review process.2
Notably, the agency did not request or recommend additional clinical efficacy or safety studies, and Zogenix scheduled a Type A meeting to clarify the issues identified.
In the first of the pair of phase 3 studies, 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. Every participant received a stable background treatment with stiripentol in addition to other antiepileptic drugs. Researchers reported that ZX008 demonstrated a median reduction of 62.7% in monthly convulsive seizures compared with a 1.2% reduction with placebo, in addition to a mean monthly reduction in convulsive seizures of 54.7% compared with placebo.3
Additionally, there were improvements reported in secondary end points. All told, 53.5% (P
<.001) of participants treated with fenfluramine 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 ZX008 and 13 days with placebo.
In this trial, the Zogenix agent was well tolerated and no participants experienced cardiac valvopathy or pulmonary hypertension. The rate of serious adverse effects was similar in fenfluramine and placebo (14% and 15.9%, respectively). It was reported that 2 participants discontinued treatment due to adverse effects in the ZX008 arm.
At the 2018 American Epilepsy Society annual meeting, Joseph Sullivan MD, director of the Pediatric Epilepsy Center at UCSF’s Benioff Children’s Hospital and an investigator in ZX008’s clinical development program, sat down with NeurologyLive in an interview to discuss the treatment’s efficacy profile. He noted that with this therapy, “the efficacy speaks for itself,” adding that “all of these drugs are going to have a side effect profile, but the side effect profile that we saw in the phase 3 programs and that has been confirmed in the open-label extension has shown that it’s a safe and well-tolerated drug.”
These data are also part of the company’s marketing authorization application submission to the European Medicines Agency (EMA), which was previously accepted for review. Zogenix anticipates a potential approval decision from the EMA in the first quarter of 2020. As well, Zogenix is also investigating fenfluramine in Lennox-Gastaut syndrome (LGS), another rare childhood-onset epilepsy, expecting top-line data from its ongoing phase 3 trial in the first quarter of 2020.
1. Zogenix Resubmits New Drug Application for FINTEPLA® for the Treatment of Dravet Syndrome to U.S. Food and Drug Administration [press release]. Emeryville, CA: Zogenix; Published 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 September 26, 2019.
2. Zogenix Receives Refusal to File Letter from U.S. Food and Drug Administration for FINTEPLA® New Drug Application [news release]. Emeryville, Calif.: Zogenix; April 8, 2019. globenewswire.com/news-release/2019/04/08/1799322/0/en/Zogenix-Receives-Refusal-to-File-Letter-from-U-S-Food-and-Drug-Administration-for-FINTEPLA-New-Drug-Application.html. Accessed September 26, 2019.
3. 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 September 26, 2019.