ARTICLE IN BRIEF
Investigators reported at the AAN Annual Meeting that adjunctive everolimus therapy demonstrated a clinically and statistically significant reduction in seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex.
VANCOUVER—Using everolimus in addition to other antiepileptic drugs (AEDs) reduces refractory partial-onset seizures related to tuberous sclerosis complex (TSC), a rare condition that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin, according to a new study presented here in April at the AAN Annual Meeting.
The findings from the Novartis-sponsored phase 3, double-blind international trial of the mTOR-inhibitor suggest a potential new approach for the hard-to-treat seizures that are often seen in patients with TSC. About four out of five TSC patients experience seizures, and about three out of five develop seizures that are resistant to treatment, the study researchers noted.
In the new study, the investigators randomized more than 360 patients into three groups: 130 received a higher dose, 9 to 15 ng/mL of everolimus, along with their other antiepileptic drugs (AEDs), 117 received a lower dose, 3 to 7 ng/mL with their other AEDs, and 119 received placebo with their AEDs.
Response rates yielded similar effects: seizure frequency was reduced by at least half in 28 percent of those in the lower dose group, by 40 percent in the high-dose group, and by 15 percent in the placebo group.
The study's principal investigator Jacqueline A. French, MD, FAAN, professor of neurology at New York University Langone Medical Center, noted that the enrolled patients had been heavily treated at baseline. Approximately half of the participants had failed six or more AEDs before enrolling, and about half were taking three or more AEDs at baseline.
Patients had to be on one to three AEDs at a stable dose for four weeks before enrollment, as well as through an eight-week baseline phase, she said.
By design, patients were having a high number of seizures at the time of enrollment — averaging at least 16 seizures over an eight-week baseline period; the median number of seizures was nearly 40 per month.
“At the time the trial was designed it was thought that we had to have patients with a high seizure burden in order to identify patients who would benefit from this particular type of therapy,” Dr. French explained.
She also noted that existing treatments are ameliorating symptoms, not the underlying illness. “The current treatment options that are available for them are not treating the underlying dysfunction, and that unfortunately is true of many of the patients with epilepsy, or essentially all the patients with epilepsy that we treat,” she said. “We're treating with neuronal stabilizers and other things that reduce seizures — they're antiseizure drugs but they are not, in fact, antiepilepsy drugs.”
In TSC, mutations in either the TSC1 or TSC2 gene are known to cause the downstream effect of dysregulation of the mTOR (mechanistic target of rapamycin) pathway. Everolimus, already available for other indications, inhibits the pathway and essentially helps bring the mTOR pathway back in line.
“This is a very different approach where we're actually identifying an underlying alteration in the brain and specifically targeting that alteration, thereby potentially giving an antiepilepsy therapy, rather than just an antiseizure therapy,” Dr. French explained.
About 17 percent of patients in the low dose group had grade 3 or 4 adverse events, as did 23 percent of those who were on the higher dose. Stomatitis, mouth ulceration, and diarrhea were the most common problems. Nonetheless, only five of 119 dropped out of the lower dose arm, and seven of 117 dropped out from the higher dose arm.
Not many people dropped out due to these adverse events, because they were able to manage them, Dr. French said, adding that both the stomatitis and mouth ulceration can be treated.
Hematologic and biochemical adverse events were also fairly common: 37 percent of those in the higher dose group experienced neutropenia compared with 23 percent in the placebo group, and 85 percent in both dose groups experienced hypercholesterolemia, compared to 58 percent in the placebo arm.
“These are things we don't usually see with antiepileptic drugs and we will have to be looking out for them as we use everolimus for this particular indication,” Dr. French said.
She suggested that the effects of everolimus in TSC might signal that it could play a role in treating other forms of epilepsy as the knowledge of the biology continues to grow.
“We are now learning more and more about the mTOR pathway and this association with epilepsy in general,” she said. “As we learn more, we find that there are more causes of epilepsy that relate to abnormalities in the mTOR pathway, including most importantly some focal cortical dysplasias, particularly ones associated with alterations of the DEPDC5 gene — there's been a lot of discussion about that recently — as well as hemimegalencephaly and other forms of focal cortical dysplasia. And we're probably gong to be learning more about disruptions that produce different types of epilepsy.”
Patients had the option to move into an extension phase of the trial — and nearly all of them chose to do so — in which patients were initially converted to an intermediate dose, after which investigators could choose the dose.
Natalia Rost, MD, MPH, FAAN, associate director of acute stroke services at Massachusetts General Hospital, who moderated the session in which the new data were presented, asked about an unusual data point that showed that more patients on the lower dose became seizure-free than those on the higher dose.
Dr. French said she doubted that it was “a real difference,” adding: “We hope that as patients proceed into the open-label extension that we will maybe see more seizure-free patients, particularly when other drugs can be adjusted and modified and patients can be on the drug longer.”
DR. JACQUELINE A. FRENCH: “This is a very different approach where we're actually identifying an underlying alteration in the brain and specifically targeting that alteration, thereby potentially giving an antiepilepsy therapy, rather than just an antiseizure therapy.”
Kimford J. Meador, MD, FAAN, clinical director of the Stanford Comprehensive Epilepsy Center, said the study findings are exciting, especially since these patients can be difficult to treat because many are resistant to standard AEDs.
“The results are very promising. Everolimus is very interesting as it is a completely different approach to the treatment of seizures,” Dr. Meador said, adding that the data presented suggested that the side effects would be manageable in many patients.
“Of course, the findings need to be reproduced, and ultimately, we need to see how the treatment works in large numbers in clinical practice,” he said. “There are some other conditions that may also benefit from everolimus treatment, so studies for these disorders need to be done.”
Elaine C. Wirrell, MD, professor of neurology at Mayo Clinic in Rochester, MN, who specializes in pediatric epilepsy, agreed that these patients with intractable focal epilepsy present a big treatment challenge. “Some patients with TSC may be candidates for resective epilepsy surgery. However, many are not,” she said, “as they have multifocal epilepsy, or have seizure onset in an eloquent region, with high risk of neurological deficits with surgery.”
“Given its mechanism of action as an mTOR inhibitor, I am very interested in the potential ability of this agent to modify epileptogenesis in TSC,” she continued. “If that is true, using this agent earlier rather than later in the course [of treatment] may be more efficacious, and this question deserves further study.”
EXPERTS: ON ADJUNCTIVE EVEROLIMUS FOR SEIZURES IN TUBEROUS SCLEROSIS COMPLEX
DR. KIMFORD J. MEADOR: “The results are very promising. Everolimus is very interesting as it is a completely different approach to the treatment of seizures... Of course, the findings need to be reproduced, and ultimately, we need to see how the treatment works in large numbers in clinical practice.”
DR. ELAINE C. WIRRELL: “Given its mechanism of action as an mTOR inhibitor, I am very interested in the potential ability of this agent to modify epileptogenesis in TSC. If that is true, using this agent earlier rather than later in the course [of treatment] may be more efficacious, and this question deserves further study.”