Rolling BLA for Ublituximab and Umbralisib in CLL Completed for FDA Submission

The rolling submission of a Biologics License Application for the combination of ublituximab and umbralisib (Ukoniq) for the treatment of chronic lymphocytic leukemia (CLL) has been completed for submission to the FDA, according to a press release by TG Therapeutics, Inc.¹

Ublixtuximab is an investigation glycoengineered anti-CD20 monoclonal antibody and umbralisib is an oral, once-daily PI3K-delta and CK1-epsilon inhibitor. The combination was previously granted both a fast track designation and an orphan drug designation by the FDA for the treatment of adult patient patients with CLL.¹

The BLA submission is based on the results of the UNITY-CLL trial (NCT02612311), which showed preliminary efficacy and tolerable safety, according to results presented during the 2020 American Society of Hematology (ASH) Annual Meeting and later published in Blood. The global, randomized Phase 3 trial has an estimated enrollment of 600 patients split into 4 arms. In arm 1, patients received an ublituxumab infusion on days 1, 8, and 15 and a fixed dose of umbralisib daily. Patients in arm 2 received an infusion of obinutuzumab on days 1, 8, and 15 in cycle 1 followed by 1 infusion in cycles 2-6. Additionally, patients received chlorambucil on days 1 and 15 during cycles 1 through 6. In arm 3, patients received ublituxumab as monotherapy on days 1,8, and 15 followed by maintenance infusions. In arm 4, patients received a fixed oral dose of umbralisib daily.¹

The primary outcome of the study is progression-free survival (PFS). The secondary outcome is overall response rate (ORR). In order to participate, patients must be at least 18 years old. Additionally, patients can be either treatment naïve or previously treated. Exclusion criteria include any major surgery, chemotherapy, or immunotherapy within the last 21 days, evidence of hepatitis B or C, or any known HIV infection. Additionally, patients previously treated with obinutuzumab and/or chlorambucil or a PI3K delta inhibitor.¹

Patients were randomized 1:1 between the two combination arms with approximately 420 subjects enrolled between them. Of the patients, 57% were treatment-naïve and 40% were relapsed or refractory. The median age was 67 and 66% of patients were male.²

At a median follow-up of 36.2 months, the combination of ublituxumab and umbralisib proved to prolong PFS when compared to obinutuzumab in combination with chlorambucil, which has a median PFS of 31.9 months vs 17.9 months (HR, 0.546, 95% CI 0.413-0.720, P <.0001; Figure 1). The projected 24-month PFS for the combination was 60.8 months and 40.4% for obinutuzumab plus chlorambucil. Patients also remained on ublituxumab plus umbralisib for much longer, 23 months compared to the 5 months on obinutuzumab plus chlorambucil.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 chronic lymphocytic leukemia,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, in a press release.1 “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.”

Aside from CLL, umbralisib is already indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20 based regimen for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least 3 prior lines of systemic therapy. Currently it is the first and only PI3K-delta and CK1-epsilon inhibitor.

_REFERENCE:

_{1. TG Therapeutics completes rolling submission of Biologics License Application to the U.S. Food and Drug Administration for ublituximab in combination with uKONIQ™(umbralisib) as a treatment for patients with chronic lymphocytic leukemia. News Release. March 29, 2021. Accessed March 29, 2021. https://bit.ly/3rDnwn7}

_{2. 543 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. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118}