FDA Accepts BLA for Ublituxumab and Umbralisib for Chronic Lymphocytic Leukemia

The FDA has accepted the biologic license application (BLA) for ublituximab in combination with umbralisib for the treatment of patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

The FDA has accepted the biologic license application (BLA) for ublituximab (TGTX-1101 )in combination with umbralisib (Ukoniq) for the treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to a press release by TG Therapeutics, Inc.1

Ublituximab, an investigational glycoengineered anti-CD20 monoclonal antibody, works by binding to B cells in order to trigger an immunological reaction, leading to cancer cell destruction. Additionally, the agent does not have the sugar molecules normally found on the antibody. The removal of these cells has been proven to enhance efficacy. Umbralisib is the only oral phosphoinositide 3 kinase (PI3K) delta and casein kinase (CK1) epsilon inhibitor.2

The BLA is based on results from the UNITY-CLL study (NCT02612311) which enrolled 600 participants and has an estimated completion date of January 2024. The primary outcome of the study is progression-free survival (PFS) and the secondary outcome is overall response rate (ORR).

The study was split into 4 arms. In arm 1 (U2), patients received an infusion of ublituxumab on days 1, 8, and 15 followed by maintenance infusions and an oral daily dose of umbralisib. In arm 2, patients received a combination of obinutuzumab (Gazyva) and chlorambucil (Leukeran) (O+Chl). In arm 3, patients received ublituxumab alone and in arm 4, umbralisib alone. 

In order to participate, patients can be either treatment-naïve or have had prior treatment. Additionally, they must have an ECOG performance score of 0 to 2. Patients who have had any major surgery, chemotherapy, or immunotherapy within the last 21 days, evidence of hepatitis B virus, autologous hematologic stem cell transplant within 3 months of study entry, transformation of CLL to aggressive non-Hodgkin lymphoma, or prior therapy with obinutuzumab and/or chlorambucil or a PI3K delta inhibitor are not eligible to participate.

Interim analysis was conducted on data collected from 421 participants randomized into U2 and O+Chl. The median age of the cohort was 67. Of the 421 participants, 57% were treatment-naïve and 43% had at least 1 prior therapy. Additionally, 56% were IgHV unmutated. The majority, 66%, were male.3

At the median follow-up of 36.2 months, the PFS for U2 was 31.9 months and 17.9 months for O+Chl (HR, 0.546; 95% CI 0.413-0.720, P <.0001). The estimated 24-month PFS for U2 was 60.8% and 40.4% respectively. The PFS improvement was consistent across all subgroups. The PFS for treatment-naïve patients in U2 was 38.5 months and 26.1 months for those in O+Chl (HR, 0.482; 95% CI, 0.316-0.736). For relapsed/refractory patients, the median was 19/5 months and 12.9 months for U2 and O+Chl respectively (HR, 0.601; 95% CI, 0.415-0.869). For patients previously treated with ibrutinib (Imbruvica), the ORR was 57% in the U2 group and 25% for O+Chl group.3

For the U2 group, median duration of treatment was 23 month and 5 months for O+Chl. Adverse events (AEs) lead to treatment discontinuation in 16.5% of patients in the U2 group and 7.6% in the O+Chl group. Neutropenia occurred in 30.6% of patients in the U2 group and 34.7% in the O+Chl group. Thrombocytopenia occurred in 3.4% in U2 and 13.1% of patients in the O+Chl group.3

“We are extremely pleased that the ublituximab BLA has been accepted by the FDA. This is an important milestone for us as it brings us one step closer to our goal of providing a novel combination treatment option to patients with both treatment naive and relapsed or refractory CLL and SLL. We look forward to collaborating with the FDA throughout this review process, said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics in a press release.

A Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022. No advisory committee meeting is planned to discuss the application.

1.TG Therapeutics announces FDA acceptance of biologics license application for ublituximab in combination with UKONIQ® (umbralisib) as a treatment for patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. TG Therapeutics. May 25, 2021. Accessed May 25, 2021. https://bit.ly/2RNbuMj
2.Ublituxumab (TG-1101) is a novel glycoengineered ANTI-CD20 monoclonal antibody. TG Therapeutics. Accessed May 25, 2021. https://bit.ly/2RKeUiS.
3.Gribben J, 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: https://doi.org/10.1182/blood-2020-134783