GW Pharmaceuticals looks to be on the verge of an important label expansion for its cannabinoid drug Epidiolex, having scored in a pivotal study of tuberous sclerosis complex patients. And the success puts even more ground between GW and its struggling competitor Zogenix.
The big question, however, will be toxicity: the latest trial tested higher Epidiolex doses than ever before, eliciting elevations in the liver enzyme alanine aminotransferase. GW stressed, however, that it saw no cases to which Hy’s law applied, ruling out the threat of liver toxicity-induced death in this small study at least.
The trial enrolled 224 subjects, and tested two Epidiolex doses, 25mg/day and 50mg/day, against placebo. The approved Epidiolex strength, in the childhood epilepsy conditions Dravet syndrome and Lennox-Gastaut, is only 10mg/day, and previous studies had taken the drug up to 20mg.
As such safety was always going to be key (Zogenix’s pain is GW Pharma’s gain, April 9, 2019). GW said 12% of the 25mg subjects experienced elevations in the liver enzyme at greater than three times the upper limit of normal, while in the higher dose this amounted to 25%, versus none in patients given placebo.
Hy’s risk low?
The relevance of this degree of liver enzyme elevation is that it is one of three components needed to satisfy Hy’s law, a rule of thumb that suggests when a patient is at high risk of death due to drug-induced liver injury. As well as ruling out Hy’s law GW said there were no deaths in this study.
As for efficacy, each Epidiolex dose comfortably beat placebo according to the trial’s primary endpoint, 16-week seizure frequency, which fell from baseline by 47.5-48.6%, versus a 26.5% reduction for placebo (p=0.0018 and 0.0009 for the two doses).
Such a result is particularly impressive given that all participants were allowed to remain on background therapy, which averaged three antiepileptic drugs per patient; subjects had on average failed four such treatments.
Tuberous sclerosis complex is a rare type of childhood epilepsy that is distinct from Dravet and Lennox-Gastaut in that it causes benign brain tumours that result in very severe seizures. These tend to be focal in type, and affect a limited area of the brain, as opposed to generalised seizures that affect the whole brain. As such, Epidiolex’s success in Dravet and Lennox-Gastaut was no indication of its chances against tuberous sclerosis complex.
|Sellside consensus for Epidiolex|
|Use||Status||2024e sales ($m)|
|Tuberous sclerosis complex||Filing due end 2019||260|
|Treatment-resistant epilepsy||Phase III||1,141|
|Rett syndrome||Phase III||17|
|Source: EvaluatePharma sales by indication.|
Epidiolex was first launched for Dravet and Lennox-Gastaut last June, but according to EvaluatePharma sellside consensus 2024 sales for tuberous sclerosis complex will nearly match both of these uses combined. The biggest indication remains general treatment-resistant epilepsy, which is already an off-label Epidiolex use, and in which an expanded-access programme is under way.
Epidiolex’s chances look particularly bright since an embarrassing procedural mistake last month resulted in a US refuse-to-file letter for Zogenix’s rival project, Fintepla, in Dravet. This morning GW opened up 8% while Zogenix was off 1%.
Zogenix is to report first-quarter financials tomorrow, and investors will mainly want to know how close the group is to resolving the filing snafu. The risk of a further delay must be allayed, especially if GW succeeds in persuading regulators that Epidiolex’s liver toxicity risk is manageable.