On April 15, 2022 TG Therapeutics, Inc. (NASDAQ: TGTX), reported that the Company has voluntarily withdrawn the pending Biologics License Application (BLA)/supplemental New Drug Application (sNDA) for the combination of ublituximab and UKONIQ (umbralisib) (combination referred to as U2) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, TG Therapeutics, APR 15, 2022, View Source [SID1234612319]). The decision to withdraw was based on recently updated overall survival (OS) data from the UNITY-CLL Phase 3 trial that showed an increasing imbalance in OS. Additional details are included below in the section entitled "ABOUT UNITY-CLL PHASE 3 TRIAL AND THE WITHDRAWAL OF THE BLA/sNDA SUBMISSION."
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In addition, the Company announced that it has voluntarily withdrawn UKONIQ from sale for the approved indications of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with follicular lymphoma (FL) who have received at least three prior systemic therapies. UKONIQ was granted accelerated approval in these indications in February 2021. The Company’s decision to withdraw UKONIQ from sale was primarily based on the withdrawal of the BLA and sNDA for U2 in CLL.
Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics stated, "We were very disappointed to see that the recently updated overall survival 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 UKONIQ 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."
Mr. Weiss continued, "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 MS community."
ABOUT UNITY-CLL PHASE 3 TRIAL AND THE WITHDRAWAL OF THE BLA/sNDA SUBMISSION
UNITY-CLL, a global, Phase 3, randomized, controlled clinical trial, compared the U2 combination, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL). The trial met its primary endpoint, with U2 significantly prolonging independent review committee (IRC) assessed progression-free survival (PFS) vs. the control arm. The UNITY-CLL Phase 3 trial was conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). Based on the results of the UNITY-CLL trial, a BLA and sNDA were submitted to the FDA for U2 to treat patients with CLL/SLL.
In November 2021, the FDA notified the Company that it planned to host an Oncologic Drug Advisory Committee (ODAC) meeting in connection with its review of the pending BLA/sNDA and to discuss the benefit risk of UKONIQ in its approved indications. While the FDA identified a number of concerns, the FDA’s desire to host an ODAC appeared to stem from an early ad hoc analysis of overall survival (OS) from the UNITY-CLL trial.
OS was designated as a secondary efficacy endpoint in the UNITY-CLL protocol but was not part of the primary analysis in accordance with the study’s statistical analysis plan agreed upon via a SPA, and therefore, was not analyzed or included in the BLA/sNDA. Additionally, the study was not powered for overall survival. As part of the ongoing review of the BLA/sNDA, the FDA requested an early analysis of OS from the UNITY-CLL trial. In a first analysis of OS using a cut-off date of September 2021, there was an imbalance in favor of the control arm (HR: 1.23). However, based on the ad hoc nature of the analysis, approximately 15% of patients had missing or outdated survival data. Further, when excluding deaths related to COVID-19, the two arms were approximately balanced (HR: 1.04). In February 2022, the Company submitted updated OS data with the same September 2021 cut-off date, but with reduced missing data and additional OS events, which showed an improvement from the previously reported OS data. Neither the original preliminary OS results nor the updated preliminary OS results were statistically significant.
Pursuant to a recent information request made by the FDA, updated OS data were collected that showed an increasing imbalance in favor of the control arm, differing from the improved results provided to the FDA in February 2022. Based on these new data, the Company decided to withdraw the pending BLA/sNDA for U2 to treat CLL/SLL and accordingly the April 22, 2022, ODAC meeting will be canceled.
In addition, based on the Company’s decision to withdraw UKONIQ from sale, we anticipate that the FDA will withdraw the accelerated approval for the product.
The FDA also has scheduled an ODAC meeting for April 21, 2022, in which it plans to discuss the appropriate approach for phosphatidylinositol-3-kinase inhibitors under development for treatment of hematologic malignancies. UKONIQ is within this class of drugs and may be discussed during this
meeting.
CONFERENCE CALL INFORMATION
The Company will host a conference call Monday, April 18, 2022, at 8:30 AM ET, to discuss the regulatory updates.
To participate in the conference call, please call 1-877-407-8029 (U.S.), 1-201-689-8029 (outside the U.S.), Conference Title: TG Therapeutics Update Call. A live audio webcast will be available on the Events page, located within the Investors & Media section, of the Company’s website at View Source An audio recording of the conference call will also be available for a period of 30 days after the call.