FDA Approves Everolimus Extended-Release Capsules in TSC-Associated SEGA

2mg, 3mg, and 5mg extended-release capsules of everolimus have been approved for patients with TSC-associated SEGA by the FDA.

The FDA has approved 2mg, 3mg, and 5mg everolimus (Afinitor) extended-release capsules in the treatment of adult and pediatric patients with tuberous sclerosis complex (TSC)–associated subependymal giant cell astrocytoma (SEGA) who need therapeutic intervention but cannot undergo curative resection, according to a press release from Amneal.¹

Everolimus was originally approved by the FDA in this indication based on supporting data from the double-blind, randomized phase 3 EXIST-1 study (NCT00789828) that evaluated the safety and efficacy of everolimus compared with placebo in SEGA associated with TSC.²

“Amneal’s competitive advantage in the Affordable Medicines business remains our core capabilities to drive innovation at scale across complex categories to expand the breadth and depth of our portfolio,” Andy Boyer, executive vice president and chief commercial officer of Affordable Medicines at Amneal, stated in the press release.¹ “With our 180-day exclusivity on memantine/donepezil [Namzaric], increasing supply for everolimus, and the tentative approval of rifaximin [Xifaxan], we are continuing to expand our differentiated portfolio and providing new key therapies for our customers, providers and patients.”

The most common AEs of any grade in the everolimus and placebo groups were stomatitis (62% vs 26%, respectively), respiratory tract infection (31% vs 23%), pyrexia (23% vs 18%), and vomiting (22% vs 13%).² Of grade 3 and 4 toxicities, they included stomatitis (9% vs 3%), pyrexia (6% vs 3%), gastroenteritis (5% vs 0%), and anxiety or other behavioral disturbances (5% vs 0%).

The most common laboratory abnormalities of any grade in the everolimus and placebo groups were hypercholesterolemia (81% vs 39%, respectively), elevated partial thromboplastin time (72% vs 44%), neutropenia (46% vs 41%), anemia (41% vs 21%), and hypertriglyceridemia (27% vs 15%). Of grade 3 or higher toxicities, they included neutropenia (9% vs 3%), elevated partial thromboplastin time (3% vs 5%), and hypophosphatemia (1% vs 0%).

There were no toxicities resulting in permanent treatment discontinuation among patients in the EXIST-1 trial. Additionally, 55% of patients in the everolimus arm required dose adjustments due to adverse effects, the most common of which was stomatitis. The median duration of treatment was 52 weeks in the everolimus arm.

A total of 117 patients were enrolled and randomly assigned, in a 2:1 ratio, to receive either 4.5 mg/m² of daily, oral everolimus that was subsequently titrated to achieve whole blood trough concentration of 5 to 15 ng/mL (n = 78) or a matching oral placebo (n = 39).³

Eligibility criteria included a definite diagnosis of TSC per modified Gomez criteria, at least 1 SEGA of at least 1 cm in diameter, evidence of SEGA worsening compared with prior MRI scans, birth control for female patients of child-bearing potential, and written informed consent.

Exclusion criteria included SEGA requiring surgery; recent heart attack, cardiac-related chest pain, or stroke; severely impaired lung function; severe liver or kidney dysfunction; current infection; history of organ transplant; pregnancy or breast feeding; surgery within 2 months prior to study enrollment; uncontrolled high cholesterol or diabetes; prior therapy with a drug in the same class as everolimus; human immunodeficiency virus; and metal implants prohibiting MRI evaluations.

The trial’s primary end point was the percentage of patients with best overall SEGA response. Secondary end points were time to SEGA progression, time to SEGA response, duration of SEGA response, time to SEGA worsening, and percentage of patients with skin lesions assessed using physician’s global assessment overall score, among others.

References

1. Amneal receives U.S. FDA approval for memantine/donepezil extended-release capsules and everolimus tablets for oral suspension, and tentative U.S. FDA approval for rifaximin. News release. Amneal. January 23, 2025. Accessed January 24, 2025. https://tinyurl.com/3uwac347
2. Prescribing information. AFINITOR® (everolimus) tablets, for oral use. FDA. 2009. Accessed January 24, 2025. https://tinyurl.com/yc2jhtja
3. Efficacy and safety of everolimus (RAD001) in patients of all ages with subependymal giant cell astrocytoma associated with tuberous sclerosis complex (TSC)(EXIST-1) (EXIST-1). ClinicalTrials.gov. Updated February 3, 2016. Accessed January 24, 2025. https://tinyurl.com/bdfw9zbn