How Does Ogsiveo Work? Mechanism of Action Explained in Plain English

When your oncologist says Ogsiveo is a "gamma secretase inhibitor" that targets "Notch signaling," that probably sounds like a foreign language. But the underlying concept is actually elegant and logical — and understanding how Ogsiveo works can help you understand why it's effective and why certain side effects occur. Let's break it down in plain English.

First: What Is a Desmoid Tumor, and What Drives Its Growth?

Desmoid tumors arise from fibroblasts — cells in connective tissue that normally help repair injured tissue. In desmoid tumors, these cells grow out of control, forming a dense mass that can invade surrounding structures. While desmoid tumors are not malignant (they don't spread through the bloodstream to other organs), they can be locally destructive and very difficult to manage.

Most desmoid tumors have mutations in the CTNNB1 gene (which codes for beta-catenin) or occur in patients with Familial Adenomatous Polyposis (FAP), who carry mutations in the APC gene. Both pathways ultimately lead to overactivation of the Wnt/beta-catenin signaling pathway, which promotes cell proliferation. Ogsiveo targets a separate but related pathway: the Notch pathway.

What Is the Notch Signaling Pathway?

Notch signaling is a fundamental communication system that cells use to control their behavior. Think of Notch receptors as antennas on the surface of cells. When a Notch receptor receives a signal from a neighboring cell, an enzyme called gamma secretase cleaves (cuts) the receptor, releasing a fragment called the Notch Intracellular Domain (NICD). The NICD then travels to the cell's nucleus and activates genes that tell the cell to grow and survive.

In desmoid tumors, this signaling system is overactive — the Notch pathway is sending too many "grow and survive" signals, which fuels tumor progression.

How Does Ogsiveo Fit In? The Role of Gamma Secretase Inhibition

Ogsiveo (nirogacestat) works by selectively blocking the gamma secretase enzyme. By blocking this enzyme:

Gamma secretase can no longer cleave the Notch receptor.

The NICD fragment is never released.

The "grow and survive" signals stop reaching the tumor cell's nucleus.

Tumor cells lose a key driver of their proliferation and survival.

Tumor growth slows, stops, or in some cases reverses (tumor shrinks).

This is why Ogsiveo is described as a "targeted therapy" — it goes after a specific molecular target (gamma secretase / Notch signaling) rather than attacking all dividing cells.

How Does This Explain Ogsiveo's Side Effects?

Gamma secretase and Notch signaling exist in many normal tissues throughout the body — not just desmoid tumor cells. When Ogsiveo blocks gamma secretase systemically, it affects these normal tissues too, which explains many of the drug's side effects:

Diarrhea: Notch signaling is important for maintaining the intestinal lining. Blocking it disrupts gut cell renewal and causes diarrhea in 84% of patients.

Ovarian toxicity: Notch signaling plays a role in follicle development in the ovaries. Blocking it can impair ovarian function, causing irregular periods or early menopause symptoms.

Skin effects (rash, increased skin cancer risk): Notch signaling helps regulate skin cell behavior. Disrupting it can cause rash and, over time, increase the risk of non-melanoma skin cancers.

Why Was Nirogacestat Originally Developed for Alzheimer's Disease?

This is a fascinating part of Ogsiveo's history. Nirogacestat was originally developed by Pfizer as an Alzheimer's disease drug. The connection: gamma secretase is the same enzyme that processes amyloid precursor protein (APP) into the amyloid-beta peptides that form the plaques associated with Alzheimer's disease. By blocking gamma secretase, researchers hoped to prevent amyloid plaque buildup.

That avenue ultimately did not succeed for Alzheimer's, partly because of the side effects caused by Notch pathway disruption. However, SpringWorks Therapeutics recognized that those same properties that were problematic in Alzheimer's — specifically, disrupting Notch signaling — could be therapeutically valuable in desmoid tumors, where Notch is a key driver of tumor growth. The rest, as they say, is history.

How Is Ogsiveo's Effect Measured?

Tumor response to Ogsiveo is typically measured using standard radiology criteria called RECIST (Response Evaluation Criteria in Solid Tumors), assessed by CT or MRI scans at regular intervals. Response categories include:

Complete Response (CR): Tumor disappears entirely on imaging (7% in DeFi trial)

Partial Response (PR): Tumor shrinks by at least 30% (34% in DeFi trial)

Stable Disease (SD): Tumor neither shrinks significantly nor grows significantly — a meaningful outcome for a progressing tumor

Progressive Disease (PD): Tumor continues to grow despite treatment

For a broader overview of Ogsiveo's clinical use, see what is Ogsiveo and how is it used. To understand the full picture of what to expect during treatment, read our guide on Ogsiveo side effects.