Drugs that aim to relieve clinical symptoms of tuberous sclerosis complex

Review question

Can rapamycin or rapalogs reduce the severity of clinical symptoms in people with tuberous sclerosis complex?

Background

Tuberous sclerosis complex is a genetic disease caused by mutations in TSC1 or TSC2 genes that affects several organs such as the brain, kidneys, heart, lungs and skin. The incidence is one in approximately 6000. Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (USA Food and Drug Administration) and EMA (European Medicines Agency) for tumours associated with tuberous sclerosis complex (renal angiomyolipoma and subependymal giant cell astrocytoma), the use of these drugs for treating other symptoms of the condition has not yet been established. This review aims to bring together clinical trials in this area to establish the clinical value of rapamycin and rapalogs for various symptoms of tuberous sclerosis complex.

Search date

The evidence is current to: 15 July 2022.

Study characteristics

The review included 10 studies with 1008 people with tuberous sclerosis complex aged between three months and 65 years of age. However, one study involved five people with sporadic lymphangioleiomyomatosis (without tuberous sclerosis complex) who we could not remove from the analysis. Studies compared rapamycin or rapalogs with placebo (containing no active ingredient) and people were selected for one treatment or the other randomly. The duration of the studies was variable. Two studies were funded by Novartis Pharmaceuticals.

Key results

Oral everolimus (rapalog) increased the number of people who achieved a 50% reduction in the size of subependymal giant cell astrocytoma and renal angiomyolipoma, as well as 25% and 50% reduction in seizure frequency. Oral everolimus also showed benefit in terms of response to skin lesions. However, those who received the systemic treatment probably had a higher risk of experiencing any adverse events as compared to those who did not receive treatment. More people receiving the systemic treatment had severe adverse events and adverse events that cause them to withdraw from the trial, temporarily stop treatment or reduce their dose compared to people receiving placebo.

Topical rapamycin increased the proportion of people who reported response to any skin lesions and probably facial angiofibroma. Absence of topical rapamycin increased the proportion of people who reported deterioration to any skin lesions. The topical rapamycin was also shown to increase improvement score and satisfaction. However, those who received the topical treatment probably had a higher risk of experiencing any adverse events, but not severe adverse events, compared to those who did not receive treatment.

Certainty of the evidence

All of the included studies generally showed a low risk of bias in study design. Four of these studies showed high risk of bias in a few areas of study design, such as whether participants knew if they were given the treatment or placebo and incomplete data in the final analyses. In eight of the studies, we need important information from trial authors in several study design areas in order to make quality judgements on those areas, such as whether people knew which group they would be put into, whether participants knew if they were given the treatment or placebo, whether research personnel knew if participants receive the treatment or placebo, whether the person who assess the effect of intervention knew if participants receive the treatment or placebo, and incomplete data in final analyses. In eight studies, some authors who are employees, stock owners, consultants, or received grants from the manufacturers of the investigational products were involved in the study design, discussion, research, overseeing of data collection and data analysis and interpretation. These studies were also supported by manufacturers of the investigational products.

The evidence from studies using systemic administration showed mixed levels of certainty. We found high-certainty evidence for 50% reduction in the size of renal angiomyolipoma, response to skin lesions, and adverse events. Outcomes related to 50% reduction in the size of SEGA, frequency of seizure, and number of participants with increased creatinine level were judged as having moderate-certainty evidence. Outcomes related to participants' well-being were of low-certainty evidence.

The evidence from studies using topical administration also showed mixed levels of certainty. We found high-certainty evidence for improvements in any skin lesions. We found moderate-certainty evidence for adverse events. Outcomes on response to facial angiofibroma, cephalic plaque, and participants' well-being were of low-certainty evidence.

Authors' conclusions: 

Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo.

Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events.

With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.

Read the full abstract...
Background: 

Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.

Objectives: 

To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.

Search strategy: 

We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences.

Date of the last searches: 15 July 2022.

Selection criteria: 

Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.

Data collection and analysis: 

Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.

Main results: 

The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies.

Systemic administration

Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence).

Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence).

Topical (skin) administration

Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in the placebo arm reported a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; 1 study; 164 participants; high-certainty evidence). More participants in the intervention arm responded to facial angiofibroma at one to three months (RR 28.74, 95% CI 1.78 to 463.19; P = 0.02) and three to six months (RR 39.39, 95% CI 2.48 to 626.00; P = 0.009; low-certainty evidence). Similar results were noted for cephalic plaques at one to three months (RR 10.93, 95% CI 0.64 to 186.08; P = 0.10) and three to six months (RR 7.38, 95% CI 1.01 to 53.83; P = 0.05; low-certainty evidence). More participants on placebo showed a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; P < 0.0001; 1 study; 164 participants; moderate-certainty evidence). The intervention arm reported a higher general improvement score (MD -1.01, 95% CI -1.68 to -0.34; P < 0.0001), but no difference specifically in the adult subgroup (MD -0.75, 95% CI -1.58 to 0.08; P = 0.08; 1 study; 36 participants; moderate-certainty evidence). Participants in the intervention arm reported higher satisfaction than with placebo (MD -0.92, 95% CI -1.79 to -0.05; P = 0.04; 1 study; 36 participants; low-certainty evidence), although again with no difference among adults (MD -0.25, 95% CI -1.52 to 1.02; P = 0.70; 1 study; 18 participants; low-certainty evidence). Groups did not differ in change in quality of life at six months (MD 0.30, 95% CI -1.01 to 1.61; P = 0.65; 1 study; 62 participants; low-certainty evidence).

Treatment led to a higher risk of any AE compared to placebo (RR 1.72, 95% CI 1.10, 2.67; P = 0.02; 3 studies; 277 participants; moderate-certainty evidence); but no difference between groups in severe AEs (RR 0.78, 95% CI 0.19 to 3.15; P = 0.73; 1 study; 179 participants; moderate-certainty evidence).