Rolling Submission of BLA to FDA Completed for Ublituximab/Umbralisib in CLL

The rolling submission of a biologics license application to support the approval of ublituximab plus umbralisib as a treatment for patients with chronic lymphocytic leukemia has been completed.

The rolling submission of a biologics license application (BLA) to support the approval of ublituximab plus umbralisib (Ukoniq) as a treatment for patients with chronic lymphocytic leukemia (CLL) has been completed, according to an announcement from TG Therapeutics, Inc.1

The application was based on data from the phase 3 UNITY-CLL trial (NCT026112311), which showed that the combination had synergistic activity in patients with CLL vs standard-of-care chemoimmunotherapy, irrespective of prior treatment.2,3

At a median follow-up of 36.7 months, ublituximab/umbralisib was found to result in a significant improvement in progression-free survival (PFS) vs obinutuzumab (Gazyva) plus chlorambucil across all subgroups analyzed. In the intent-to-treat population, the median PFS in the in the investigative arm was 31.9 months (95% CI, 28.2-35.8) compared with 17.9 months (95% CI, 16.1-22.6) in the control arm (HR, 0.546; 95% CI, 0.413-0.720; P <.0001). Moreover, the 24-month PFS rate was 60.8% with ublituximab plus umbralisib vs 40.4% with obinutuzumab plus chlorambucil.

Among treatment-naïve patients, the median PFS with ublituximab/umbralisib was 38.5 months (95% CI, 33.2–not evaluable) vs 26.1 months (95% CI, 19.4-33.1) with the obinutuzumab regimen (HR, 0.482; 95% CI, 0.316-0.736; P <.001). The 24-month PFS rates in the investigative and control arms were 76.6% and 52.1%, respectively.2

In a subset of patients who had received a median of 2 prior therapies (range, 1-9), patients who received ublituximab plus umbralisib also experienced a PFS benefit over those who received the chemoimmunotherapy, at 19.5 months vs 12.9 months, respectively (HR, 0.601; 95% CI, 0.415-0.869; P <.01).2

“The rapid completion of this BLA submission is a critical step forward in our mission to bring our first proprietary combination regimen to patients with both treatment naïve and relapsed or refractory CLL,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, stated in a press release. “The FDA has previously granted the U2 combination both fast track designation as well as orphan drug designation for patients with CLL and we look forward to continuing to work closely with the FDA with the goal of bringing this novel treatment regimen to patients as quickly as possible.”

In a total of 421 patients with treatment-naïve or relapsed/refractory CLL were included in the primary analysis of the trial; of those enrolled, 57% had treatment-naïve disease and 43% had relapsed/refractory disease. Patients were randomized in a 1:1 fashion between ublituximab plus umbralisib vs obinutuzumab plus chlorambucil.

Participants received oral umbralisib at a once daily dose of 800 mg until either disease progression or treatment discontinuation. Ublituximab was given intravenously at 900 mg on days 1/2 (150 mg on day 1 followed by 750 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 to 6, and on day 1 every 3 cycles following cycle 6. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1/2 (100 mg on day 1 followed by 900 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 through 6. Oral chlorambucil was delivered at a dose of 0.5 mg/kg on days 1 and 15 of cycles 1 through 6. Each treatment cycle was 28 days.

The primary end point was PFS per independent review committee (IRC) assessment, while key secondary end points comprised IRC-assessed overall response rate (ORR), complete response (CR), and safety assessed from the first dose until 30 days following the last dose.

Additional results showed that the ORR with ublituximab plus umbralisib was 83.3% (n = 210) vs 68.7% (n = 211) with obinutuzumab/chlorambucil (P <.001). Among those who responded in the investigative arm, 5% achieved a CR or CR with incomplete marrow recovery, while 79% experienced a partial response; these rates were 1% and 67%, respectively, in the control arm.

Results from a stratified analysis demonstrated an ORRs of 84% in those who were treatment naïve and received ublituximab plus umbralisib, 82% in those who were previously treated and were given the investigative regimen, and 57% in those who previously received a BTK inhibitor and were given ublituximab/umbralisib. In the control arm, these ORRs were 78%, 57%, and 25%, respectively.

Regarding safety, continuous treatment with the investigative regimen led to an over 4-fold longer exposure and reporting period for the regimen vs the control regimen. Adverse effects of clinical interest that were grade 3 or 4 in severity in the investigative vs control arms included elevated alanine aminotransferase (8.3% vs 1.0%), 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%).

Thirty-five patients in the investigative arm experienced toxicities that resulted in treatment discontinuation vs 16 patients in the control arm.

In October 2020, the FDA granted fast track designation to the investigational CD20-directed monoclonal antibody ublituximab plus the PI3K-delta inhibitor umbralisib for the treatment of adult patients with CLL; the decision was supported by data from UNITY-CLL.


  1. TG Therapeutics completes rolling submission of biologics license application to the US Food and Drug Administration for ublituximab in combination with UKONIQ (umbralisib) as a treatment for patients with chronic lymphocytic leukemia. News release. TG Therapeutics, Inc. March 29, 2021. Accessed March 29, 2021.
  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. Blood. 2020;136(suppl 1):37-39. doi:10.1182/blood-2020-134783
  3. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118