PI3K Inhibitor Umbralisib for Marginal Zone Lymphoma Has FDA Approval Withdrawn


According to a recent article, the PI3K inhibitor umbralisib used to treat marginal zone lymphoma has had its approval withdrawn by the FDA.


Marginal Zone Lymphoma (MZL)

Marginal zone lymphoma (MZL) is a cancer of the lymphatic system—a widespread network of lymph nodes, organs and other structures that make up part of your immune system. Just as blood vessels transport blood, the lymphatic system’s job is to transport lymph, a fluid that contains disease-fighting cells.

Lymphomas are often classified based on how quickly they spread, and marginal zone lymphoma is usually a slow-growing (or indolent) cancer. It is a type of non-Hodgkin B-cell lymphoma. MZL patients make up about 8 percent of non-Hodgkin lymphoma (NHL) cases, according to the Lymphoma Research Foundation.



Umbralisib (TGR-1202) is an oral inhibitor of PI3K-delta and CK1-epsilon administered once daily. The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in many important cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking, and immunity.


Safety Considerations

After safety concerns surrounding the inhibitor were brought up, the FDA decided to pull their approval. Earlier, the agency sent out a statement on the safety of umbralisib, saying it could increase the possibility of death in patients who take it. After this announcement, the FDA Oncologic Drugs Advisory Committee (ODAC) voted for data pertaining to survival from randomized trials be required for the approval of future PI3K applications.

In addition, TG Therapeutics recently announced they are withdrawing their application for a license for their ublituximab and umbralisib combination. It was going to be used to treat chronic lymphocytic leukemia, as well as small lymphocytic lymphoma. They also announced their withdrawal of approved indication for marginal zone lymphoma and follicular lymphoma.


Withdrawing Approval

As the results of the UNITY-CLL clinical trial came in, researchers noted the possibility of increased death risk in people being treated with umbralisib. When this information was released, the FDA decided the potential hazards of umbralisib outweighed the benefits of it, thus they withdrew their approval for it. Although there was a benefit of progression-free survival in patients taking umbralisib, the overall survival was worse. Researchers have hypothesized that toxicity might be the cause of the worsened overall survival.

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