The World's First PI3Kδ/CK1ε Inhibitor Was Frustrated

On April 15, TG Therapeutics announced the voluntary withdrawal of the Biologics License Application (BLA)/Supplemental New Drug Application for the U2 combination Ukoniq (umbralisib) in combination with ublituximab in adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). sNDA). The decision to withdraw is based on recently updated overall survival (OS) data from the Phase III UNITY-CLL trial.

In addition, the company has voluntarily stopped selling Ukoniq, meaning the company's only product will also be withdrawn from the market. In February 2021, Ukoniq received accelerated FDA approval for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based therapy regimen and who have received at least third-line systemic therapy. of adult patients with relapsed or refractory follicular lymphoma (FL). Ukoniq is the first and only approved once-daily oral phosphoinositide 3-kinase (PI3K) delta and casein kinase 1 (CK1) epsilon inhibitor.

The UNITY-CLL trial is a global phase III randomized controlled trial to compare the U2 combination vs. chlorambucil + obinutuzumab in patients with untreated and relapsed or refractory CLL Efficacy. The trial met its primary endpoint, with U2 significantly extending independent review committee (IRC)-assessed progression-free survival (PFS) compared to the control arm, with mPFS of 31.9 months and 17.9 months, respectively. Based on the PFS results, in May 2021, the FDA accepted a BLA application for the combination of U2 in CLL and SLL.

In September 2021, TG received a letter from the FDA, and the FDA stated that it would convene an expert advisory committee to discuss the BLA application for the U2 combination in the treatment of CLL/SLL, and to discuss the benefits and risks of Ukoniq in approved indications. The main reason is that the results of an earlier analysis of OS in the UNITY-CLL trial showed that the U2 combination did not show a significant difference in OS compared to the control group. In February 2022, the company submitted updated OS data, but the OS results were still not statistically significant.

Following a recent FDA request, TG collected updated OS data, however data showed a skew in favor of the control group, and based on these new data, the company decided to withdraw the BLA/sNDA for U2 in CLL/SLL, thus April 22, 2022 The ODAC meeting that will be held on 11 March has also been cancelled accordingly.

Additionally, the FDA is expected to withdraw accelerated approval for the product based on the company's decision to stop marketing Ukoniq.

Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, said: "The company will focus its resources on the multiple sclerosis and autoimmune platforms. Ublituximab is currently under FDA review for relapsing forms of multiple sclerosis with a PDUFA date of September 28, 2022."