Facial angiofibromas are a major feature of TSC and can be seen in at least 80% of people with the condition. This study investigates the use of a shelf-stable topical cream containing rapamycin (an mTOR inhibitor) to treat facial angiofibromas in people with TSC.
About this study
Using rapamycin in a cream or gel form that can be applied to the skin has already been found to be effective in treating facial angiofibromas. Other earlier studies have shown that this method is well-tolerated by patients and doesn’t require invasive procedures.
One challenge with topical forms of rapamycin is that they can be difficult to produce in a way that keeps the medication stable. Rapamycin can break down, making the product less effective. Because of this, most topical formulations have a short shelf life and need to be refrigerated during transport and storage.
In this Phase II/III, double-blinded, randomised, placebo-controlled clinical trial, researchers compared the effectiveness and safety of two different strengths (1% and 0.5%) of a new rapamycin cream that has been formulated to remain stable. This stability is achieved through the cream’s base, which protects the rapamycin molecules from breaking down easily. The cream can stay stable at room temperature conditions (around 25°C/60% relative humidity) for up to 36 months. This study aimed to assess the cream’s effectiveness and safety compared to a placebo over 26 weeks of daily use.
How the study was conducted
The study involved 107 patients aged 6 to 65 who are living with TSC and had mild to moderate angiofibromas. The patients applied either rapamycin cream (0.5% or 1%) or a placebo cream daily for 26 weeks – the patients did not know which they were applying. Clinical assessments were made at various intervals. Adverse events, blood rapamycin concentration and tolerability were also monitored.
Outcomes of the study
- Investigator’s Global Assessment (IGA): IGA is a method used by researchers to evaluate and assess a person’s overall condition or response to treatment. The researchers found that 60.6% of the people using 1% rapamycin and 55.6% of those using 0.5% rapamycin saw at least a one-grade improvement. In comparison, only 23.7% of the placebo group experienced this level of improvement. This indicates a meaningful improvement for those using the rapamycin creams.
- Facial Angiofibroma Severity Index (FASI): The FASI is a scale to evaluate the extent and severity of facial angiofibromas. In this study, both 1% and 0.5% rapamycin creams resulted in significantly improved FASI scores compared to placebo.
- Percentage Improvement Scores: The 1% rapamycin group reported an average subjective improvement score of 54.1%, while the 0.5% rapamycin group had a score of 57.1%. In comparison, the placebo group had an average subjective improvement score of 30.8%. Objective improvement scores were also significantly higher in the rapamycin groups.
- Categorical Improvement: Both rapamycin treatment groups had a higher percentage of participants reporting improvement from baseline as ‘moderately’ or ‘significantly’ better compared to the placebo group.
- Adverse Events: Adverse events like skin burning sensation, itching, redness, and dry skin were more frequently reported by patients using rapamycin than those using the placebo. However, no serious adverse events were linked to the application of the rapamycin cream. Additionally, there were no clinically significant changes observed in various health parameters like blood tests or urine tests in both the rapamycin treatment groups and the placebo group. In another clinical trial, a gel formulation of 0.2% rapamycin applied to the skin showed detectable levels of rapamycin in blood tests. In this study, at the end of treatment, no participant had detectable levels of rapamycin in their blood, suggesting that the effect of the cream formulation used in this research was localised to the skin.
Limitations of the study
The study faced challenges like a low recruitment rate due to TSC’s rarity and the impact of the COVID-19 pandemic. The researchers used the IGA scale as the main assessment tool – it wasn’t initially designed for facial angiofibroma assessment. There was a possibility that patients could guess their group assignment, although dropouts were infrequent and consistent across groups. Results indicated that stopping treatment quickly reversed its benefits, suggesting that ongoing treatment might offer more improvements.
Further research with larger sample sizes and longer treatment durations may provide more insights into the sustained benefits of rapamycin cream.
Important implications of the study
This study suggests that both 1% and 0.5% rapamycin creams are well-tolerated and lead to significant improvements in facial angiofibromas associated with TSC. The findings support the use of topical rapamycin as a potential non-invasive treatment option for facial angiofibromas, offering a meaningful benefit to patients with this condition.
The authors state that due to the cream only acting locally there is a potential for safe use of this cream alongside oral mTOR inhibitors. The lack of systemic absorption found in this study minimises the risk of drug interactions with anti-seizure medications prescribed in TSC.
Currently the topical rapamycin formulations that are available are pharmacy-compounded. Most are only stable for a short time and require refrigeration. The cream used in this study is designed to be stable at room temperature for many years. And, now that we have the results of a Phase II/III, double-blinded, randomised, placebo-controlled clinical trial (the most rigorous level of trial), an application is being made in Australia for TGA (Therapeutics Goods Administration) approval. In the near future this will hopefully lead to this type of rapamycin cream being available on a commercial scale with listing on the Pharmaceutical Benefits Scheme (PBS).
Aitken, P., Stanescu, I., Boddington, L., Mahon, C., Fogarasi, A., Liao, Y.-H., Ivars, M., Moreno-Artero, E., Trauner, D., DeRoos, S. T., Jancic, J., Nikolic, M., Balážová, P., Price, H. N., Hadzsiev, K., Riney, K., Stapleton, S., Tollefson, M. M., Bauer, D., … Atkinson, H. (2023). A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: A double-blinded, randomised, placebo-controlled trial. British Journal of Dermatology, ljad243.
Abstract available at: https://doi.org/10.1093/bjd/ljad243
Full paper available at: https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljad243/7226135?login=false
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.
TSA would like to acknowledge and thank all the health care professionals and patients who participated in this important trial, particularly those at Queensland Children’s Hospital and Christchurch Hospital in New Zealand.
TSA would also like to acknowledge AFT Pharmaceutical’s support of the trial and its work to hopefully make this cream more widely available.