Zogenix looks to have capped a remarkable September for biotech stocks, joining Alnylam with a knockout phase III result that hit primary and key secondary efficacy measures.
For Zogenix the data related to its lead asset, Fintepla, in a rare childhood epilepsy called Dravet syndrome, and the hotly awaited readout sent the group’s stock up 140% this morning. The immediate loser was GW Pharmaceuticals, whose own Dravet asset is further advanced, but whose regulatory filing has been delayed; GW opened off 13%.
Both companies had already received a boost when Zynerba’s cannabinoid gel ZYN002 – a concept similar to GW’s Epidiolex – flunked a phase II trial in adult epileptics with focal seizures (GW approaches crunch time, August 8, 2017). Zynerba had an arguable success yesterday with ZYN002 in fragile X syndrome.
There appears to be little doubt about Zogenix’s Dravet data, however, with Fintepla’s 0.8mg/kg/day dose cutting mean convulsive seizure frequency – the trial’s primary endpoint – by 63.9% versus placebo between baseline and 14 weeks.
The group did not provide the absolute seizure numbers in the two groups, but said the lower dose, 0.2mg/kg/day, also hit statistical significance, and both doses hit key secondaries including proportion of patients achieving greater than 50% reductions in monthly convulsive seizures, and comparisons in seizure-free intervals.
Importantly, there was a dose-response relationship in the endpoints that Zogenix disclosed. The trial, Study 1, was a pool of two placebo-controlled phase III tests called 1501 and 1502, and comprised 119 subjects between two and 18 years old.
With the caveat of the unreliability of across-trial comparisons, which might be affected by different baseline patient characteristics, another Zogenix secondary endpoint – median reduction in monthly seizure frequency – suggests that Fintepla has a stronger effect versus placebo than GW’s Epidiolex.
|Fintepla vs Epidiolex 14-week data|
|Project||Study||Endpoint||Active dose||Placebo||p value||Baseline seizure frequency||Trial ID|
|Fintepla||Study 1||Median reduction in monthly convulsive seizure frequency*||72.4%||17.4%||Not disclosed||~40 (mean)||NCT02682927|
|Epidiolex||GWPCARE1||Median reduction in monthly convulsive seizures**||39%||13%||p=0.01||13 (median)||NCT02091375|
|Note: *Secondary endpoint, 6-week baseline period; **primary endpoint, 4-week baseline period.|
Certainly it appears that Zogenix managed to recruit into its trial some patients who responded extremely strongly to Fintepla and drove the overall benefit. This can be seen in the company’s presentation of treatment-free interval data, which shows large differences between mean and median numbers.
For now Zogenix says it will await data from a separate trial, 1504, before submitting a US filing. While this puts Zogenix on track to file in the second half of 2018 – GW’s Epidiolex rolling submission is due to be completed next month – Zogenix said on today’s analyst call that it would discuss the latest results with the regulator.
Repurposing old drugs
Beyond an efficacy hit that confirms earlier single-arm trials, perhaps the most interesting aspect of the data is that they lend support to a new mechanism of action in epilepsy.
Fintepla is nothing more than repurposed, low-dose fenfluramine, a 5-HT reuptake inhibitor and sigma-1 receptor modulator. Biotech investors with long memories will remember fenfluramine as one half of the Wyeth Fen-Phen anti-obesity combo that was withdrawn in 1997 after being linked to heart valve problems.
Naturally, Zogenix was keen to highlight the lack of cardiac valvulopathy or pulmonary hypertension seen with Fintepla, though in a study this short perhaps this was not a surprise. Zogenix also said it was planning to start a phase III trial by the end of this year in Lennox-Gastaut syndrome, another form of childhood epilepsy for which GW is also filing Epidiolex this year.
With positive pivotal data now in, perhaps the biggest worry for Zogenix bulls will now be their company’s ability to defend patents on a drug as old as fenfluramine.