Results of a phase III study published in The Lancetshows that more than 40% of patients with Tuberous Sclerosis Complex (TSC) treated with everolimus (Afinitor?/Votubia?; Novartis) had their kidney tumor volume reduced by at least half with no tumor progression. Data from a separate study showed that 35% of TSC patients treated with everolimus had their Subependymal Giant Cell Astrocytomas (SEGA) brain tumor volume reduced by one half or more  and Tuberous Sclerosis Complex (TSC), a genetic disorder, may cause non-cancerous tumors to form in vital organs, including the kidney and brain.
The data published today showed that patients on everolimus tablets with non-cancerous kidney tumors known as renal angiomyolipomas associated with tuberous sclerosis complex (TSC) experienced a significant reduction in tumor size and the absence of tumor progression.  Angiomyolipomas are slow-growing tumors associated with constitutive activation of mammalian target of rapamycin (mTOR). They areare common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. Additionally, a recent issue of The Lancet featured results from a separate everolimus trial demonstrating a reduction in the size of non-cancerous brain tumors known as subependymal giant cell astrocytomas (SEGAs) associated with TSC. 
Wrinting for The Lancet,findings suggest a clear advantage for everolimus over placebo in reducing angiomyolipoma volume with an acceptable safety profile in patients with tuberous sclerosis. 
A rare genetic disorder
Affecting one to two million people worldwide, TSC is a genetic disorder that may cause non-cancerous tumors to form in vital organs, including the kidney and brain. Everolimusused for the treatment of certain patients with TSC, is the first and only medication for adult patients with these kidney tumors associated with TSC who do not require immediate surgery. The drug is also used to tratpediatric and adult patients with SEGAs who require therapeutic intervention but are not amenable to surgery,.
Subependymal Giant Cell Astrocytomas or SEGA, is a rare genetic disease that causes the development and growth of benign tumos throughout the body. In SEGA these tumors are found in the ventricles, the fluid-filled spaces within the brain, where they can obstruct spinal fluid flow and cause neurologic symptoms. The disease occurs, on average, in 1 out of 10 patients with TSC (Tuberous Sclerosis Complex) and generally develops during childhood and adolescence.
“The positive findings of these two trials published in The Lancet represent a significant advance for people living with TSC,” said John J. Bissler, lead EXIST-2 study(EXamining everolimus In a Study of TSC) author and Clark D. West Endowed Chair of Nephrology atCincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. “Rare diseases such as TSC are often overlooked, making publication of these studies important to help further awareness among the medical community, as well as reinforcing the importance of monitoring individuals for this serious and difficult-to-treat condition.”
The Phase III EXIST-2 trial published in The Lancet reported that 42% of patients taking everolimus experienced an angiomyolipoma response versus 0% of patients in the placebo arm (p<0.0001). Everolimus also demonstrated superiority to placebo for both secondary endpoints assessed. Time to angiomyolipoma progression was statistically significantly longer in patients on everolimus versus placebo (p<0.0001). In patients with skin lesions, a key concern for those with TSC, a 26% response rate was seen with everolimus versus 0% with placebo (p=0.0002).
Results from a separate Phase III trial of TSC patients called EXIST-1, also published in a recent issue of The Lancet, showed that 35% of patients with SEGAs associated with TSC treated with everolimus experienced a 50% or greater reduction in SEGA volume versus 0% of patients on placebo (p<0.0001).
Renal angiomyolipomas, or potentially life-threatening kidney tumors, occur in up to 80% of patients with TSC, with typical onset occurring between the ages of 15 and 30 and prevalence increasing with age.
SEGAs occur in up to 20% of children and adults with TSC and may pose a significant medical risk, including the potential for swelling in the brain (hydrocephalus). Everolimus works by inhibiting mTOR, a protein implicated in many tumor-causing pathways. TSC is caused by defects in the TSC1 and/or TSC2 genes . When these genes are defective, mTOR activity is increased and can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism,.
A broad range of diseases
“Novartis has a long-standing commitment to meeting the needs of patients affected by rare diseases, such as TSC, with a focus on understanding the fundamental mechanisms of the underlying condition,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “We strive to improve the lives of these patients with the goal of bringing the right treatment to the right patient across a broad range of diseases, based on patient need, not population size.” Novartis is committed to supporting individuals affected by TSC through therapeutic innovation, patient assistance, disease education and support of advocacy organizations.
