FDA Grants Orphan Drug Designation to Umbralisib for Patients with Follicular Lymphoma


The FDA granted orphan drug designation to umbralisib based on results from the phase IIb UNITY-NHL trial cohort of patients with follicular lymphoma who have received at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

The FDA granted orphan drug designation to umbralisib, an investigational dual inhibitor of PI3K-delta and CK1-epsilon, for the treatment of patients with follicular lymphoma, according to TG Therapeutics, the agent’s developer.1

Umbralisib is being evaluated across multiple types of lymphoma in the UNITY-NHL phase IIb registration directed clinical trial, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. Patients are being randomized to either umbralisib alone, umbralisib plus ublituximab, or umbralisib plus ublituxiumab and bendamustine (Treanda).

The follicular lymphoma cohort within the UNITY-NHL trial is designed to assess the safety and efficacy of umbralisib in patients with follicular lymphoma who have received at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. 

In October 2019, the developer announced that the follicular lymphoma cohort of 118 patients had met the primary endpoint of overall response rate (ORR) with a primary response target of 40%-50% ORR. 

“The receipt of orphan drug designation for umbralisib to treat patients with follicular lymphoma is another important milestone in the development and anticipated commercialization of umbralisib in marginal zone lymphoma and follicular lymphoma,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in a press release. “We were pleased to announce last year that both the marginal zone lymphoma and follicular lymphoma cohorts of the UNITY-NHL trial met their primary endpoints and have commenced our first rolling submission for these indications. We are excited by the progress so far and look forward to completion of this submission targeted in the first half of this year.” 

In January 2019, the FDA granted umbralisib a breakthrough therapy designation for the treatment of adult patients with marginal zone lymphoma who received 1 prior anti-CD20 regimen, based on interim data from the UNITY-NHL cohort. Further, in January 2020 the company initiated a rolling submission of a New Drug Application to the FDA for umbralisib as a treatment for patients with previously treated marginal zone lymphoma and follicular lymphoma. 

Previous results from the UNITY-NHL trial, presented at the 2019 AACR Annual Meeting, indicated that single-agent umbralisib had an ORR of 52% in patients with relapsed or refractory marginal zone lymphoma.2,3 The primary endpoint in this cohort was ORR, which was determined by an IRC by 2007 International Working Group Criteria. Secondary endpoints included duration of response, progression-free survival, time to response, and safety.

Seventy-two patients with marginal zone lymphoma were enrolled between July 2017 and August 2018 and at the time of data reporting, 69 participants had received the umbralisib therapy, 42 of which had 9 months of follow-up. Patients were treated with 800 mg of umbralisib monotherapy daily until disease progression or unacceptable toxicity. To be eligible, patients had to have splenic, nodal, or extranodal marginal zone lymphoma that required treatment, relapsed or refractory disease that progressed on ≥1 prior lines of therapy that included at least 1 CD20-directed regimen, and an ECOG performance status ≤2.

At a median follow-up of 12.5 months (range, 8.3-18.5) in the interim efficacy population, the complete response rates were 19% and 12%, and partial response rates were 33% and 40%, in the IRC- and investigator-assessed cohorts, respectively. The stable disease rates were 36% and 31%, respectively, and progressive disease rates were 7% and 10%. Moreover, the clinical benefit rate was 88% as determined by IRC assessment. 

Ten (24%) subjects discontinued therapy for disease progression, 5 (12%) for treatment-related adverse events (TRAE), 2 (5%) due to a non-TRAE, 1 (2%) withdrew consent, and 1 (2%) discontinued due to the investigator’s decision.

Overall, the dual inhibitor was found to be well tolerated in all of the treated patients, with the highest grade ≥3 adverse event being diarrhea (10%). Grade 3 infections, including bronchitis, pneumonia, and influenza, occurred in 3 patients.

The FDA previously granted orphan drug designation to umbralisib for the treatment of patients with all three types of marginal zone lymphoma, including nodal, extranodal, and splenic marginal zone lymphoma.


1. TG Therapeutics Receives Orphan Drug Designation for Umbralisib from the U.S. Food and Drug Administration for the Treatment of Follicular Lymphoma [news release]. New York. Published March 5, 2020. ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-receives-orphan-drug-designation-umbralisib-us-0. Accessed March 10, 2020. 

2. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, registration directed phase II study. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT132.


3. Davids MS, Flinn IW, Mato AR, et al. Long term integrated safety analysis of umbralisib (TGR-1202), a PI3K-DELTA/CK1-EPSILON inhibitor with a differentiated safety profile, in patients with relapsed/refractory lymphoid malignancies. Presented at: 2018 European Hematology Association Congress; June 14 to 17, 2018; Stockholm, Sweden. Abstract PF444.

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