GW’s Dravet lock looks broken as Zogenix data scores

Battle in a rare form of epilepsy queued up following positive phase III trial.

Prescribe a novel cannabinoid or an old drug once pulled from the market for safety reasons? This might soon be the choice for neurologists treating children with Dravet syndrome, as phase III data for Zogenix’s low-dose fenfluramine pill ZX008 suggest that it will be a worthy competitor to GW Pharma’s cannabis-derived Epidiolex.

Epidiolex, now approved in the US and awaiting drug scheduling before launch, should have about a year’s lead, but could also serve to prime the pump for competitors as there are no other specific treatments for this rare seizure disorder. Zogenix investors are enthused today, bidding shares up 15% in early trading, as the best-case scenario emerged, of clean safety and similar or better efficacy for ZX008 versus Epidiolex (see table below).

Low dose

Zogenix today reported data from the second of two phase III trials of ZX008, in which the oral fenfluramine solution, taken on top of a backbone of stiripentol, significantly reduced the frequency of seizures when compared with stiripentol alone – this was important for European approval, where the marketed drug is the standard of care in Dravet syndrome.

The trial, called study 1504, showed a difference of 54.7% in mean monthly convulsive seizures for the ZX008 arm versus placebo. ZX008 was taken at a daily dose of 0.5mg/kg, up to a maximum 20mg.

Sizing them up
  Zogenix's ZX008 GW Pharma's Epidiolex
  Study 1504 (background stiripentol, n=87) Study 1* (n=119) GWPCARE1 (n=120)
  0.5 mg/kg/d N=40 (0.8 mg/kg/d)  N=39 (0.2 mg/kg/d)  n=120 (20 mg/kg/day)
% difference from placebo in reduction in mean monthly seizures (primary endpoint) 54.7% (p<0.001) 63.9% (p<0.001) 33.7% (p=0.019) 23% (p=0.01)
Proportion of patients achieving >50% reduction in mean monthly seizures (key secondary) 53.50% 70% 45% 43%
*prospective merged analysis of two identical double-blind, placebo controlled studies conducted in US/Canada and Europe/Australia. Source: Zogenix statements, NEJM for Epidiolex data

The maximum dosage is an important consideration, given that in the wake of the fenfluramine safety scandal of the 1990s, when it was paired with phentermine as a weight-loss regimen, those taking 60mg or more daily were over nine times more likely to suffer valvular heart disease than those taking 40mg or less.

Nevertheless, the cardiovascular safety profile of ZX008 is being closely watched, and will no doubt be a concern of both physicians and patients. This trial revealed no cases of cardiac valvulopathy or pulmonary hypertension; a long-term safety analysis will be part of Zogenix’s US FDA submission, which company executives said would be ready in the fourth quarter of 2018.

Heart or liver

FDA drug reviewers have a long memory, so the safety data will be closely examined. Any risk of cardiovascular side effects will need to be balanced against the risk of seizures in Dravet patients, where a syndrome called “sudden unexplained death in epilepsy” is responsible for nearly half of all premature deaths and status epilepticus another 34%. 

And given that this is a rare form of epilepsy, the reviewers might be more inclined towards approval since not many patients are likely to be exposed to any theoretical or real cardiovascular risk.

Assuming that ZX008 joins Epidiolex on the market sometime next year, the spectre of fen-phen could give the edge to GW. On the other hand, Epidiolex also resulted in some liver enzyme elevations, so it has its own concerns (The smoke clears for Epidiolex, April 19, 2018).

And given that this is a rare form of epilepsy, the reviewers might be more inclined towards approval since not many patients are likely to be exposed to any theoretical or real cardiovascular risk.

Assuming that ZX008 joins Epidiolex on the market sometime next year, the spectre of fen-phen could give the edge to GW. On the other hand, Epidiolex also resulted in some liver enzyme elevations, so it has its own concerns (The smoke clears for Epidiolex, April 19, 2018).

For its part, Zogenix was keen to push what looks like better efficacy with its project. “The strength of our seizure reduction data will be extremely important as we enter the market,” chief executive Stephen Farr said on a conference call. “This condition is treated with a variety of drugs – it will not be a winner-takes-all scenario, all treatments will have a role – but we are very encouraged by our seizure reduction trials.”

If ZX008’s safety profile remains benign it is hard to see how it would not threaten to take a significant chunk of Epiodelex’s market. The sellside seems to believe Zogenix has an edge, but GW will not give up without a fight.

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