VANCOUVER -- The mTOR inhibitor everolimus (Afinitor) diminished seizure frequency in patients with tuberous sclerosis who'd been refractory to other therapy, researchers reported here.
In a phase III randomized controlled trial, seizure frequency was significantly reduced in those on either a high or low dose of the drug compared with those on placebo (about 40% and 29% versus 15%), , of NYU Langone Medical Center, reported at the .
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- The immunomodulatory drug everolimus (Afinitor) diminished seizure frequency in tuberous sclerosis refractory to other therapy, in a phase III, placebo-controlled, randomized trial.
- Everolimus targets the mTOR pathway, hyperactive signaling of which is thought to cause the rare genetic disorder of tuberous sclerosis complex, which affects about one million people globally.
French explained that targeting the mTOR pathway may get at an underlying cause of the disease and could be a disease-modifying therapy.
"It is working on a different aspect from what we've considered to be the pathology of the disease," said , of Harvard, who moderated the session during which the findings were presented. "It is not working on the excitability of the cells, but can we affect the milieu in which cells reside so that they are not sensitizing as much? Being able to modify the disease itself would be very interesting."
Tuberous sclerosis complex, a rare genetic disorder, affects about one million people globally. It is thought to be caused by hyperactive signaling of the mTOR pathway, which can lead to cortical malformations, neuronal hyperexcitability, and impaired synaptic plasticity -- and could ultimately contribute to seizures, French said.
Current treatment options include anti-epileptic drugs, vagal nerve stimulation, surgery, and a ketogenic diet, but these are limited.
To assess whether everolimus could be an additional therapeutic candidate, French and colleagues conducted the EXIST-3 study, a phase III, three-arm, double-blind, placebo-controlled study of the safety and efficacy of high and low doses of everolimus as adjunctive therapy in patients with tuberous sclerosis who have treatment-resistant seizures and are already taking one to three other anti-epileptic drugs.
They enrolled 366 patients who were randomized to either a low or high dose of everolimus (3 to 7 ng/mL or 9 to 15 ng/mL) or to placebo.
The percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to either the low (29.3% P=0.003) or high dose of everolimus (39.6%, P<0.001) compared with placebo (14.9%).
A larger proportion of patients also had at least a 50% reduction in seizures with the low (28.2%, P=0.008) and high dose of the drug (40%, P<0.001) compared with placebo (15.1%).
French said the safety profile was consistent with the established tolerability profile of everolimus in other tuberous sclerosis trials and didn't overlap with the safety profile of conventional anti-epileptic drugs.
The most common adverse events occurring in at least 20% of patients taking everolimus were stomatitis (28.2% and 30.8% versus 3.4%), mouth ulceration (23.9% and 21.5% versus 4.2%), and diarrhea (17.1% and 21.5% versus 5%).
There were also more serious adverse events for those on the drug (13.7% and 13.8% versus 2.5%).
French concluded that the results from EXIST-3, along with existing evidence from treating SEGA and renal angiomyolipoma in patients with tuberous sclerosis, suggest that everolimus may be a disease-modifying therapy for this condition.
An extension phase of the EXIST-3 study is currently ongoing, she added.
, of the University of Missouri, who was not involved in the study, said the work was "very promising."
"It is very difficult to take care of these kids," he told ľֱ. "They have multiple seizures, they develop complications from seizures, and it affects the whole family. Most of the medications we now give are only a symptomatic treatment to try to control the seizures, and we keep adding on. When the third add-on doesn't work, we try the ketogenic diet or vagal nerve stimulation. But it is a downward spiral."
"But now," he continued, "if this acts on the pathology itself, and not just as a bandaid, we could be in a whole new world in epilepsy treatment."
Rost, who is a co-chair of the meeting's scientific program committee, said the work opens the door to the question of whether everolimus could be useful in other seizure disorders.
"Just like we think of inflammatory disorders in general, could a subset of epilepsy disorders be modifiable from that perspective," she told ľֱ.
Disclosures
French disclosed financial relationships with Acorda, Alexza, Anavex, BioPharm Solutions, Concert Pharmaceuticals, Eisai, GW Pharma, Lundbeck, Marinus, Montens, Nestle Health Science, Neurelis, Novartis, Pfizer, Pronutria, Roivant, Sage, SciFluor, SK Life Sciences, Sunovion, Takeda, UCB, Upsher Smith, Vertex, Xenon Pharma, and Zogenix.
Primary Source
American Academy of Neurology
French J, et al "Adjunctive everolimus therapy for the treatment of refractory seizures associated with tuberous sclerosis complex: results from a randomized, placebo-controlled, phase III trial" AAN 2016.