FDA Extends PDUFA Date for BLA/sNDA of Ublituximab Plus Umbralisib in CLL/SLL

The 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) seeking the approval of ublituximab plus umbralisib (Ukoniq; U2) in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.¹

The regulatory agency notified TG Therapeutics, Inc. that the updated overall survival analyses that had been submitted in February 2022, represented a major amendment to the applications. As such, the FDA decided to extend the decision date to allow for enough time to adequately review the submissions.

“As mentioned on our earnings call earlier this week, we believed the extension of the PDUFA date was a likely scenario especially given the proposed timing of the upcoming Oncologic Drugs Advisory Committee [ODAC] meeting,” Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, stated in a press release. “We hope this extension provides the time needed to give proper attention and review to the U2 BLA/sNDA. We continue to believe in the potential of U2 to provide a meaningful treatment option to patients with CLL and SLL.”

Discussion topics that are slated to be covered during the meeting,² which is expected to take place in March or April 2022, will include:

• The benefit-risk of the U2 combination in patients with CLL/SLL
• The benefit-risk of umbralisib in patients with relapsed/refractory marginal zone lymphoma or follicular lymphoma
• As part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including adverse effects (AEs), discontinuations because of AEs, and dose modifications

In February 2022, the FDA announced that they were investigating umbralisib after initial findings from the phase 3 UNITY-CLL trial (NCT026112311) revealed a potential increased risk of death in those who received the agent.³

Although overall survival (OS) was designated as a secondary efficacy outcome in the trial protocol, it was not part of the primary analysis in accordance with the study’s statistical analysis plan that had been agreed upon via a Special Protocol Assessment. Because of this, this information was not evaluated or included in the application, according to TG Therapeutics, Inc. Moreover, the study was not powered for OS.

As part of the review process, the FDA requested an early analysis of OS from the trial. As of September 2021, which was the cutoff date of this analysis request, an imbalance was observed in favor of the control arm (HR, 1.23); however, the result was not noted to be of statistical significance. When excluding deaths associated with COVID-19, the 2 arms were approximately balanced (HR, 1.04); again, however, no statistically significant difference was observed between the arms.

In February 2022, TG Therapeutics, Inc. submitted updated OS data with the same September 2021 cutoff date. The company also shared plans to continue to examine this end point over time, as more events occur, underscoring that they will continue to assess how COVID-19 may impact the analysis.

The BLA/sNDA submissions were supported by findings from the phase 3 UNITY-CLL trial, which compared the use of U2 with that of obinutuzumab (Gazyva) and chlorambucil in patients with treatment-naïve or relapsed/refractory CLL.

Study participants were randomized into 1 of 4 treatment arms: ublituximab monotherapy, umbralisib monotherapy, U2, and obinutuzumab/chlorambucil. For the prespecified interim analysis, investigators examined the contribution of U2 in the combination arm and allowed for the termination of the monotherapy arms. The study then continued enrollment in a 1:1 ratio to 2 combination arms: U2 or obinutuzumab/chlorambucil.

The primary analysis of the trial included a total of 421 patients, 57% of whom were treatment naïve and 43% of whom relapsed/refractory disease. Those on the investigative combination arm were given oral umbralisib at 800 mg once daily until disease progression or treatment discontinuation. Intravenous (IV) ublituximab was given 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 following cycle 6.

Those in the control arm received IV obinutuzumab at 1000 mg on days 1 and 2 (100 mg given on day 1 followed by 900 mg given on day 2), 8, and 15 of cycle 1; and day 1 of cycles 2 through 6. Oral chlorambucil was administered at 0.5 mg/kg on days 1 and 15 of cycles 1 through 6. Each treatment cycle was comprised of 28 days.

The primary end point of the trial was progression-free survival (PFS) per independent review committee (IRC), and key secondary end points included overall response rate (ORR) per IRC, complete response (CR), and safety evaluated from the first dose of treatment up to until 30 days following the last dose of treatment.

The trial met the primary end point, with U2 significantly prolonging IRC-assessed PFS vs the control, at a median of 31.9 months (95% CI, 28.2-35.8) vs 17.9 months (95% CI, 16.1-22.6), respectively (HR, 0.546; 95% CI, 0.413-0.720; P < .0001), at a median follow-up of 36.7 months.^4,5 The 24-month PFS rates in the investigative and control arms were 60.8% and 40.4%, respectively.

In the subset of patients who were treatment naïve, the median PFS with U2 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). The 24-month PFS rates in the investigative and control arms were 76.6% and 52.1%, respectively.

In a subgroup of patients who received a median of 2 prior therapies (range, 1-9), the median PFS with U2 was 19.5 months vs 12.9 months with obinutuzumab/chlorambucil (HR, 0.601; 95% CI, 0.415-0.869; P < .01).

Additional data presented during the 2020 ASH Annual Meeting demonstrated that U2 elicited an ORR of 83.3% (n = 210) vs 68.7% (n = 211) with obinutuzumab/chlorambucil (P < .001).6 Of those who responded to the U2 regimen, 5% achieved a CR or CR with incomplete marrow recovery, and 79% experienced a partial response (PR). In the control arm, the CR rate was 1% and the PR rate was 67%.

Moreover, data from a stratified analysis showed that the ORR was slightly higher in those who were treatment naïve and received U2 vs those who received prior treatment, at 84% vs 82%, respectively. In those who previously received a BTK inhibitor, the ORR with the U2 regimen was 57%. These rates were 78%, 57%, and 25%, among those who received the control regimen.

In terms of safety, grade 3 or 4 toxicities of clinical interest in the investigative and control arms included elevated 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%). More patients who received the U2 regimen discontinued treatment because of adverse effects vs those who were given obinutuzumab plus chlorambucil (n = 35 vs n = 16).

References

1. TG Therapeutics announces extension of US FDA BLA/sNDA PDUFA date for ublituximab plus UKONIQ (U2) to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; March 3, 2022. Accessed March 3, 2022. https://bit.ly/3CamENT
2. TG Therapeutics provides regulatory update. News release. TG Therapeutics; November 30, 2021. Accessed March 3, 2022. https://bit.ly/3d6biPa
3. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). News release. FDA; February 3, 2022. Accessed March 3, 2022. https://bit.ly/3L9QaHw
4. 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
5. 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
6. Jacobs R, Jurczak W, Flinn IW, et al. Efficacy and safety of ublituximab in combination with umbralisib (U2) in patients with chronic lymphocytic leukemia (CLL) by treatment status: a sub-analysis of the phase 3 UNITY-CLL study. Blood. 2021;138(suppl 1):3726. doi:10.1182/blood-2021-147460