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Research News: October 2016

A selection of recently published articles with a focus on high impact and Australian TSC research. Summaries written by Kate Fessey and Clare Stuart. This article was first published in the October 2016 issue of Reach Out, TSA’s twice-yearly magazine.

Long-Term Use of Everolimus in Patients with TSC

New evidence supporting the efficacy and safety of Everolimus (an mTOR inhibitor medicine) as a treatment for TSC associated SEGA has been published from the long-term EXIST-1 Study. This has added to the evidence for the effectiveness of long-term Everolimus use and the benefits of using Everolimus compared with placebo to treat growing SEGAs.

Why are we concerned about SEGA?
SEGA are a type of benign tumour, meaning they are not cancerous (do not spread to other parts of the body). They can be a cause of harm and death in TSC patients. As they grow, they can block the flow of fluid in the brain.

Findings of the study
The trial has shown Everolimus can be an effective treatment option for symptomatic, growing SEGAs. Whilst some patients might not initially respond to Everolimus, a response might be achieved with continued exposure, as demonstrated in the trial with the number of patients who had a reduction in SEGA volume over time.
This study has confirmed that Everolimus can be a safe and effective long-term therapeutic option for patients with TSC-associated SEGA, and it has also shown that Everolimus may also reduce the risk for clinical complications of SEGA, such as hydrocephalus.

Limitations of the study
More testing is required to assess the long-term implications of Everolimus treatment and to fully assess the effects in the wider manifestations that have been associated. Further research is also required to guarantee there are no long-term effects of mTOR inhibitors on growth and sexual maturation. But existing clinical data does not indicate that these areas are impacted by long term use of Everolimus, showing no association with growth disturbances and no impact on sexual maturation.
Any adverse effects that did appear were generally quite minor like ulcers and usually occurred in the first year of treatment. These were managed by dose adjustment or interruption. No new safety concerns were raised through this longer term analysis and all safety results obtained during this long-term study remained consistent with those previously reported in TSC-associated clinical settings with Everolimus.

Franz, D.N., et al., Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study. PLoS One, 2016. 11(6): p. e0158476.

Tuberous Sclerosis Complex Associated with Vascular Anomalies or Overgrowth

Australian TSC researchers have co-authored a study regarding the associations between TSC and vascular anomalies or overgrowth, motivated by a significant underreporting in this area.

Findings of the study
The study has shown that vascular anomalies and asymmetric growth may be more frequent in people with TSC than previously appreciated. Five cases are reported in this paper across three centres in Australia, Canada and USA.

It is conceivable that the same mTor pathway dysregulation that stimulates tumor formation in TSC could also be driving vascular anomalies and limb overgrowth. The coexistence of these conditions in several cases has provided an opportunity to assess the response to inhibition of mTOR and thus provided further evidence that the mTOR pathway is significant in some cases of overgrowth and vascular anomalies.

The results of the study highlight the potential for the use of mTOR inhibition in these cases. In the study, six patients with complicated vascular anomalies that had been unmanageable by other measures were successfully treated using sirolimus.

Jenkins, D., et al., Tuberous Sclerosis Complex Associated with Vascular Anomalies or Overgrowth. Pediatr Dermatol, 2016. 33(5): p. 536-42.

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

This trial examined the use of Everolimus in people with TSC for whom existing treatment options had failed to control their focal epilepsy.

What the study looked at
The 366 patients in this trial were between 2 and 65 years old and recruited from 99 centres in 25 countries. This included a number of patients in Australia and Dr John Lawson from Sydney Children’s Hospital is an author on the research paper. The patients were divided into three groups: one received low dose of the medicine; one received high dose of the medicine; one received placebo (sugar pill). A seizure diary was used to record how frequently the person had seizures both before and during the 18 week treatment.
All patients in the trial were on at least one anti-epileptic medication and remained on their medications throughout the study.

Findings of the study

The study reported the percentage of patients who had a 50% or greater reduction in their seizure frequency. Overall the study found Everolimus treatment did reduce seizure frequency. Actual percentages in the three groups are shown below, along with their 95% confidence interval and the number of people in the group):

  • Placebo group: 15.1% (9.2 – 22.8%; n=18);
  • Low dose 28.2% (20.3 – 37.3%; p=0.0077; n=33);
  • High dose 40.0% 31.5-49.0% p<0.0001; n=52).

The study also showed an increase in seizure free days for those on treatment and that the effects of the medicine increased over time.
Adverse events (side effects) were monitored and were similar to previous studies of this medicine in people with TSC. These included mouth ulcers, diarrhoea, inflammation and infections.

Limitations of the study
The study looked at short-term effectiveness only. The participants in the trial will continue to be monitored to improve our understanding of the effectiveness and side effects of the medicine.
The study was designed to collect information on patient behaviour but this was not possible due to the chosen tool not being suited to patients with substantial intellectual disability. Lastly, the differences between low and high dose were not as large as intended. This raises the possibility that an even higher dose of the medicine may be useful in patients that do not experience a benefit.

French, J.A., et al., Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet, 2016.

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