On February 6th, Zogenix announced that the FDA had granted “breakthrough therapy” designation to ZX-008 (low-dose fenfluramine), its Phase III drug for seizures associated with Dravet Syndrome (DS), a rare form of epilepsy.1 This status is granted to drugs that are intended “to treat a serious or life-threatening condition” and “may demonstrate substantial improvement over existing therapies.” Although there may be some debate about whether all drugs granted this status ultimately fulfill the “breakthrough” promise, I do believe that ZX-008 will truly be a breakthrough for DS, and here’s why:

No drugs are approved for DS in the United States and only one is approved in Europe. Diacomit (stiripentol) is approved in Europe, but only in combination with valproic acid and clobazam, and interviewed experts report that ~30% of DS patients do not respond to or cannot tolerate Diacomit. The lack of proven alternatives means that neurologists treating patients with DS have to choose among a range of untested off-label antiepileptic drugs (AEDs), often with limited success, because…

DS is a highly treatment-refractory condition. Few clinical studies have been conducted for DS, but available literature suggests that marketed AEDs are insufficient for most DS patients - a conclusion substantiated by the high rate of treatment-refractoriness in this population.2-3 Neurologists often have to try multiple options and prescribe combination regimens; for example, DS patients recruited for a recent Phase III trial of GW Pharma’s Epidiolex had, on average, already tried five AEDs and were taking three concomitant AEDs at baseline.4 Thus, it was a momentous day when…

ZX-008 demonstrated outstanding efficacy in a pivotal Phase III trial in DS. Treatment-refractory DS patients taking the higher of two tested doses (0.8 mg/kg/day) experienced a significant reduction in monthly convulsive seizures compared to placebo after 14 weeks (mean: 64% placebo adjusted; median: 72% for ZX-008 vs. 17% for placebo).5 Moreover, a significantly greater proportion of ZX-008-treated patients achieved a >50% or >75% reduction in convulsive seizures (70% and 45%, respectively, vs. 7.5% and 2.5% for placebo), and 7.5% of patients became seizure-free. Crucially, ZX-008 was also safe and generally well tolerated.

Neurologists will inevitably compare ZX-008’s results to those of GW Pharma’s Epidiolex, a highly anticipated cannabidiol product also in development for rare epilepsy syndromes.4 Epidiolex was tested in a similar population as ZX-008 and demonstrated a significant 39% median reduction in monthly convulsive seizures (vs. 13% for placebo), and 43% of patients experienced a >50% reduction in convulsive seizures (vs. 27% for placebo). The limitations of cross-trial comparisons are well established, but as one U.S. KOL explained in November 2017:

“Typically, for most epilepsy placebo-controlled trials, you’re looking at a 20% improvement in the placebo group compared to a 35-40% improvement in the treatment arm. The efficacy for ZX-008 is an amazing number if it’s higher than 60% - that’s a really high number. The natural tendency would be to think that you have a superior drug, but though this is a placebo-controlled trial, it’s not a head-to-head comparison against anything else out there. There are limits to that kind of comparison, but this does invite the kind of thinking that ZX-008 may be a more effective drug.”

Zogenix is currently conducting a second Phase III trial for ZX-008 in DS and expects results in Q2 2018. If the company files for approval in the United States and Europe by the end of 2018, ZX-008 could be available to DS patients next year. In addition to breakthrough status in the United States, ZX-008 has also been awarded orphan drug designation in the United States and Europe and fast-track status in the United States; these designations will likely pave the way for priority review. This would put ZX-008 hot on the heels of Epidiolex, which is fast approaching a PDUFA date in June 2018 but could be slowed down by DEA scheduling.

Of note, ZX-008 is also in development for Lennox-Gastaut syndrome (LGS), another rare form of epilepsy; the pivotal Phase III trial is expected to complete in December 2019. I am hopeful that ZX-008 will be as successful in these patients, which would suggest the drug may have broad antiseizure efficacy. If it does, there will likely be considerable use of ZX-008 off-label across multiple epilepsy syndromes, not just in DS and LGS.

All in all, it promises to be a landmark year in the epilepsy space. We’ll be posting here again throughout the year, so stay tuned…

 

References:

  1. Zogenix announces receipt of FDA breakthrough therapy designation for ZX008 in Dravet syndrome [press release]. February 6, 2018.
  2. Wirrell EC. Treatment of Dravet syndrome. Can J Neurol Sci. 2016; 43: S13-S18.
  3. Kassai B, et al. Severe myoclonic epilepsy in infancy: A systematic review and a meta-analysis of individual patient data. 2008; 49(2): 343-348.
  4. Devinsky O, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017; 376:2011-2020.
  5. Lagae L, et al. ZX-008 (fenfluramine HCL oral solution) in Dravet syndrome: Results of a Phase 3, randomized, double-blind, placebo-controlled trial. Poster presented at: 71st Annual Meeting of the American Epilepsy Society; December 2017, Washington DC. Available online here.

 

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