Stellar Zogenix Phase III Epilepsy Data Lift ZX008's Competitive Position

Company is planning to file in the second half with two pivotal studies, but says it is "worth exploring" with the US FDA whether data from the first study could support an application.

Impressive results from Zogenix Inc.'s first Phase III study of ZX008 (low-dose fenfluramine) in the life-threatening epilepsy condition Dravet syndrome are holding up well so far in comparison to the leading drug in the development space – GW Pharmaceuticals PLC 's Epidolex (cannabidiol, or CBD) – and may support an earlier filing than expected.

In a top-line release on Sept. 29 from Study 1, the first of two pivotal trials to report, Zogenix reported strikingly positive data for the drug as an add-on treatment to standard epilepsy therapies.

Study 1 was a randomized, double-blind, multinational study testing two doses of ZX008 (0.8 mg/kg/day and 0.2 mg/kg/day) against placebo in 119 children and adolescents on background therapy. The primary endpoint was a composite of the difference in the mean number of monthly convulsive seizures after 14 weeks of treatment on the 0.8 mg/kg/day dose relative to placebo and compared to baseline.

On this primary endpoint, the drug reduced the mean number of convulsive seizures by 63.9% relative to placebo (p<0.001), the company reported.

The median percent reduction in monthly convulsive seizure frequency was 72.4% for the arm taking ZX008 0.8 mg/kg/day vs. 17.4% for placebo.

"Not only did the clinical trial meet its primary endpoint with a high degree of statistical significance – the magnitude of clinical benefit was better than we expected, and in the ballpark of prior compassionate use studies that conveyed an unprecedented level of benefit," Leerink Partners analyst Paul Matteis said in a Sept. 29 note.

Matteis added that the "magnitude of clinical benefit looks highly meaningful in the context of both Dravet syndrome, and when compared to refractory epilepsy trials more broadly. The 64% reduction in monthly convulsive seizures for the 0.8mg/kg dose of ZX008 is quite large – not only for a sick population such as DS – but also in the context of refractory epilepsy more generally where even a low-teens benefit over placebo has historically been approvable."

Only top-line results from the first pivotal Phase III study are available and cross-trial comparisons are fraught with complications, but what is known at this point suggests the drug may wind up in a strong competitive position relative to other new drugs, notably GW Pharma’s Epidiolex.

In a pivotal study of Epidiolex in 120 children and young adults with Dravet syndrome and drug-resistant seizures, the mean frequency of seizures dropped by 39% vs. 13% for placebo. GW plans to file Epidiolex with FDA in October.

While ZX008 has not been compared head-to-head with GW Pharma's CBD, at first glance the difference relative to CBD is impressive, commented Harry Tracy, president of NI Research, a consultancy specializing in central nervous system disorders.

Zogenix is planning to report top-line results from its second Phase III pivotal trial – Study 1504 – in the first half of 2018 and to submit filings in the US and Europe in the second half of the year.

However, during a Sept. 29 investor call, execs said that whether the first Phase III study alone may support a filing is "worth exploring" with the FDA "as soon as we can."

Zogenix also noted during the call that it has four issued patents in the US that cover the method of use of ZX008 in the treatment of seizures in Dravet syndrome that last until 2033. The company said it is confident of getting orphan drug exclusivity for this indication.

Stock price closed up by 172.23% at $35.05 on Sept. 29.

Secondary Endpoints Hit The Mark

Study 1 appears to have been an all-around success, based on the top-line data. ZX008 demonstrated statistically significant improvements relative to placebo on all secondary endpoints. For example, the lower dose demonstrated a reduction of 33.7%, statistically better performance relative to placebo (p=0.019).

"Collectively, these top-line data suggest a dose-response relationship for ZX008 in the adjunctive treatment of convulsive seizures in Dravet syndrome," Zogenix said.

ZX008 Study 1: Secondary Efficacy Endpoints
Endpoint	ZX008 0.8 mg/kg/day (n=40)	ZX008 0.2 mg/kg/day (n=39)	Placebo (n=40)
Patients with ≥50% reduction in monthly convulsive seizures	70.0% (p<0.001)	41.0% (p=0.001)	7.5%
Patients with ≥75% reduction in monthly convulsive seizures	45.0% (p=0.001)	20.5% (p=0.033)	2.5%
Longest seizure-free interval (median)	20.5 days (p<0.001)	14 days (p=0.011)	9 days

Zogenix also reported that the drug was generally well tolerated. The rate of treatment-emergent adverse events and serious adverse events were 95% for ZX008 at the high dose, 94.9% at the lower dose and 65% for placebo. Serious adverse event rates were similar: 12.5% for the high dose, 10.3% for the lower dose and 10% for placebo.

"Prospective cardiac safety monitoring throughout the study demonstrated no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension," the company said.

The firm has not yet analyzed long-term safety data from its long-term, open-label safety trial (Study 1503), but a data safety monitoring committee has been reviewing data on an ongoing basis for the entire program, including that dataset, and they continue to report they are not seeing anything unexpected based on the known safety profile of fenfluramine and have not advised trial modifications, Chief Medical Officer Bradley Galer told the call.