Everolimus has long-term efficacy in tuberous sclerosis complex

SAN DIEGO – Everolimus reduces the frequency of epileptic seizures in patients with tuberous sclerosis complex (TSC), and its effect appears to gain strength over time. By the end of an extension study, half of patients had at least a 31.7% reduction in seizure frequency at 18 weeks, and that percentage rose to 56.9% at 2 years.

The drug was chosen because it inhibits mammalian target of rapamycin (mTOR), which plays a central role in protein synthesis, cell division, and other vital processes. In patients with TSC, the kinase is overactive, and this leads to abnormalities in brain development. Overall, 85% of TSC patients experience seizures, and 60% are refractory to antiepileptic drugs.

The success of everolimus (Afinitor) is encouraging, and it’s the first epilepsy drug to be chosen for its mechanism of action, David Neal Franz, MD, said in an interview. “It has been used off label, but this study really shows that it has a statistically significant benefit that improves over time. A lot of things are used off label, but most don’t have this kind of class II evidence to support being used,” said Dr. Franz, who presented the study at the annual meeting of the American Neurological Association.

The drug was particularly effective in children, who experienced a greater reduction in seizure frequency over time. That suggests that earlier treatment with everolimus could counter some of the damage in these patients before it becomes entrenched. “We’re planning to do studies to evaluate that. Because if you can avoid intractable epilepsy and its effects on development, there’s the potential to have a very significant benefit for children,” said Dr. Franz, who is a professor of pediatrics and neurology and founding director of the Tuberous Sclerosis Clinic at the University of Cincinnati. He noted that some previous studies showed that early treatment of infantile spasms is associated with lower risk of intellectual disability and autism.

The study enrolled 361 TSC patients with epilepsy across a wide age range (2-65 years). Their epilepsy had remained uncontrolled following treatment with at least six previous drugs. The core phase of the trial lasted 18 weeks, followed by an extension phase in which patients in the placebo group were switched to everolimus with a target dose of 3-15 ng/mL.

The primary efficacy outcome was the change in weekly seizure frequency. The researchers defined a response as a 50% or higher reduction.

In the original pivotal trial (EXIST-3), 15.1% of patients on placebo responded (95% confidence interval, 9.2%-22.8%) at week 18, compared with 28.2% of patients receiving a 3-7 ng/mL dose of everolimus (95% CI, 20.3%-37.3%; P = .0077) and 40% of patients receiving a 9-15 ng/mL dose of everolimus (95% CI, 31.5%-49%; P less than .0001).

The response rate at 18 weeks of treatment when combining both the original everolimus-treated patients and also the group switching over to everolimus in the extension phase was 31% (95% CI, 26.2%-36.1%). By 1 year, 46.6% had responded (95% CI, 40.9%-52.5%), and 57.7% had responded at 2 years (95% CI, 49.7%-65.4%).

The median percentage reduction in seizure frequency rose from 31.7% at week 18 (95% CI, 28.5%-36.1%) to 46.7% at 1 year (95% CI, 40.2%-54.0%) and 56.9% at 2 years (95% CI, 50%-68.4%).

Younger patients experienced greater improvements over time. At 2 years, 76% of 101 patients aged 0-6 years had responded (95% CI, 58.8%-88.2%), compared with 58.5% of patients aged 6-12 years (95% CI, 44.1%-71.9%), 51.1% of patients aged 12-18 years (95% CI, 35.8%-66.3%), and 43% of patients 18 years and older (95% CI, 24.5%-62.8%).

A sensitivity analysis of patients who discontinued the drug and were categorized as nonresponders showed the drug was still associated with a risk reduction of 30.2% at week 18 (95% CI, 25.5%-35.2%), 38.8% at 1 year (95% CI, 33.7%-44.1%), and 41% at 2 years (95% CI, 34.6%-47.7%).

Adverse events declined over time from 76.1% during the first 6 months of treatment to 46.8% at 1 year and 45.2% at 2 years. A total of 40.2% of patients experienced grade III/IV adverse events, and 13% of patients discontinued medication as a result. Another 1.7% experienced pneumonia, and 1.4% experienced stomatitis.

The most concerning side effects noted were tied to infection risk, which was not surprising given that everolimus is an immunosuppressive agent that is also used to prevent organ rejection. “The good thing is that you can hold everolimus when patients get sick or have a fever, and it doesn’t immediately lose efficacy. It binds avidly to mTOR, and so you can often go several weeks off the drug before you see loss of seizure control,” Dr. Franz said.

The study was funded by Novartis. Dr. Franz has received travel funding and honoraria from Novartis.