The FDA announced that it has withdrawn approval for umbralisib (Ukoniq, TG Therapeutics), based on an updated analysis of the phase 3 UNITY-CLL clinical trial, which continues to show “a possible increased risk of death” in patients receiving the medication, the agency noted.

Umbralisib, a dual inhibitor of PI3 kinase-delta and CK1-epsilon, was approved in February 2021 to treat marginal zone lymphoma (MZL) and follicular lymphoma (FL). 

Although UNITY-CLL did not include patients with MZL and FL—it was part of a supplemental application seeking approval to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)—“we believe [the elevated mortality risk in the trial has] implications for its approved uses,” the FDA stated. “In  addition, clinical trials of other medicines in the same PI3 kinase inhibitor class as Ukoniq have shown similar safety concerns.”

The FDA announcement is not the first to cite safety concerns related to umbralisib. On April 15, 2022, TG Therapeutics issued a statement noting that it was withdrawing its application for the CLL and SLL indications, based on updated data on overall survival (OS) from the UNITY-CLL trial. Those data “showed an increasing [survival] imbalance in favor of the control arm, differing from the improved results provided to the FDA” in an earlier data submission, the company noted. 

The April announcement from TG Therapeutics followed a February statement from the FDA which noted that the agency was investigating the elevated mortality risk in the UNITY trial.
 

The FDA has instructed healthcare professionals to stop prescribing umbralisib and to switch patients to alternative treatments. Additionally, patients who are currently taking the medication should be “informed of the increased risk of death seen in the clinical trial” and advised to stop taking the medicine.

“In limited circumstances in which a patient may be receiving benefit from Ukoniq, TG Therapeutics plans to make it available under expanded access,” the agency added.

The FDA also urged healthcare professionals and patients to report side effects of umbralisib to the FDA MedWatch program.

Approval Data

For practitioners considering continuing patients on umbralisib under expanded access, the drug’s initial safety and efficacy data, detailed when it was approved for MZL and FL in February 2021, may be instructive. 

The drug was approved for adults with relapsed or refractory MZL who have received at least one prior anti–CD20-based regimen and adults with relapsed or refractory FL who have received at least three prior lines of systemic therapy.

Approval was based on the multicenter, multicohort, open-label, phase 2 UNITY-NHL trial (ClinicalTrials.gov Identifier: NCT02793583), which included 69 patients with MZL who received at least one prior therapy, including an anti–CD20-containing regimen, and 117 patients with FL after at least two prior systemic therapies. Patients received 800 mg of umbralisib orally once daily until disease progression or unacceptable toxicity. Efficacy was analyzed by overall response rate (ORR) and duration of response (DOR) using modified 2007 International Working Group criteria assessed by an independent review committee.

For patients with MZL, the ORR was 49% (95% CI, 37.0%-61.6%), with 16% achieving a complete response (CR) and 33% achieving a partial response (PR). Median DOR was not reached (95% CI, 9.3 months-NE) in these patients. For patients with FL, the ORR was 43% (95% CI, 33.6%-52.2%), with 3% achieving a CR and 39% achieving a PR. Median DOR was 11.1 months (95% CI, 8.3-16.4 months).

The safety of umbralisib was assessed in a pooled population from the 221 adults with MZL and FL in three single-arm, open-label trials and one open-label extension trial. The most common (≥15% of patients) adverse events (AEs) were increased creatinine, diarrhea/colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite and rash. Serious AEs, most often diarrhea/colitis and infection, occurred in 18% of patients.

The prescribing information provides warnings and precautions for AEs, including infections, neutropenia, diarrhea and noninfectious colitis, hepatotoxicity, and severe cutaneous reactions.

For more information, read the full prescribing information for umbralisib.