Rolling Submission of BLA to FDA Initiated for Ublituximab Plus Umbralisib in CLL

A rolling submission of a Biologics License Application (BLA) to the FDA has been initiated for the combination of ublituximab (TGTX-1101) plus umbralisib (TGR-1202; U2) as treatment of patients with chronic lymphocytic leukemia (CLL), announced TG Therapeutics, Inc., in a press release.¹

The FDA previously granted a Fast Track designation to the U2 regimen as treatment of adult patients with CLL, as well as an Orphan Drug designation. The rolling submission of the BLA is expected to be completed by the first half of 2021.

“The initiation of a BLA submission for ublituximab in combination with umbralisib is an important milestone for us, and 1 that brings us 1 step closer to our goal of developing combination therapies for patients in need,” said Michael S. Weiss, executive chairman and chief executive officer, TG Therapeutics, in a statement. “This application, as well as the recently granted Fast Track Designation, is supported by the UNITY-CLL phase 3 trial which met its primary endpoint of improvement in progression-free survival [PFS] compared to obinutuzumab [Gazyva] plus chlorambucil and will be presented in an oral presentation at the 2020 American Society of Hematology (ASH) annual meeting beginning this weekend.”

The improvement in PFS with U2 compared with obinutuzumab plus chlorambucil was statistically significant (P <.0001) in the phase 3 UNITY-CLL clinical trial (NCT02612311), and the study was stopped early for superior efficacy, according to topline findings announced in May 2020, by TG Therapeutics in a press release.²

“We believe, if approved, U2 has the potential to become an important treatment option to both front line and relapsed/refractory patients with CLL,” stated Weiss.

UNITY-CLL is a randomized, controlled study comparing U2 to obinutuzumab plus chlorambucil as treatment of patients with either treatment-naïve or relapsed/refractory CLL. Patients were randomized to 1 of 4 treatment arms, which include ublituximab alone, umbralisib alone, U2, or the anti-CD220 monoclonal antibody obinutuzumab plus chlorambucil chemotherapy as the control arm. The trial is being conducted under a Special Protocol Assessment agreement with the FDA.

The study completed enrollment in October 2017. The primary end point of the study is superior PFS, and the secondary end point is objective response rate (ORR). Approximately 420 patients were enrolled to the study, whereas 60% had treatment-naïve disease, and 40% had relapsed/refractory CLL.

To be included in the study, patients had to have either treatment-naïve or previously treated CLL who required treatment and had an ECOG performance status of 0 to 2. Patients were excluded from the study if they had any major surgery, chemotherapy, or immunotherapy within the last 21 days; evidence of hepatitis B virus, hepatitis C virus, or a known HIV infection; autologous hematologic stem cell transplant within 3 months of study entry, transformation of CLL to an aggressive non-Hodgkin lymphoma, such as Richter’s transformation; or prior therapy with obinutuzumab and/or chlorambucil or a PI3K delta inhibitor. Patients had to be 18 years or older to enroll to the study.

_References

_{1. TG Therapeutics initiates rolling submission of Biologics License Application to U.S. Food and Drug Administration for ublituximab in combination with umbralisib as a treatment for patients with chronic lymphocytic leukemia. News Release. December 1, 2020. Accessed December 1, 2020. https://bit.ly/3mrm05P}

_{2. TG Therapeutics announces positive topline results from the UNITY-CLL phase 3 study evaluating the combination of umbralisib and ublituximab (U2) for the treatment of patients with chronic lymphocytic leukemia. News Release. TG Therapeutics. May 5, 2020. Accessed December 1, 2020. https://bit.ly/3b1DnUh}