Nirogacestat, known by its brand name OGSIVEO, is an oral, targeted therapy. It is prescribed for adults with a specific type of rare, progressing tumor that requires systemic treatment.
Approved Use for Desmoid Tumors
Nirogacestat is approved for treating adults with progressing desmoid tumors, and its FDA approval on November 27, 2023, made it the first therapy authorized for this condition. Desmoid tumors, also called aggressive fibromatosis, are non-cancerous soft-tissue growths that do not metastasize, or spread, to other parts of the body. Despite being benign, their locally invasive growth can infiltrate surrounding tissues and organs.
This aggressive behavior can lead to serious health problems. Patients often experience severe pain, and the tumors can interfere with the function of nearby organs, leading to considerable morbidity. In some instances, desmoid tumors can become life-threatening depending on their location.
Mechanism of Action
Nirogacestat functions as a gamma-secretase inhibitor, targeting a biological pathway involved in cell growth. This pathway, known as the Notch signaling pathway, is a communication system that regulates cellular processes like proliferation and differentiation. In many desmoid tumors, this signaling pathway is overactive, which contributes to the uncontrolled growth of the tumors.
The activation of the Notch pathway depends on a multi-protein enzyme complex called gamma-secretase. This enzyme’s job is to cleave transmembrane proteins, including the Notch receptor. This cleavage event releases the active part of the receptor, which then travels to the cell’s nucleus and turns on genes that drive cell proliferation.
Nirogacestat directly blocks the action of the gamma-secretase enzyme. This blockage prevents the cleavage and activation of the Notch receptor. Interrupting this signal shuts down the overactive pathway that fuels the growth of desmoid tumors, slowing their progression.
Administration and Patient Monitoring
Nirogacestat is taken as a 150 mg tablet twice daily, with or without food. Patients should swallow the tablets whole without breaking, crushing, or chewing them. If a dose is missed or vomiting occurs after taking it, the patient should not take an extra dose but wait until the next scheduled time.
Treatment requires consistent monitoring by a healthcare provider. Before starting therapy, females of reproductive potential must undergo a pregnancy test. During treatment, regular monitoring includes liver function tests to check for elevated enzymes and tests for electrolyte levels like phosphate and potassium.
Patients are also monitored for specific side effects, including routine dermatologic evaluations for non-melanoma skin cancers. Females of reproductive potential are monitored for changes in their menstrual cycle or symptoms of estrogen deficiency, such as hot flashes or night sweats.
Potential Side Effects and Management
Treatment with nirogacestat can lead to a range of side effects, managed through supportive care and dose adjustments. The most frequently reported adverse reactions in clinical trials include:
- Diarrhea
- Nausea
- Fatigue
- Stomatitis (mouth sores)
- Headache
- Abdominal pain
- Rash
- Alopecia (hair loss)
A notable potential side effect is ovarian toxicity in females of reproductive potential. This can manifest as ovarian failure, premature menopause, or amenorrhea (absence of menstruation). In a clinical trial, this side effect was observed in a high percentage of women of childbearing age, though for many, the condition resolved after stopping the medication.
For severe or persistent diarrhea, physicians may prescribe antidiarrheal medications and recommend withholding the drug until the issue resolves, potentially restarting at a lower dose. For other reactions, the dose may be reduced or treatment paused or discontinued based on the severity and recurrence of the side effect.
Clinical Trial Efficacy
The effectiveness of nirogacestat was demonstrated in the Phase 3 DeFi clinical trial, an international, randomized, placebo-controlled study of 142 adults with progressing desmoid tumors. The primary measure of efficacy was progression-free survival (PFS), the length of time patients live with the disease without it worsening.
The trial demonstrated a 71% reduction in the risk of disease progression for patients taking nirogacestat compared to a placebo. After two years of follow-up, 76% of patients in the nirogacestat group had not experienced disease progression, compared to 44% in the placebo group.
Another outcome was the objective response rate (ORR), which measures the percentage of patients whose tumors shrink. The ORR for patients treated with nirogacestat was 41%, compared to 8% for the placebo group. Among those responding to nirogacestat, 7% experienced a complete response, where their tumors disappeared entirely, and patient-reported outcomes showed improvements in pain and quality of life.