FDA Approval Application for U2 Regimen in CLL and SLL Voluntarily Withdrawn

The pending biologics license application (BLA)/supplemental new drug application (sNDA) for the combination of ublituximab (TG-1101) and umbralisib (Ukoniq), or U2, for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been withdrawn.¹

This decision was based on the overall survival (OS) data which was recently updated from the phase 3 UNITY-CLL trial (NCT02612311), showing an increasing imbalance in OS, according to a press release from TG Therapeutics, Inc.

TG Therapeutics, Inc. has also announced that it has voluntarily withdrawn umbralisib from the market for the treatment of patients with marginal zone lymphoma (MZL) who have received at least 1 prior anti-CD20-based regimen and for the treatment of adult patients with follicular lymphoma (FL) who have received at least 3 prior systemic therapies.

“We were very disappointed to see that the recently updated overall survival data showed an increasing survival imbalance in favor of the control arm. Accordingly, we and our advisors determined that we should withdraw the BLA/sNDA for U2 in CLL,” said Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, Inc. stated in the press release. “Additionally, we made the difficult decision to withdraw Ukoniq from sale for the approved indications in MZL/FL.”

The FDA extended its review of the BLA/sNDA for U2 in patients with CLL and SLL in March 2022, after umbralisib was granted accelerated approval in these indications in February 2021. In November 2021, an Oncologic Drug Advisory Committee meeting was planned by the FDA for April 2022, to determine if U2 should be an FDA approved regimen for these patients.

The global, randomized, controlled UNITY-CLL trial compared the U2 combination to an active control arm of obinutuzumab (Gazyva) plus chlorambucil in patients with treatment-naïve and relapsed or refractory CLL.² Within the study, patients were randomized to 1 of 4 treatment arms, which included ublituximab alone, umbralisib alone, the combination of the 2, or the anti-CD220 monoclonal antibody obinutuzumab plus chlorambucil chemotherapy as the control arm.

Umbralisib was given orally at a dose of 800 mg once a day until disease progression or treatment discontinuation. Ublituximab was administered intravenously (IV) at 900 mg on days 1/2 with (150 mg given on day 1 followed by 750 mg on day 2), day 8, and day 15 of cycle 1, day 1 of cycles 2 to 6, and on day 1 every 3 cycles after cycle 6. Obinutuzumab was given IV 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 to 6. Additionally, chlorambucil was given orally at 0.5 mg/kg on day 1 and 15 of cycles 1 to 6. Each cycle was 28 days.

The primary end point of the trial was independent review committee (IRC)-assessed progression-free survival (PFS) with key secondary end points including IRC-assessed overall response rate, complete response, and safety assessed from the first dose until 30 days after the last dose.

Data showed that at a median follow-up of 36.2 months, the median PFS was 31.9 months with U2 vs 17.9 months in the control arm (HR, 0.546; 95% CI, 0.413-0.720; P <.0001). In the U2 arm, the estimated 24-month PFS was 60.8% compared with 40.4% in the control arm, demonstrating that the trial met its primary endpoint, with U2 significantly prolonging PFS compared to the control arm.

Regarding the secondary end point, the U2 regimen achieved a higher ORR of 83.3% (95% CI, 78.1%-88.6%) vs 68.7% (95% CI, 62.2%-75.2%) in the control arm (P <.001).

In a first analysis of OS at a cut-off date of September 2021, an imbalance was shown in favor of the control arm (HR, 1.23). However, missing or outdated survival data occurred for approximately 15% of patients, and when excluding deaths related to COVID-19, the two arms were approximately balanced (HR, 1.04).

OS data with the same cut-off date were collected in February 2022. However, reduced missing data and additional OS events showed an improvement from the previously reported data, and neither the original results nor the updated results were statistically significant.

“While we had hoped to bring U2 to patients with CLL, this will now permit us to focus our attention, passion and energy to building out our multiple sclerosis and autoimmune platform. With our ublituximab BLA pending for patients with relapsing forms of multiple sclerosis and a PDUFA goal date of September 28, 2022, we are excited about the possibility of bringing ublituximab to patients with RMS. If approved, we believe the differentiated profile of ublituximab with its one-hour infusion will be welcomed by the MS community,” added Weiss in the press release.

REFERENCES:

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 18, 2022. https://bit.ly/3KU5ffY

2. Ublituximab + TGR-1202 compared to obinutuzumab + chlorambucil in patients With untreated and previously treated chronic lymphocytic leukemia (UNITY-CLL). Clinicaltrials.gov. Accessed April 18, 2022. https://bit.ly/3JSfCPW