Nirogacestat, known by its brand name OGSIVEO, is an oral medication developed as a targeted therapy. In November 2023, it became the first treatment approved by the U.S. Food and Drug Administration (FDA) for adults with progressing desmoid tumors, offering a dedicated option where none previously existed. The treatment is administered as a 150 mg dose, taken orally twice a day.
Understanding Desmoid Tumors
Desmoid tumors, sometimes called aggressive fibromatosis, are rare growths that arise from connective tissue. These tumors are considered benign because they do not metastasize, or spread, to distant parts of the body. However, their behavior can be locally aggressive, meaning they can grow into and invade surrounding tissues and organs. This invasive growth can cause severe pain, disfigurement, and interfere with the function of nearby structures.
These tumors can develop in various locations, including the abdomen, limbs, and chest wall. The unpredictable nature of their growth and the potential for high rates of recurrence make them challenging to manage. Their capacity to cause significant morbidity highlights the need for effective treatment.
The Mechanism of Nirogacestat
Nirogacestat is a gamma-secretase inhibitor. Gamma-secretase is a protein complex that acts like molecular scissors, cutting and releasing other proteins embedded in the cell membrane. One of the proteins it cleaves is the Notch receptor. This action is a central step in the Notch signaling pathway, a communication system cells use to regulate growth, proliferation, and cell fate decisions.
In many desmoid tumors, the Notch signaling pathway is overactive, sending continuous signals that promote tumor cell growth and survival. These tumors often produce high levels of Notch protein, which fuels their progression. Nirogacestat works by directly blocking the gamma-secretase enzyme.
By inhibiting gamma-secretase, nirogacestat prevents the cleavage and activation of the Notch receptor. This stops the release of the Notch intracellular domain (NICD), a component that would normally travel to the cell’s nucleus and turn on genes responsible for proliferation. This interruption of the Notch signaling pathway halts the growth signals, controlling desmoid tumors.
Clinical Efficacy and Results
Nirogacestat’s approval was based on the Phase 3 DeFi clinical trial, an international, randomized, and placebo-controlled study. This trial evaluated the drug’s effectiveness in 142 patients with progressing desmoid tumors that were not suitable for surgery. The study’s primary measure was progression-free survival (PFS), the length of time patients live without their disease worsening.
The study found a 71% reduction in the risk of disease progression or death compared to the placebo group. While the median PFS was 15.1 months for patients receiving the placebo, it was not yet reached in the nirogacestat arm because a large percentage of those patients had not experienced disease progression by the time of analysis. At the two-year mark, 76% of patients on nirogacestat showed no evidence of their tumors getting worse, compared to 44% in the placebo group.
Beyond halting growth, nirogacestat also led to tumor shrinkage. The objective response rate (ORR), which measures the proportion of patients whose tumors shrink by a certain amount, was 41% for the nirogacestat group, compared to just 8% for the placebo group. A complete response, meaning the tumors were entirely eradicated, was seen in 7% of patients taking nirogacestat, with no complete responses observed in the placebo group. Patients also reported meaningful improvements in pain, physical functioning, and overall quality of life.
Known Side Effects and Patient Considerations
The most frequently reported side effects in clinical trials include:
- Diarrhea
- Nausea
- Fatigue
- Skin rash
- Stomatitis (mouth sores)
- Abdominal pain
Diarrhea was particularly common, affecting approximately 84% of patients, with the median time to its first appearance being nine days.
A primary consideration for females of reproductive potential is the risk of ovarian dysfunction. This can manifest as changes in the menstrual cycle, premature menopause, or ovarian failure. In the DeFi trial, ovarian toxicity was observed in 75% of women of childbearing potential who received the drug. For many of these women, this effect was reversible after discontinuing the treatment.
Medical teams manage these side effects through supportive care, such as prescribing antidiarrheal medications, or by adjusting the dose of nirogacestat. Due to the risk of ovarian toxicity, female patients should discuss potential fertility impacts with their doctor before starting the medication. Regular monitoring for other potential issues, like liver problems or non-melanoma skin cancer, is also a standard part of the treatment protocol.