On March 3, 2022 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) goal date to June 25, 2022 for the Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for ublituximab in combination with UKONIQ (umbralisib) as a treatment for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, TG Therapeutics, MAR 3, 2022, View Source [SID1234609444]).
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The FDA notified the Company that the updated overall survival analyses which were submitted to the FDA in February 2022, constituted a major amendment to the applications, and therefore the FDA is extending the PDUFA date to provide time for a full review of the submissions.
Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics stated, "As mentioned on our earnings call earlier this week, we believed an extension of the PDUFA date was a likely scenario especially given the proposed timing of the upcoming ODAC meeting. We hope this extension provides the time needed to give proper attention and review to the U2 BLA/sNDA." Mr. Weiss continued, "We continue to believe in the potential of U2 to provide a meaningful treatment option to patients with CLL and SLL."
ABOUT THE ODAC MEETING
In general, the Oncologic Drugs Advisory Committee (ODAC) reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes appropriate recommendations to the Commissioner of Food and Drugs. Although the FDA will consider the recommendation of the ODAC Committee, the final decision regarding the approval of a product is made solely by the FDA.
The FDA has notified the Company that potential questions and discussion topics for the ODAC include: the benefit-risk of the U2 combination in the treatment of CLL or SLL, and the benefit-risk of UKONIQ in relapsed/refractory marginal zone lymphoma (MZL) or follicular lymphoma (FL). In addition, as part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including adverse events (serious and Grade 3-4), discontinuations due to adverse events, and dose modifications, is expected to be reviewed. The FDA’s concern giving rise to the ODAC meeting appears to stem from an early analysis of overall survival from the UNITY-CLL trial.
Overall survival was designated as a secondary efficacy outcome 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 Special Protocol Assessment (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 overall survival from the UNITY-CLL trial. As of September 2021, the cut-off date for the overall survival analysis requested by the FDA during their review, there was an imbalance in favor of the control arm (HR: 1.23) though this result was not statistically significant. However, when excluding deaths related to COVID-19, the two arms were approximately balanced (HR: 1.04) with again no statistically significant difference between the treatment groups with regard to overall survival. In February 2022, the Company submitted updated overall survival data with the same September 2021 cut-off date. The Company will continue to evaluate this endpoint over time as more events are available and will continue to analyze how COVID-19 may be impacting the analysis.
The date of the ODAC meeting has not yet been determined, although the FDA has stated that it is targeting holding the ODAC in March or April 2022.
ABOUT UNITY-CLL PHASE 3 TRIAL AND THE BLA/sNDA SUBMISSION
UNITY-CLL is a global, Phase 3, randomized, controlled clinical trial comparing the combination of ublituximab plus UKONIQ (umbralisib), or U2, 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 randomized patients into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and an active control arm of obinutuzumab plus chlorambucil. A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms. Accordingly, the UNITY-CLL Phase 3 trial continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil. Approximately 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory. The primary endpoint for this study was superior progression-free survival (PFS) for the U2 combination compared to the control arm. The trial met its primary endpoint, with U2 significantly prolonging independent review committee (IRC) assessed PFS vs. control (median 31.9 months vs 17.9 months; hazard ratio 0.546 (p<0.0001)) at a median follow-up of 36.7 months, and results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. The UNITY-CLL Phase 3 trial is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).
The BLA/sNDA submissions of U2 to treat CLL were based on the results of the UNITY-CLL trial. The FDA previously granted Fast Track designation to the U2 combination for the treatment of adult patients with CLL and orphan drug designation for ublituximab in combination with UKONIQ for the treatment of CLL.
ABOUT CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. It is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States in 2020 and approximately 45,000 new cases globally in 2020.1,2 Although signs and symptoms of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.