Umbralisib (Ukoniq): Drug recall because increased risk of patient death

Umbralisib (Ukoniq): Drug recall because increased risk of patient death

Last Updated on June 28, 2022 by Joseph Gut – thasso

May 08, 2022 – Umbralisib (Ukoniq) is a medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). Umbralisib (Ukoniq) inhibits multiple kinases. In biochemical and cell-based assays, Umbralisib inhibited PI3Kδ and casein kinase CK1ε. PI3Kδ is expressed in normal and malignant B-cells; CK1ε has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies. Umbralisib (Ukoniq) also inhibited a mutated form of ABL1 in biochemical assays. Umbralisib (Ukoniq) inhibited cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration in lymphoma cell lines in studies conducted in vitro.

Follicular Lymphoma (FL)

Umbralisib (Ukoniq) was granted breakthrough therapy designation by the American. Food and Drug Administration (FDA) in February 2021. FDA approval was based on two single-arm cohorts of an open-label, multi-center, multi-cohort trial, UTX-TGR-205 (NCT02793583), in 69 participants with marginal zone lymphoma (MZL) who received at least one prior therapy, including an anti-CD20 containing regimen, and in 117 participants with follicular lymphoma (FL) after at least two prior systemic therapies. The application for Umbralisib (Ukoniq)was granted priority review for the marginal zone lymphoma (MZL) indication and orphan drug designation for the treatment of MZL and follicular lymphoma (FL). In particular, FDA approved Umbralisib (Ukoniq) to treat adults with two types of lymphoma: i) Marginal Zone Lymphoma (MZL), when this type of lymphoma cancer has returned or it did not respond to prior treatment with at least one specific type of medicine; and ii) Follicular Lymphoma (FL), when this type of lymphoma cancer has returned or it did not respond to at least three prior treatments.

We should be aware, that  this medicine came, from the beginning, with an impressive catalogue of serious adverse effects. The most common side effects include increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash. However, when reading the Warnings und Precautions Section (i.e., Section 5) of the Drug Label Document of Umbralisib (Ukoniq), one is  getting an understanding of the seriousness of some of these events. Of course, FDA, through their pharmacovigilance program, is continuously monitoring all these effects. In fact, in the beginning of February 2022, these continuous investigations led to the identification of a so-called “safety signal” which indicated an association between Umbralisib (Ukoniq) and increased risk of death in patients treated with Umbralisib

Splenic Marginal Zone Lymphoma (MZL)

(Ukoniq) for their lymphoma cancer. Consequently, FDA released on February 3, 2022, a Drug Safety Communication entitled “FDA investigating possible increased risk of death with lymphoma medicine UKONIQ (Umbralisib)“.

In particular. FDA stated that they conducted an initial review of data from UNITY, a phase 3, randomized, controlled clinical trial in patients with chronic lymphocytic leukemia (CLL). The trial is evaluating Umbralisib (Ukoniq) in combination with a monoclonal antibody drug that targets a specific protein called CD20 compared to the control arm in which patients received standard treatment. The results showed a possible increased risk of death in patients receiving the combination of Umbralisib (Ukoniq) and the monoclonal antibody compared to the control arm. The UNITY trial was conducted in CLL patients, which is not an approved use but rather a use of this drug that is being studied; however, FDA believe these findings have implications for its approved uses for MZL and FL Furthermore, FDA continuied to evaluate the results from the clinical trial called UNITY. FDA indicated that they may hold a future public meeting to discuss these findings and explore the continued marketing of Umbralisib (Ukoniq). As these evaluations are going on, there was a general suspension of enrollment of new patients in other ongoing clinical trials of Umbralisib (Ukoniq) while the UNITY findings were still reviewed and the  final conclusions and recommendations will be communicated in due time.

In the meantime, on April 15, 2022, TG Therapeutics announced the voluntary withdrawal of Umbralisib (Ukoniq) from sale for its approved use in the treatment of marginal zone lymphoma and follicular lymphoma, mainly because of the increased risk of death associated with Umbralisib (Ukoniq). Furthermore, the company withdrew the pending Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) which utilized Umbralisib (Ukoniq) in tandem with ublituximab, known as the “U2” regimen. The decision was based on the most recent overall survival (OS) data from the Phase 3 trial, Unity-CLL, that illustrated an increasing imbalance in OS.

Overall, this example of Umbralisib (Ukoniq) illustrates the risk associated with patients safety when drugs, in order to relief unmet medical needs, are approved by authorities through accelerated, emergency, or breakthrough procedures, very often based on a limited number of patients in the underlying clinical trials.




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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.