EXIST-2 is the first double-blind, randomized, placebo-controlled, international, multicenter Phase III study to evaluate the treatment of patients with renal angiomyolipomas associated with TSC. Trial patients (median age=31, range 18-61) were randomized 2:1 to receive either everolimus (n=79) or placebo (n=39) at a daily dose of 10 mg. The median exposure duration of blinded study treatment was 38 weeks in the everolimus arm and 34 weeks in the placebo arm.
In the EXIST-2study, 42% of patients treated wotheverolimus (33 of 79; 95% confidence interval [CI] 31-53) experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI 0-9; p<0.0001), defined as a reduction in angiomyolipoma volume (sum of volumes of all target angiomyolipomas identified at baseline) of 50% or more relative to baseline and absence of angiomyolipoma progression.
Everolimus demonstrated superiority to placebo for both secondary efficacy outcomes measured: time to angiomyolipoma progression and skin lesion response rate. There were three patients in the everolimus arm and eight patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. The time to angiomyolipoma progression was statistically significantly longer in patients on everolimus (hazard ratio [HR] 0.08, 95% CI 0.02-0.37; p<0.0001). Skin lesion response rate was significantly higher in the everolimus arm, with a 26% response rate seen with everolimus versus 0% with placebo (p=0.0002).
Adverse events were mostly consistent with the known everolimus safety profile. Stomatitis, nasopharyngitis, acne-like skin lesi
ons, headache, cough and hypercholesterolaemia were the most common adverse events with everolimus therapy (each reported in >=20% of patients) and were primarily Grade 1-2. Infections (most frequently urinary tract and upper respiratory tract infections) occurred in 65% (51 of 79) of patients on everolimus and 72% (28 of 39) on placebo; there were no Grade 4 infections. Adverse events leading to discontinuation occurred in 4% (3 patients) of everolimus patients and 10% (4 patients) of placebo patients.
EXIST-1 is the first randomized, placebo-controlled, double-blind, international, multicenter Phase III study examining the efficacy and safety of everolimus for the treatment of patients with SEGA and TSC irrespective of age. A total of 117 patients (median age=9.5 years, range 0.8-26.6) were randomized to receive either everolimus (n=78) or placebo (n=39) at a daily starting dose of 4.5 mg/m2 and adjusted to a trough of 5-15 ng/ml. The median duration of study treatment was 41.9 weeks (range 24.0-78.9) for individuals in the everolimus group and 36.1 weeks (13.9-79.7) for those in the placebo group.
In the study, 35% of patients on everolimus (27 of 78) experienced a SEGA response versus 0% on placebo (0 of 39; p<0.0001), defined as a reduction in the total volume of all target SEGAs of 50% or more relative to baseline, in the absence of worsening of non-target SEGAs, new lesions of 1 cm or greater in diameter and new or worsening hydrocephalus. Key secondary endpoints as reported in The Lancet included absolute change from baseline to 24 weeks in seizure frequency, time to SEGA progression and skin lesion response rate of SEGA in patients with at least one skin lesion at baseline. In this trial, the impact on seizure frequency was not demonstrated.
Analysis of change in seizure frequency was inconclusive because most patients had no seizures at baseline or at follow-up. Seizure frequency was evaluated as a secondary endpoint only and patients were selected for the trial on the basis of their need for intervention for progression of the SEGAs, rather than presence of seizures. Given the results of the first secondary endpoint, the statistical plan did not provide for a formal analysis of subsequent secondary endpoints. Of those patients receiving everolimus, 0% of patients (0 of 78) experienced disease progression, while 15% of patients (6 of 39) on placebo progressed.
A skin lesion response was observed in 42% of patients (30 of 72) receiving everolimus, compared with 11% of patients (4 of 38) receiving placebo (p=0.0004). No complete responses were observed.
The adverse event profile was consistent with the known safety profile of everolimus. Most adverse events were Grade 1 or 2. The most common events were mouth ulceration, stomatitis, convulsion and pyrexia. The most common Grade 3 adverse events were stomatitis, pyrexia and convulsion; Grade 4 events were rare. Infections, mostly of the upper respiratory tract, were reported by 56 (72%) patients in the everolimus group and 26 (67%) in the placebo group. Other than one (1%) case of Grade 1 herpes zoster in the everolimus group, no opportunistic infections were reported; one (1%) infection (gastroenteritis in the everolimus group) was classified as Grade 4. 
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Photo: John J. Bissler,Chair of Nephrology at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. Photo courtesy: Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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