TG Therapeutics Backpedals on BLA for Lymphoma, Leukemia Treatment

FDA Stop_Sarah Silbiger/Getty Images

Courtesy of Sarah Silbiger/Getty Images

New York-based TG Therapeutics voluntarily withdrew its pending Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for its combination of ublituximab and Ukoniq (umbralisib), dubbed U2, for adults with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The company indicates the withdrawal was due to recently updated overall survival (OS) data from the Phase III Unity-CLL trial “that showed an increasing imbalance in OS.” The trial compared U2 to an active control arm of Obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory CLL. That trial hit the primary endpoint, with U2 significantly prolonging assessed progression-free survival (PFS) compared to the control arm.

Based on that study, a BLA and sNDA were submitted to the U.S. Food and Drug Administration for CLL/SLL.

The FDA informed TG Therapeutics in November 2021 that it was going to run an Oncologic Drug Advisory Committee (ODAC) meeting over the review to discuss the benefit-risk profile of Ukoniq in its approved indications. There were several concerns, apparently, but the FDA’s primary issue seemed to be from an early ad hoc analysis of OS in the Unity-CLL study.

OS was only a secondary efficacy endpoint of the trial but was not part of the primary analysis as part of the trial’s statistical analysis plan agreed upon by way of a Special Protocol Assessment (SPA) the company had with the FDA. As a result, it wasn’t analyzed or part of the BLA/sNDA. Also, the trial wasn’t designed to be powered for OS.

But the FDA requested an early analysis of OS from the trial as part of an ongoing review of the regulatory submissions. The first analysis of OS leveraged a cut-off date of September 2021. There was an imbalance in favor of the control arm. But because of the ad hoc nature of the analysis, about 15% of patients weren’t included in the survival data, or the data was outdated.

When the company excluded deaths associated with COVID-19, the two arms were about equal. Then, in February 2022, TG Therapeutics submitted updated OS data with the same September 2021 cut-off date but had fewer missing data and more OS events. These demonstrated improvements from the previous OS data, but neither were viewed as statistically significant.

The FDA then requested more data. This demonstrated an increasing imbalance favoring the control arm, which didn’t correlate with the data they provided the FDA in February 2022. Based on the new information, TG Therapeutics decided to withdraw the BLA/sNDA for U2 to treat CLL/SLL. The FDA also is canceling the ODAC meeting. TG also expects the FDA to withdraw the accelerated approval for Ukoniq.

“We were very disappointed to see that the recently updated overall survival data showed an increasing survival imbalance in favor of the control arm,” stated Michael S. Weiss, TG’s chairman and CEO. “Accordingly, we and our advisors determined that we should withdraw the BLA/sNDA for U2 in CLL. Additionally, we made the difficult decision to withdraw Ukoniq from sale for the approved indications in MZL/FL. We want to thank the patients, families and practitioners who worked with us in our search for novel treatment options for patients with B-cell malignancies.”

Ukoniq is the first and only oral inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. It was indicated for adults with r/r marginal zone lymphoma (MZL) who received at least one previous anti-CD20-based therapy and for adults with r/r follicular lymphoma (FL) who had at least three previous lines of systemic therapy.

Weiss went on to say that it will now focus its resources on its multiple sclerosis and autoimmune platform. Ublituximab is currently under review by the FDA for relapsing forms of multiple sclerosis with a target action date of September 28, 2022.

This leaves the company currently with no products to market.

In February, the FDA reported it was investigating a potential increased death risk for Ukoniq. It informed physicians and patients of the investigation and went back to evaluate the Unity trial. It also suspended enrollment of new patients in other trials of the drug while it reviewed the Unity findings

Ukoniq first entered the market in February 2021 when the FDA granted it Accelerated Approval for r/r MZL and FL.

At TG's 2021 annual report on March 1, the company reported 2021 product revenue of $6.537 billion, with $152 million in license revenue. As of December 31, 2021, it held $350.3 million in cash, cash equivalents and investment securities. It reported a net loss for the year of $348.1 million.

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