Ukoniq Withdrawn Due to Overall Survival Concerns
TG Therapeutics has withdrawn its accelerated approval of Ukoniq (umbralisib), a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon, for treating adults with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen, and with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy. The company also withdrew a pending BLA and a supplemental NDA for the combination of ublituximab and Ukoniq (umbralisib) for the treatment of adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. The company says its decision to withdraw the approval and pending submissions was based on recently updated overall survival (OS) data from its UNITY-CLL Phase 3 trial that showed an increasing imbalance in OS.
A BLA is still under review for ublituximab in patients with relapsing forms of multiple sclerosis (MS), according to the company, adding that its user fee review action target date is 9/28. “If approved, we believe the differentiated profile of ublituximab with its one-hour infusion will be welcomed by the MS community,” the company says.
Recent concerns stem from a safety alert earlier this year on the possible increased risk of death with Ukoniq. FDA requested an early analysis of OS from the UNITY-CLL trial as part of the ongoing review of the BLA/sNDA. “In a first analysis of OS using a cut-off date of 9/2021, there was an imbalance in favor of the control arm (HR: 1.23),” the company says. “However, based on the ad hoc nature of the analysis, approximately 15% of patients had missing or outdated survival data.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 2/2022, the company submitted updated OS data with the same 9/2021 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.”
The withdrawals are also in line with FDA’s latest concerns with PI3K inhibitors. Late last month, FDA discouraged MEI Pharma and Kyowa Kirin from seeking accelerated approval of a BLA for zandelisib, a PI3K inhibitor drug candidate for treating patients with B-cell malignancies, based on data from their single-arm Phase 2 TIDAL study. In a recent meeting, FDA told the companies that its position now requires a randomized trial to adequately assess drug efficacy and safety of PI3K inhibitor drug candidates, including zandelisib, according to an MEI release. The agency encouraged the companies to continue efforts with the ongoing, randomized Phase 3 COASTAL study as planned.
FDA’s PI3K inhibitor safety concerns have led to a planned a 4/21-22 Oncologic Drugs Advisory Committee meeting to review the issue further. A recent Federal Register notice indicates that panel members on 4/21 will discuss the “appropriate approach for PI3K inhibitors currently under development in patients with hematologic malignancies and whether randomized data should be required to support a demonstration of substantial evidence of effectiveness and that the drug is safe for its intended use in the proposed population.” The panel was also set to discuss TG Therapeutics’ now withdrawn submissions on 4/22, but that discussion has now been canceled.