Real-world evidence study on the long-term safety of everolimus

About this study

The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety study that assessed the long-term safety of everolimus in patients with TSC in the European Union.

The secondary aims of the study were to look at associated TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility.

Data was collected from March, 2013 until January 2020. There were 136 study participants who completed the study: 30 children and 106 adults.  55.9% of the participants had SEGAs, 83.2% had AMLs and 84.4% had epilepsy.

How data was collected

This was an observational study – no specific visit schedules were mandated.  No clinical, instrumental, or laboratory assessments/interventions were performed other than those required for disease management during routine clinical management of patients. The recommended frequency of data collection was 3-monthly intervals, with a minimum of once-yearly follow-up visits.

Outcomes of the study

Pleasingly, there were no new safety concerns for everolimus identified. Over the course of the study, two-thirds of patients reported adverse events, but most of these were treatable with dosage adjustments or additional medications.

Overall, 67.6% of study participants reported Adverse Events (AEs).  The most frequent AEs reported were stomatitis-mouth soreness and mouth ulcers (14.5%) and high cholesterol (6.1%).  AEs were reported more frequently in children, approx. 69% vs 33% in adults.   The authors speculated that this might be because children are more thoroughly monitored, and that some children may have needed a lower dosage.  Under-reporting of AEs in the adult population also cannot be ruled out.  The rates of AEs reported were similar between males and females.

Severe infections – an identified risk of everolimus – were reported in 35.8% of patients. These included common cold, pneumonia, UTI, bronchitis, influenza.  6% of patients reported AEs that led to discontinuation of sirolimus; the authors note this was lower than discontinuation rates reported in other studies.

Secondary aims

The researchers found that as in previous studies there was low reporting of TAND evaluation which is suggestive of under diagnosis and treatment of TAND in clinical settings.  The limited data collected did not suggest abnormal sexual development or reproductive issues for individuals taking everolimus, and overall, the available data was not indicative of delays in sexual maturation.


The results from this TOSCA study show that everolimus has a well- documented and acceptable safety profile in TSC.  Despite AEs being reported, everolimus is regarded by health professionals as a valuable treatment option in TSC.  AEs were managed with a combination of treatment breaks and dosage changes.

However, given the observational nature of the study and the fact that only data already available from clinical practice were collected, the authors recommend that additional larger studies are needed.

Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results.Ruiz-Falcó Rojas ML, Feucht M, Macaya A, Wilken B, Hahn A, Maamari R, Hirschberg Y, Ridolfi A, Kingswood JC.Front Pharmacol. 2022 Apr 8;13:802334. doi: 10.3389/fphar.2022.802334. eCollection 2022.PMID: 35462939 Free PMC article.

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This information is intended to provide some insights into recent TSC-related research.  It is not intended to, and it should not, constitute medical or other advice.  Readers are warned not to take any action without first seeking medical advice.