The FDA has announced that it has withdrawn its approval of umbralisib (Ukoniq®, TG Therapeutics) for treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). Umbralisib had previously been granted accelerated approval in February 2021 based on the UNITY-NHL trial (NCT02793583). The withdrawal of this treatment was determined due to updated data from the UNITY-CLL trial (NCT02612311), which revealed a possible increased risk of death in patients receiving umbralisib. TG Therapeutics previously announced a voluntary withdrawal of umbralisib from the market for these indications.
The phase 3 UNITY-CLL trial enrolled 600 patients with treatment-naive and relapsed or refractory chronic lymphocytic leukemia (CLL) in a 1:1 ratio to receive ublituximab plus umbralisib (U2) or obinutuzumab plus chlorambucil. The primary end point was progression-free survival, with a key secondary end point of overall response rate. Although overall survival was not studied in the primary analysis of the trial, upon request of the FDA, an early analysis of overall survival was implemented.
At the median follow-up of 36.2 months, the trial met progression-free survival, which showed significant favor of U2 when compared with obinutuzumab/chlorambucil. Based on these results, a Biologics License Application (BLA) and supplemental New Drug Application (sNDA) were submitted to the FDA for approval. The request for analysis of overall survival was shown to be favorable of U2 in the data provided in September 2021 and February 2022, yet recent updated data revealed increasing imbalances between the two arms, with an eventual significance in favor of the obinutuzumab/chlorambucil arm. Upon analysis of these new data, TG Therapeutics withdrew their BLA and sNDA and withdrew umbralisib from the market for treatment of patients with MZL and FL.
"We were very disappointed to see that the recently updated overall survival data showed an increasing survival imbalance in favor of the control arm," stated Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics, in the press release announcing the withdrawal of the medicine. "Accordingly, we and our advisors determined that we should withdraw the BLA/sNDA for U2 in CLL. Additionally, we made the difficult decision to withdraw [umbralisib] from sale for the approved indications in MZL/FL. We want to thank the patients, families and practitioners who worked with us in our search for novel treatment options for patients with B-cell malignancies."
For More Information
US Food and Drug Administration (2022). FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approval-lymphoma-medicine-ukoniq-umbralisib-withdrawn-due-safety-concerns
TG Therapeutics (2022). TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. Available at: https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-voluntary-withdrawal-blasnda-u2-treat
Ukoniq® (umbralisib) prescribing information (2022). TG Therapeutics. Available at: https://www.tgtherapeutics.com/prescribing-information/uspi-ukon.pdf
Clinicaltrials.gov (2022). Study to assess the efficacy and safety of ublituximab + umbralisib with or without bendamustine and umbralisib alone in patients with previously treated non-Hodgkins lymphoma (UNITY-NHL). NLM identifier: NCT02793583.
Clinicaltrials.gov (2022). Ublituximab + TGR-1202 compared to obinutuzumab + chlorambucil in patients with untreated and previously treated chronic lymphocytic leukemia (UNITY-CLL). NLM identifier: NCT02612311.
Gribben JG, Jurczak W, Jacobs R, et al (2020). Umbralisib plus ublituximab (U2) Is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. 62nd American Society of Hematology Meeting and Exposition. Abstract 543.
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