Long-Lasting Effect of Everolimus in Tuberous Sclerosis

Pauline Anderson

May 11, 2017

BOSTON — Improvements in seizures documented earlier in patients with tuberous sclerosis complex (TSC) taking everolimus (Afinitor, Novartis) in the phase 3 EXIST-3 trial have continued during an open-label extension phase of the trial.

"We see a sustained effect that actually tends to improve over time, so the response seems to improve the longer you take the drug," David Neal Franz, MD, founding director, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital, Ohio, told Medscape Medical News.

During the recent American Academy of Neurology 2017 Annual Meeting (AAN), Dr Franz presented long-term efficacy and safety results for patients who completed at least 48 weeks of the extension phase of the study.

TSC is a rare genetic disorder caused by overactivation of the mammalian target of rapamycin (mTOR) pathway that promotes cell growth. The condition leads to seizures, cortical malformations, and neuronal hyperexcitability. A common feature of TSC is subependymal giant cell astrocytomas (SEGAs).

Everolimus works by "correcting" this underlying genetic defect, said Dr Franz. "This is really a new type of antiepileptic treatment; this does something different than any other drug on the market that treats seizures."

Main results of the EXIST-3 trial of everolimus — an oral agent developed as a cancer drug — were released at the AAN meeting last year (and covered by Medscape Medical News).

The study included 366 patients, median age 10 years, with at least 16 treatment-resistant seizures and receiving 1 to 3 antiepileptic drugs (AEDs) at stable doses. In about half of the patients, 6 or more AEDs had failed before enrollment.

The overall median baseline seizure frequency per 28 days was 37.5.

After an 8-week baseline phase, patients were randomly assigned to receive, in addition to their AEDs, placebo, lower-dose everolimus (3 to 7 ng/mL) or higher-dose everolimus (9 to 15 ng/mL). After a 6-week titration phase, patients completed a 12-week maintenance phase.

Response Rate

The study showed that 15.1% of the placebo group, 28.2% of the low-dose everolimus group (P = .008 vs placebo), and 40% of the high-dose everolimus group (P < .001 vs placebo) attained the primary endpoint of a 50% responder rate.

The percentage reduction in seizure frequency was 14.9% for placebo, 29.3% for low dose (P = .003 vs placebo), and 39.6% for the high dose (P < .001 vs placebo).

Total seizure freedom was achieved by 0.8% of the placebo group compared with 5.1% of the low-dose everolimus group and 3.8% of the high-dose everolimus group.

The three study groups had a similar safety profile. Adverse events were consistent with known risks associated with the drug. The most common ones were stomatitis, diarrhea, mouth ulceration, nasopharyngitis, and upper respiratory tract infection.  

Most of the study patients continued in the 2-year extension phase. During this phase, the blind was broken, and treating physicians determined the dose of everolimus.

Because placebo patients were crossed over at the beginning of the extension phase, their percentage change was not from baseline but after the 18-week core phase.

Response rate at week 18 (corresponding to the 12-week window of weeks 7 to 18 after the start of everolimus) was 31% (95% confidence interval [CI], 26.2% - 36.1%; n = 352) compared with 46.6% (95% CI, 40.9% - 52.5%; n = 298) at 1 year and 57.7% (95% CI, 49.7% - 65.4%; n = 163) at 2 years of everolimus exposure.

Consistent with the trends observed in the response rates, the median percentage reduction in seizure frequency was 31.7% (95% CI, 28.5% - 36.1%; n = 352) at week 18 vs 46.7% (95% CI, 40.2% - 54%; n = 298) at 1 year and 56.9% (95% CI, 50% - 68.4%; n = 163) at 2 years of everolimus exposure.

Sustained seizure reduction was observed across all age groups. The response rate ranged between 26% and 39% after 18 weeks of treatment and between 40% and 53% after 1 year of treatment, for all age groups.

Dr Franz called these new results "very exciting."

The safety of the drug was similar to that reported previously. Again, the most common adverse events were stomatitis, pyrexia, diarrhea, mouth ulceration, nasopharyngitis, and upper respiratory tract infection.

While the overall type, incidence, and severity of adverse events were similar for adults and pediatric patients, infections were reported at a higher frequency and severity in younger children, especially pneumonia (24.8% in children aged 1 to under 6 years)

The study authors noted that at the data cutoff, less than 40% of patients had been exposed to 2 years of everolimus treatment. This, they said, prevents a definitive interpretation of results.

