The FDA still hasn't found what its looking for in TG Therapeutics’ application for the leukemia and lymphoma combo treatment nicknamed U2, and so the therapy will be examined at an advisory committee meeting.
Shares of New York-based TG tumbled as the markets opened Tuesday, dropping more than 40% to $12.89 compared to a prior close of $23.36.
TG is seeking approval of the biologics license application (BLA) to combine ublituximab with Ukoniq. The latter is already marketed for use in two types of relapsing lymphoma in previously treated patients. The company is now seeking to add the new therapy to the mix for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
But the FDA wants to know more, according to a company statement issued Nov. 30. The agency will now hold a session of the Oncologic Drugs Advisory Committee to examine the combo. A date for the meeting has not been determined. The FDA is expected to decide on the U2 combo by March 25, 2022.
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Questions to be examined include the benefit-risk ratio of the combo in CLL and SLL and the benefit-risk of Ukoniq in its approved indications in relapsed/refractory marginal zone lymphoma and follicular lymphoma. The committee will also consider the safety profile of the combo, specifically serious adverse events, discontinuations after adverse events and dose modifications.
These concerns seem to be coming from an early analysis of overall survival from the phase 3 UNITY-CLL clinical trial. In that study, the combo beat the control arm on a measure of progression-free survival and set TG up for an FDA filing. The combo was compared to Roche’s Gazyva along with chemo drug chlorambucil in the trial.
But the early analysis of overall survival apparently raised red flags for the regulator. TG said that this was a secondary efficacy goal of the trial and not part of the primary analysis, which means it was not included in the BLA.
The study was also “not powered for overall survival,” the biotech said. But the FDA, nevertheless, asked for the early analysis from the trial. TG submitted information on this measure as of the September cutoff date and the limited data apparently had “an imbalance in favor of the control arm.” The result was not statistically significant, the company added.
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But when TG filtered out patients who had died due to COVID-19—which is known to be a serious risk for lymphoma patients—the two arms of the trial were more balanced. TG said that with this caveat, there was no statistically significant difference between patients taking the U2 combo and the Gazyva treatment in terms of overall survival.
TG plans to continue to analyze overall survival in the trial given the preliminary nature of this initial data and COVID-19's potential impact. The company believes the data submitted so far support the BLA as filed, according to Chairman and CEO Michael Weiss.
As for safety, TG posted an analysis of Ukoniq's adverse event profile in September, with Weiss touting a low rate of discontinuations. According to the analysis, 51 patients out of 371 discontinued treatment, a rate of 13.7%. Serious treatment-emergent adverse events occurred in 95 out of 371 patients. The most common adverse events "of special interest" were pneumonia, which occurred in 29 patients, noninfectious colitis in nine patients and pneumonitis in four people.
Ukoniq is a PI3K-delta inhibitor, a class of drugs that has historically seen limited use due to high discontinuation rates, according to the safety analysis study's lead author, Matthew Davids, M.D., director of Clinical Research in the Division of Lymphoma at the Dana-Farber Cancer Institute. Weiss said the results set TG's therapy apart from others in the class.