How Do Gamma Secretase Inhibitors Work?

Gamma secretase inhibitors are a first-in-class medications used to treat progressing desmoid tumors that require systemic treatment. Gamma secretase inhibitors work by blocking the activity of gamma secretase, an enzyme that promotes the growth of desmoid tumors.

Desmoid tumors, also known as aggressive fibromatosis, are a genetic and rare subtype of soft tissue sarcomas. Desmoid tumors do not spread but can grow rapidly locally and invade surrounding tissues causing pain, disfigurement, disability and other severe complications such as nerve damage and bowel perforations.

People with familial adenomatous polyposis, a genetic condition, are at a greater risk for developing desmoid tumors. Desmoid tumors usually develop at a young age but can occur at any age. Until now, surgery and chemotherapy have been the primary treatments for desmoid tumors, but typically fail to control the disease for long.

Gamma secretase enzyme activates the signaling pathway of a protein known as Notch. Research indicates that the growth of desmoid tumors may be driven by abnormal activation of Notch pathway and production of high amounts of Notch protein. Gamma secretase inhibitors bind to Notch receptors and block their activation by gamma secretase enzyme.

Currently, nirogacestat (Ogsiveo) is the first and only formulation available in the gamma secretase inhibitor class. The drug received Fast Track, Breakthrough Therapy and Orphan designation from the FDA and was finally approved by the FDA in November 2023.

Gamma secretase inhibitors are oral tablets used to treat adults with progressing desmoid tumors that require systemic treatment.

Side effects of gamma secretase inhibitors include the following:

• Diarrhea
• Nausea
• Oral inflammation (stomatitis)
• Abdominal pain
• Ovarian toxicity including:
• Ovarian failure
• Premature menopause
• Absence of menstruation (amenorrhea)
• Electrolyte abnormalities including:
• Decrease in phosphate levels
• Decrease in potassium
• Increased glucose excretion in urine
• Increased protein excretion in urine
• Rash
• Loss of hair (alopecia)
• Fatigue
• Headache
• Liver toxicity
• Increase in liver enzyme aspartate aminotransferase (AST)
• Increase in liver enzyme alanine aminotransferase (ALT)
• Cough
• Shortness of breath (dyspnea)
• Upper respiratory tract infection

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of gamma secretase inhibitors include:

• nirogacestat
• Ogsiveo