Ublituximab/Umbralisib BLA/sNDA in CLL and SLL Voluntarily Withdrawn


The pending biologics license application and supplemental new drug application seeking the approval of the combination of ublituximab and umbralisib in adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma has been voluntarily withdrawn by TG Therapeutics, Inc.

The pending biologics license application (BLA) and supplemental new drug application (sNDA) seeking the approval of the combination of ublituximab and umbralisib (Ukoniq; U2) in adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been voluntarily withdrawn by TG Therapeutics, Inc.1

The decision follows updated overall survival (OS) data yielded from the phase 3 UNITY-CLL trial (NCT026112311), which demonstrated an increasing imbalance in survival in favor of the control arm.

The company also announced the decision to voluntarily withdraw umbralisib from sale for the approved indications of adult patients with marginal zone lymphoma (MZL) who have previously received at least 1 anti-CD20–based regimen and for adult patients with follicular lymphoma who previously received at least 3 systemic therapies.

Umbralisib was granted an accelerated approval from the FDA in February 2021 for these indications based on data from 2 single-arm cohorts of the open-label, multicenter, phase 2/3 UNITY-NHL trial (NCT02793583).2 Here, the agent produced an objective response rate of 49% (95% CI, 37.0%-61.6%) in patients with MZL (n = 69), which included a complete response (CR) rate of 16%. The ORR achieved with the agent in patients with follicular lymphoma (n = 117) was 43% (95% CI, 33.6%-52.2%), which included a CR rate of 3%.

“We were very disappointed to see that the recently updated OS data showed an increasing survival imbalance in favor of the control arm,” Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, stated in a press release. “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 Uknoiq from sale for the approved indications in MZL and follicular lymphoma. 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.”

In the global, phase 3 UNITY-CLL trial, investigators set out to compare the U2 regimen with a control arm comprised of obinutuzumab (Gazyva) plus chlorambucil in patients with treatment-naïve and relapsed/refractory CLL.

Patients were randomized to 1 of the following 4 treatment arms: single-agent ublituximab, single-agent umbralisib, U2, or obinutuzumab/chlorambucil. For the prespecified analysis of the trial, investigators evaluated the U2 combination and allowed for the monotherapy arms to be terminated. The study continued to enroll patients in a 1:1 ratio to the 2 combination arms.

A total of 421 patients were included in the primary analysis of the trial; 57% of these patients were treatment naïve and 43% had relapsed or refractory disease. Patients on the U2 arm received oral umbralisib at a once-daily dose of 800 mg until progressive disease or treatment discontinuation, and intravenous ublituximab at 150 mg on day 1, followed by 750 mg on day 2, and 900 mg on days 8 and 15 of cycle 1; day 1 of cycles 2 to 6; and on day 1 every 3 cycles after cycle 6. Those on the control arm were given IV obinutuzumab at 1000 mg on days 1 and 2 (100 mg given on day 1 followed by 900 mg give on day 2), 8, and 15 of cycle 1; and day 1 of cycles 2 to 6. These patients also received oral chlorambucil, which was given at 0.5 mg/kg on days 1 and 15 of cycles 1 to 6.

The primary end point of the trial was progression-free survival (PFS) per independent review committee (IRC) assessment, and secondary end points comprised IRC-assessed ORR, CR, and safety.

The trial met its primary end point, when at a median follow-up of 36.7 months, the U2 regimen resulted in a median IRC-assessed PFS of 31.9 months (95% CI, 28.2-35.8) vs 17.9 months (95% CI, 16.1-22.6) with obinutuzumab/chlorambucil (HR, 0.546; 95% CI, 0.413-0.720; P < .0001).3,4 The PFS rates at 24 months in the investigative and control arms were 60.8% and 40.4%, respectively.

Among those who were treatment naïve, the median PFS with the U2 regimen was 38.5 months (95% CI, 33.2–not evaluable) vs 26.1 months (95% CI, 19.4-33.1) with obinutuzumab plus chlorambucil (HR, 0.482; 95% CI, 0.316-0.736; P < .001). In this subset, the 24-month PFS rates were 76.6% and 52.1%, respectively. In patients who previously received a median of 2 therapies (range, 1-9), the median PFS in the investigative and control arms was 19.5 months and 12.9 months, respectively (HR, 0.601; 95% CI, 0.415-0.869; P < .01).

Additional findings that read out during the 2020 ASH Annual Meeting showed that U2 elicited an ORR of 83.3% (n = 210) vs 68.7% (n = 211) with obinutuzumab/chlorambucil (P < .001).5 Among responders to U2, 5% achieved a CR or CR with incomplete marrow recovery, and 79% had a partial response (PR). Among those who responded to the control regimen, the CR and PR rates were 1% and 67%, respectively.

When looking at data from a stratified analysis, the ORR with U2 in those who were treatment naïve was 84%; this rate was 82% in those who previously received treatment. Among those who previously received a BTK inhibitor, the ORR achieved with the U2 regimen was 57%. Among those who received the control regimen, the ORR was 78% in those who were treatment naïve, 57% in those who previously received treatment, and 25% in those who had a prior BTK inhibitor.

In November 2021, the FDA notified TG Therapeutics that it planned to host an Oncologic Drug Advisory Committee meeting in connection with its review of the pending application to discuss the risk-benefit ratio of umbralisib in its approved indications. Although the regulatory agency identified several concerns, the desire for the meeting stemmed from an early ad-hoc analysis of OS from UNITY-CLL, according to TG Therapeutics.

In February 2022, the FDA announced that they were investigating umbralisib following initial findings from UNITY-CLL revealed a potential increased risk of death in those who received the agent.5

OS served as a secondary end point of the trial but was not part of the primary analysis; therefore, OS information was not analyzed or included in the application. Moreover, the study was not powered for OS, according to TG Therapeutics.

As part of the review process for the BLA/sNDA, the regulatory agency requested an early analysis of OS from the trial. In a first analysis that utilized a September 2021 cutoff date, an imbalance in favor of the control arm was observed (HR, 1.23), but approximately 15% of patients had missing or outdated survival data. When deaths associated with COVID-19 were excluded, the 2 arms were approximately balanced (HR, 1.04).

In the same month, the company submitted updated OS data with the same cutoff date; this included reduced missing data and additional OS events and illustrated an improvement over OS data that had previously been reported. However, the original preliminary results and the updated preliminary results were both not determined to be 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,” according to the press release.

Based on this information, the company decided to voluntarily withdraw the pending BLA/sNDA. As such, the ODAC meeting slated for April 22, 2022, will be cancelled. Moreover, the company’s decision to withdraw umbralisib from sale is anticipated to result in the regulatory withdrawal of the accelerated approval for the agent in the MZL and follicular lymphoma indications.


  1. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; April 15, 2022. Accessed April 15, 2022.
  2. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA; February 5, 2021. Accessed April 15, 2021.
  3. 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
  4. 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
  5. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). News release. FDA; February 3, 2022. Accessed April 15, 2022.
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