UPDATE: TG disbands cancer program after pulling FDA request for U2 combo therapy

TG Therapeutics is winding down its oncology program after removing the FDA-approved cancer med Ukoniq from the market in two indications that were granted accelerated approval in addition to withdrawing an approval request for a combo med dubbed U2. 

The decision to redirect the pipeline was announced in an investor call Monday morning and follows Friday’s announcement regarding Ukoniq and ublituximab. Updated survival data from TG's phase 3 UNITY combo trial of the two meds for chronic lymphocytic leukemia (CLL), analyzed at the request of the FDA, showed that overall survival favored the control arm rather than the treatment arm. 

CEO Michael Weiss said Monday that UNITY will be put on hold and related work will be curtailed. Similarly, new enrollment in the company’s earlier stage programs looking at B cell malignancies will be paused. He added that axing the U2 program “definitely changes a lot of how we think about our oncology business.” 

“I know I speak for all of us at TG when I say this is a very disappointing outcome,” said Weiss. Following the news, TG's shares fell more than 20%, down $1.89 to just under $7 per share. 

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With the oncology program now fully on the back burner, TG is looking to its multiple sclerosis and autoimmune programs to buoy the business. The former is most promising, with the company submitting an approval request to the FDA for ublituximab to treat relapsing MS back in September 2021. The agency is scheduled to make a decision by Sept. 28. As of now, TG said the FDA is not planning to convene an advisory committee meeting before the decision, but Weiss noted that a meeting was eventually added to the calendar for the U2 combo.

TG doesn’t currently have any assets in its pipeline distinctly indicated for autoimmune diseases but Weiss hinted that some of the early oncology programs could be retooled to focus on those indications. However, a more concrete portfolio assessment won’t happen until the company launches ublituximab into MS. 

“I think we have a portfolio that can be translated from oncology to autoimmune diseases if, when we go ahead and do a full review, that makes the most sense,” he said. 

The news marks a disappointing end to a quickly evolving saga regarding the safety of Ukoniq. In February, the FDA alerted health professionals about a possible elevated risk of death from the drug, which won accelerated approval a year earlier in 2021 as a monotherapy to treat two types of lymphoma. The FDA identified the risk via an ongoing phase 3 combo trial testing Ukoniq with the company’s new asset, umbralisib, to treat CLL. 

In that trial, the regulatory agency found “possible increased risk of death in patients receiving the combination of Ukoniq and the monoclonal antibody compared to the control arm.” The FDA also found that treated patients had more serious adverse effects than the control arm. 

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“The Unity trial was conducted in CLL patients, which is not an approved use but rather a use of this drug that is being studied; however, the FDA believes these findings have implications for its approved uses for marginal zone lymphoma (MZL) and follicular lymphoma (FL),” the alert said. 

But even before the FDA sent out an official notice that the drug could do more harm than good, it began probing concerns about the UNITY trial. The trouble for TG began in November 2021 when the company reported that overall survival data provided to the agency at its request showed an elevated risk of death for treated patients. After excluding COVID-19 deaths from the data, the survival data were essentially the same. 

Two months later, at the end of January, the company disclosed that the FDA slapped clinical holds on select studies of U2 in CLL and NHL. That constituted at least five of TG's trials at the time and the company didn’t specify which ones were impacted. The company did say, however, that “most studies” included in the partial hold had already been closed to new enrollment or were on administrative hold. That disclosure set the stage for the FDA’s warning which came a week later.

In its announcement Friday, TG said that a more recent update of overall survival data provided to the FDA "showed an increasing imbalance in favor of the control arm, differing from the improved results provided to the FDA in February 2022." Monday, the company said updated data resembled the data first provided in November. 

RELATED: FDA expands oversight over TG's stalled U2 cancer combo therapy, sinking shares

As a result of TG’s decision to withdraw its application for the combo therapy, an FDA advisory committee meeting scheduled for next week to examine the U2 combo has been canceled. The company also said that, given its decision to withdraw Ukoniq from the market, it expects the FDA will take back the accelerated approval as well. 

Ukoniq’s fall from grace comes less than 15 months after it first hit the market through the FDA’s accelerated approval pathway to treat two types of blood cancer. According to phase 2 data used to validate the approval, the overall response rate among patients with relapsed refractory marginal zone lymphoma who had previously received at least one line of treatment was 49%. For patients with relapsed or refractory follicular lymphoma after at least three lines of treatment, the overall response rate was 43%. Among 221 patients from three single-arm, open-label studies, serious side effects were reported in 18% of patients. Ukoniq joined a list of other PI3K delta inhibitors to treat cancer, which have been known to have high toxicity risks. 

The accelerated approval program has come under scrutiny recently, primarily following the approval of Biogen’s Aduhelm to treat Alzheimer’s disease. The top issue at play for the FDA is consistent but nevertheless contentious: how to balance a lack of options versus a lack of data. In the case of Aduhelm, the agency approved the drug against the recommendations of its advisors. 

In a recent interview with Fierce Biotech, FDA Commissioner Robert Califf, M.D., suggested one way to improve faith in the program would be for companies to launch phase 4—also known as “confirmatory”—trials before a drug nabs approval. It was an idea he got from the agency’s oncology chief, Robert Pazdur, M.D., who noted in a separate interview with Fierce Biotech that the agency is hoping to expand the accelerated approval program in cancer.

Editor's note: This story was updated at 10:53 a.m. ET on April 18, 2022, to include commentary from a Monday investor's call.