Umbralisib Granted Orphan Drug Status for Follicular Lymphoma


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

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

The designation, which facilitates the develop of treatments for rare diseases or conditions, is based on data from the 118-patient follicular lymphoma cohort of the phase IIb UNITY-NHL trial. TG reported in October 2019 that umbralisib achieved the primary endpoint of a target overall response rate (ORR) of 40% to 50% in the cohort, which was comprised of patients who had received ≥2 prior lines of treatment, including an alkylating agent and a CD20-targeting monoclonal antibody. The company plans to present the results of the trial at an upcoming medical meeting.

TG reported in January 2020 that they had initiated a rolling submission to the FDA of a new drug application for umbralisib for use as a treatment in patients with previously treated marginal zone lymphoma (MZL) or follicular lymphoma.

“We were pleased to announce last year that both the MZL 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,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in a press release.

In the ongoing, open-label, multicenter, multicohort phase IIb UNITY-NHL trial (NCT02793583), investigators are evaluating umbralisib as a single agent or in various combination regimens in patients with previously treated non-Hodgkin Lymphoma (NHL). Specific NHL subtypes being evaluated include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and MZL. Patients are randomized to umbralisib alone, umbralisib plus ublituximab, or umbralisib plus ublituximab and bendamustine (Treanda).

Previous UNITY-NHL results presented at the 2019 AACR Annual Meeting showed that single-agent umbralisib had an ORR of 52% in patients with relapsed/refractory MZL.2,3

Seventy-two patients with MZL were enrolled between July 2017 and August 2018. Sixty-nine patients had received umbralisib therapy at the time of the data reporting, 42 of whom had 9 months of follow-up—these patients comprised the data from the interim efficacy cohort.

Patients were treated with 800 mg of umbralisib monotherapy daily until disease progression or unacceptable toxicity. To be eligible for enrollment, patients could have splenic, nodal, or extranodal MZL that required treatment; relapsed/refractory disease that progressed on ≥1 prior lines of therapy that included at least 1 CD20-directed regimen; and an ECOG performance status ≤2.

In the interim efficacy population, 23 patients (55%) had extranodal disease, followed by 12 (29%) with nodal and 7 patients (17%) with splenic MZL; this was comparable with the safety population of all patients treated (n = 69). The median age in both cohorts was 67 (range, 34-81); there were more females in the interim efficacy (n = 25; 60%) and safety (n = 36; 52%) populations. The majority of patients in the interim efficacy group (n = 32; 76%) had received rituximab (Rituxan)-based chemoimmunotherapy compared with 50 (72%) in the safety population. Moreover, 8 patients (19%) in the interim efficacy cohort were refractory to their most recent therapy; in the safety population, 18 patients (26%) were refractory to their last treatment. Similarly, 6 (14%) and 15 patients (22%) were refractory to prior anti-CD20 therapy in the interim efficacy and safety populations, respectively.

The primary endpoint was ORR determined by an IRC by 2007 International Working Group criteria; secondary endpoints included duration of response, progression-free survival, time to response, and safety.

At a median follow-up of 12.5 months (range, 8.3-18.5) in the interim efficacy population, the ORR was 52% as assessed by both IRC and investigator assessment. The complete response (CR) 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%. Additionally, the clinical benefit rate was 88% as determined by IRC assessment.

The median duration on treatment was 10.1 months (range, 5.6-15.7), and 55% of patients remain on therapy; this includes all patients who were in CR via IRC assessment.

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

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

In January 2019, the FDA granted umbralisib a breakthrough therapy designation for the treatment of adult patients with MZL who have received 1 prior anti-CD20 regimen, based on interim data from the UNITY-NHL cohort. The FDA also previously granted orphan drug designation to umbralisib for the treatment of patients with 3 MZL subtypes: nodal, extranodal, and splenic MZL.


1. TG Therapeutics Receives Orphan Drug Designation for Umbralisib from the U.S. Food and Drug Administration for the Treatment of Follicular Lymphoma. Published online March 5, 2020. Accessed March 6, 2020.

2. Fowler NH, Samaniego F, Jurczak , 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.

This article originally appeared on OncLive as, "FDA Grants Umbralisib Orphan Drug Status in Follicular Lymphoma."

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