Two patients died during the extension phase, both children. One death was attributed to pneumonia and the other to sudden unexpected death from epilepsy (SUDEP).

"After the data cutoff, there were two additional on-treatment deaths; one attributed to SUDEP and the other to septic shock," said Dr Franz.

Everolimus was approved by the European Medicines Agency in January as an adjunctive treatment in patients whose seizures are associated with TSC. In the United States, in addition to being approved for treating some cancers, the drug is approved to treat patients with TSC who have a type of kidney tumor or SEGA.

Next Generation

In commenting on the new study for Medscape Medical News, Lily C. Wong-Kisiel, MD, assistant professor of neurology, Division of Child and Adolescent Neurology, Mayo Clinic Children's Center, Rochester, Minnesota, said everolimus, a treatment targeted at the disease pathophysiology of tuberous sclerosis, represents the "next generation of precision medicine" for patients with TSC.

Dr Wong-Kisiel noted that the results of the extension study show efficacy and safety of everolimus in patients across different life stages. Inclusion of children is important, she said, because TSC is a genetic disorder with initial seizure presentation during the first year of life.

She also pointed out that the current study shows sustained responder rates over time, without cumulative incidence of adverse events with longer everolimus use.

Although not addressed in this new study, the potential impact of seizure reduction, particularly in young children who showed the greatest median percentage reduction in seizure frequency, may extend beyond seizure reduction, said Dr Wong-Kisiel.

"Many children with TSC have early-onset epilepsy and associated neurocognitive delays. Studies have found early treatment and control of seizures to be associated with better cognitive outcome compared to those with delayed treatment.  Future directions may include reporting on the impact of cognitive effects of those patients treated with everolimus." 

Dr Wong-Kisiel stressed that the current management of TSC-related epilepsy is "less than ideal." AEDs provide seizure-free control in only about a third of patients, with most patients continuing to have frequent seizures despite numerous prior medication trials and use of multiple concurrent AEDs.

She added that although epilepsy surgery can be an option in selected patients with TSC, seizures may persist in a third of these patients. Vagus nerve stimulation and the ketogenic (high-fat, low-carbohydrate) diet offer nonpharmacologic therapies for patients whose epilepsy remains difficult to manage.

Medscape Medical News also asked Gregory D. Cascino, MD, the Whitney MacMillan, Jr, Professor of Neuroscience, Mayo Clinic School of Medicine, Rochester, Minnesota, and past-president of the American Academy of Neurology, to comment on the study. 

The study is important, said Dr Cascino, because it identifies a potential treatment for drug-resistant epilepsy in patients with TSC. Everolimus is an inhibitor of mTOR, and its effect is restricted to the mTORC1 protein complex. The mTOR pathways may be dysregulated in TSC and in several cancers, he said.

The drug is US Food and Drug Administration (FDA) approved for advanced hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer, progressive neuroendocrine tumors of pancreatic origin, advanced renal cell carcinomas, and both renal angiomyolipoma and SEGA with TSC, he noted. Everolimus is also FDA approved as an immunosuppressant in patients undergoing renal transplantation.

Dr Cascino suggested that this is a provocative study because of the significant and sustained reduction in seizure activity in this patient cohort with TSC and intractable epilepsy. "The favorable effect on seizure tendency persisted at 2 years," he said. "Everolimus potentially may be disease modifying in patients with TSC."

He cautioned that everolimus may have significant adverse effects. The drug has been associated with an increased risk for noninfectious pneumonitis, stomatitis, nephrotoxicity, certain infections, venous thrombosis, and the development of selected malignancies. "Importantly, everolimus is very expensive, which may restrict the off-label use of the drug for epilepsy," he said.

Dr Cascino indicated that the outcome of this study provides compelling evidence that drugs with this unique mechanism of action may be effective in reducing seizure tendency in individuals with TSC and drug-resistant epilepsy.

The study was sponsored by Novartis Pharmaceuticals Corporation. Dr Franz reports salary support from Cincinnati Children's Hospital for consulting work, research grants, speaker honoraria, and travel reimbursement from Novartis. Dr Wong-Kisiel has disclosed no relevant financial relationships.

American Academy of Neurology 2017 Annual Meeting (AAN). Emerging Science Platform Session 007. Presented April 25, 2017.

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