Phase 3 of Potential Lennox-Gastaut Syndrome Therapy Underway

Mathew Shanley

ZX008, a potential adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS), is currently being evaluated in a Phase 3 clinical trial.

Zogenix, Inc., the developers of the drug, announced this morning that the first child was enrolled in the company’s study for its lead investigational therapy. The Phase 3 follows a Phase 2 open-label, dose-finding investigator-initiated clinical trial, of which results were presented at the 70th Annual Meeting of the American Epilepsy Society last December.

Change in the amount of seizures that result in drops between baseline and the combined titration and maintenance periods at the 0.8 mg/kg/day dose is serving as the primary endpoint of the clinical trial. Fundamental secondary endpoints include change in the number of seizures that result in drops between baseline and the combined titration and maintenance periods at the 0.2 mg/kg/day dose, as well as the percentage of patients achieving a 50% reduction in drop seizures.

LGS, or childhood epileptic encephalopathy, is a life-threatening iteration of epilepsy with no known cause, and seizures that most frequently begin before a patient turns 4 years old. The types of seizures vary from patient-to-patient, however, often include tonic, atonic, atypical absence, and myoclonic seizures. The condition can also be characterized by mental retardation or regression and abnormal findings on electroencephalography (EEG).

In the Phase 2, 13 subjects were enrolled and 54% (n=7) achieved at least a 50% reduction in the number of major motor seizures, with a range of 50%-90% improvement. Additionally, there was an estimated increase in the number of responders on a dose of 0.4 mg/kg/day compared to 0.2 mg/kg/day. Dose escalation was stopped when a patient’s major motor seizure frequency was reduced by 50% of baseline or more.

“There is a significant need for new medicines that can substantially reduce seizure activity in LGS, and I am hopeful that this Phase 3 trial of ZX008 may offer hope to the children and adults living with this debilitating condition,” said Associate Professor Kelly Knupp, M.D., MSCS, FAES of Children’s Hospital Colorado, and Principal Investigator of the U.S. arm of the trial in a press release.

The Phase 3 is targeting a total of 225 patients to be enrolled in 85 sites across North America, Europe, Asia-Pacific, South America, South Africa, and Australia, and it will be divided into 2 parts; the first being a double-blind, placebo-controlled investigation to evaluate the safety, tolerability and efficacy of ZX008, low-dose fenfluramine, when added to a patient’s current anti-epileptic therapy. The two dose levels to be studied include 0.2 mg/kg/day and 0.8 mg/kg/day, up to a maximum daily dose of 30 mg, both compared to placebo. After baseline seizure frequency is established for 4 weeks, randomized patients will be titrated to their dose over a 2-week titration period, followed by a 12-week fixed dose maintenance period.

Part 2 of the clinical trial will be a 12-month open-label extension to evaluate the long-term safety, tolerability and effectiveness of the potential therapy.

“Following the recent positive top-line results from our first Phase 3 clinical trial for ZX008 in Dravet syndrome, the initiation of this Phase 3 program in LGS represents another important clinical milestone for our ZX008 development program in intractable childhood-onset epilepsy syndromes,” said Gail M. Farfel, Ph.D., Chief Development Officer of Zogenix. “Based on these results, as well as those from the investigator-initiated study led by Professor Lagae, we are excited to evaluate the potential of ZX008 as a safe and effective treatment for children and adult patients with LGS.”

In January 2016, Zogenix received Fast Track Designation from the U.S. Food and Drug Administration (FDA) for ZX008 indicated for the treatment of seizures associated with Dravet Syndrome. In June, the company received Orphan Drug Designation for the prospective therapy as it pertains to LGS.

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