Based on phase 3 data supporting the use of ublituximab in combination with umbralisib versus an existing standard-of-care regimen for chronic lymphocytic leukemia and small cell lymphoma, the FDA has moved forward with a review of the application for approval.
A biologics license application (BLA) for ublituximab in combination with umbralisib for the treatment of patients with chronic lymphocytic leukemia (CLL) and small cell lymphoma was accepted by the FDA, according to the company responsible for developing both agents, TG Therapeutics, Inc.1
Results of the phase 3 UNITY-CLL trial (NCT02612311) served as supporting data for the application after results indicated better outcomes were observed with the combination versus obinutuzumab (Gazyva) plus chlorambucil in patients with treatment-naïve or relapsed-refractory disease.
Ublituximab is a glycoengineered monoclonal antibody targeting CD20. Umbralisib is a dual inhibitor of PI3K-δ and CK1-ε.
“We are extremely pleased that the ublituximab BLA has been accepted by the FDA. This is an important milestone for us as it brings us one step closer to our goal of providing a novel combination treatment option to patients with both treatment naive and relapsed or refractory CLL and SLL,” Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics, said in a press release. “We look forward to collaborating with the FDA throughout this review process.”
Results of the trial were previously presented at the 2020 American Society of Hematology Annual Meeting & Exposition, with the experimental therapy outperforming the standard of care in patients with CLL regardless of prior treatment exposure.2
Median progression-free survival (PFS) was significantly improved with the ublituximab/umbralisib combination at 31.9 months versus 17.9 months with the obinutuzumab/chlorambucil combination (HR, 0.546; 95% CI, 0.413-0.720; P <.0001) in the intention-to-treat population. With a median follow-up of 36.7 months, the rates of PFS at 2 years were 60.8% and 40.4%, respectively.
In patients with treatment-naïve disease, the median PFS was 38.5 months in the experimental arm versus 26.1 months with the active comparator (HR, 0.482; 95% CI, 0.316-0.736; P < .001). The 2-year PFS rates were 76.6% and 52.1%, respectively.
For the secondary end point of objective response rate, ublituximab/umbralisib outperformed the control with 83.3% patients responding versus just 68.7%, respectively (P <.001). Corresponding rates of complete response (CR) or CR with incomplete marrow recovery were 5% and 1%.
It is notable that the combination of ublituximab plus umbralisib resulted in an over 4-fold longer exposure and reporting period versus obinutuzumab plus chlorambucil. Adverse effects (AEs) of grade 3/4 in severity included alanine aminotransferase (8.3% vs 1.0%, respectively), elevated aspartate aminotransferase (5.3% vs 2.0%), noninfectious colitis (1.9% vs 0%), infectious colitis (0.5% vs 0.5%), pneumonitis (0.5% vs 0%), rash (2.4% vs 0.5%), and opportunistic infections (5.8% vs 1.5%). Corresponding rates of AEs leading to treatment discontinuations were 17% and 8%.
On the trial, oral umbralisib was administered at 800 mg daily until progression or treatment discontinuation. Intravenous ublituximab was given at 900 mg split between days 1 and 2, then again on day 8 and 15 of cycle 1; day 1 of cycles 2 to 6; and on day 1 every 3 cycles after cycle 6.
Prior to regulatory submission, the FDA previously granted fast track and orphan drug designations to the combination of ublituximab and umbralisib in patients with CLL. The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022.
1. TG Therapeutics Announces FDA Acceptance of Biologics License Application for Ublituximab in Combination with UKONIQ® (umbralisib) as a Treatment for Patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. News release. TG Therapeutics, Inc. May 25, 2021. Accessed May 25, 2021. https://bit.ly/34gxnGj
2. Gribben JG, Jurczak W, Jacobs R, et al. 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. Presented at: American Society of Hematology Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 543. Accessed December 7, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134783.html