Ublituximab/Umbralisib Applications Voluntary Withdrawn for CLL and SLL Indications


TG Therapeutics made the decision to voluntarily pull the biologics license application and supplemental new drug application for ublituximab/umbralisib in patients with chronic lymphocytic leukemia and small lymphocytic leukemia.

A biologics license application (BLA) and supplemental new drug application (sNDA) for the ublituximab plus umbralisib (Ukoniq; U2) combination have been voluntarily withdrawn for a previously submitted application in chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia indications, according to a press release from developer TG Therapeutics.

The decision came because of findings from the phase 3 UNITY-CLL trial (NCT02612311), which highlighted a growing imbalance in overall survival (OS). Additionally, umbralisib has been withdrawn for sale in approved indications such as marginal zone lymphoma (MZL) following 1 or more prior anti-CD20 therapies and follicular lymphoma following 3 or more previous systemic therapies. Umbralisib previously received accelerated approval from the FDA in February 2021 in the aforementioned MZL and follicular lymphoma indications. The decision to withdraw umbralisib in these indications is based primarily on the U2 withdrawal in patients with CLL.

“We were very disappointed to see that the recently updated OS data showed an increasing survival imbalance in favor of the control arm. 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,” according to Michael S. Weiss, chairman and chief executive officer at TG Therapeutics, said in a press release.

The randomized, controlled UNITY-CLL trial sought to assess the efficacy of U2 vs obinutuzumab (Gazyva) and chlorambucil in a population of patients with CLL that was either treatment naïve or relapsed/refractory. Notably, the study met its primary end point of increased progression-free survival by independent central review committee.

The FDA stated its intentions to review the risk/benefit profile of U2 as part of an Oncologic Drug Advisory Committee (ODAC) in relation to the pending applications. During the meeting, the FDA highlighted several concerns including findings from an early ad hoc OS analysis. Although OS was a secondary end point in the study, it was not included in the primary analysis in accordance with the agreed statistical analysis plan and was therefore not analyzed and/or included in the applications. Additionally, the ad hoc nature of the analysis meant that about 15% of patients had missing or outdated survival data. Updated survival findings were submitted in February 2022, with a reduction in missing findings and additional OS events that highlighted an improvement over prior OS findings.

An information request made by the FDA again highlighted an increasing imbalance in OS that favored the control arm and deviated from the improved findings that were submitted to the FDA in February 2022. With the application withdrawal, the ODAC meeting planned for April 22, 2022 has been cancelled.

“While we had hoped to bring U2 to patients with CLL, this will now permit us to focus our attention, passion, and energy to building out our multiple sclerosis and autoimmune platform. With our ublituximab BLA pending for patients with relapsing forms of multiple sclerosis and a PDUFA goal date of September 28, 2022, we are excited about the possibility of bringing ublituximab to patients with RMS. If approved, we believe the differentiated profile of ublituximab with its one-hour infusion will be welcomed by the [multiple sclerosis] community,” Weiss concluded.


TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics. April 15, 2022. Accessed April 18, 2022. https://bit.ly/3Oj4GOW

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