TG Therapeutics is a biopharmaceutical company dedicated to developing innovative therapies for patients with B-cell mediated diseases. Recently, the company announced that it has initiated rolling submission of new drug applications (NDA) to the US Food and Drug Administration (FDA), seeking to expedite approval of the company's oral, daily, inositol-3-kinase δ (PI3Kδ) and CK1-ε double-acting inhibitor umbralisib (TGR-1202) is used in patients with marginal zone lymphoma (MZL) and follicular lymphoma (FL) who have previously been treated. The company has received FDA guidance that a single DNA submission is acceptable for MZL and FL indications. Earlier, the FDA has granted orphan drug status (ODD) and breakthrough drug status (BTD) for umbralisib for MZL. The company expects to complete the rolling submission of NDAs in the first half of 2020.
TG Therapeutics Executive Chairman and CEO Michael S. Weiss said: "We are very pleased to initiate the submission of a new drug application for umbralisib and receive guidance from the FDA to include MZL and FL into a single NDA. This is extremely important to us. A milestone as it brings us closer to providing a new treatment option for the previously treated MZL and FL patient population. I want to thank the patients and their families and the research team, as well as TG, for participating in these important trials and helping advance umbrasib The team is working tirelessly to initiate this NDA submission. This is the beginning of an influential 2020, as we look forward to the Phase III data from the UNITY-CLL trial and the ULTIMATE I & II trial for multiple sclerosis, as well as potential regulation based on these submit."
This NDA submission is based on data from the MZL cohort and FL cohort that evaluated the umbralisib single-agent Phase IIb Registered Guided Clinical Study (UNITY-NHL). This is a multicenter, open-label study. The MZL cohort is designed to evaluate umbralisib monotherapy for MZL patients who have previously received at least one anti-CD20 regimen. The FL cohort is designed to evaluate umbralisib monotherapy for FL patients who have previously Received at least two treatment regimens, including anti-CD20 regimens and alkylated formulations; the primary endpoints for both cohorts were determined total response rates (ORR) assessed by the Independent Central Review Board (IRC).
In April 2019, MZL cohort data released at the American Cancer Research Association (AACR) annual meeting showed that in patients with relapsed or refractory MZL who have previously received at least one anti-CD20 therapy, the total amount of umbralisib monotherapy The response rate (ORR) was 52%, with a complete response rate (CR) of 19%, a partial response rate (PR) of 33%, and a stable disease rate (SD) of 36%. At a median follow-up of 12.5 months, the median duration of response (DoR) had not been reached. Additional efficacy data include: 88% clinical benefit, 86% reduction in tumor burden, median time from treatment to remission of 2.7 months, 12-month progression-free survival rate of 66%, and median progression-free survival achieve. In the study, umbralisib was well tolerated and safe.
In October 2019, TG announced that the FL cohort reached the ORR primary endpoint for all treated patients (n = 118) as determined by the IRC evaluation, and the company achieved its target ORR of 40-50%. Importantly, umbralisib monotherapy was well tolerated and safety was consistent with previous reports. Detailed data will be announced at a future medical conference.
Umbralisib is an oral, once-daily PI3Kδ and CK1-ε dual-acting inhibitor, which may allow it to overcome some of the tolerance issues associated with the first generation of PI3Kδ inhibitors. Phosphatidylinositol-3 kinase (PI3K) is a class of enzymes involved in various cell functions such as cell proliferation and survival, cell differentiation, intracellular transport, and immunity. There are four subtypes of PI3K (α, β, δ, and γ). The δ subtype is strongly expressed in cells of hematopoietic origin and is often associated with B-cell-associated lymphoma.
Umbrasib has nanomolar potency on the delta isoform of PI3K, and has high selectivity on alpha, beta, and gamma isoforms. Umbralisib also uniquely inhibits casein kinase 1-ε (CK1-ε), which may have a direct anti-cancer effect and may also regulate T cell activity associated with immune-mediated adverse events previously observed in PI3K inhibitors.
Currently approved PI3Kδ inhibitors are associated with autoimmune-mediated toxicity, such as liver toxicity, lung toxicity, and colitis. Compared with approved PI3K inhibitors, the specific differences of umbralisib, its unique inhibitory effect on CK1-ε, and its unique and patented chemical structure may have differentiating characteristics among PI3K inhibitors.
Umbralisib has demonstrated its activity in preclinical models and clinical studies of hematological malignancies. Currently, Phase IIb and Phase III trials in CLL and NHL patients are continuing to assess the therapeutic potential of umbralisib.
In addition to umbralisib, TG is also developing a monoclonal antibody drug ublituximab (TG-1101), a glycoengineered chimeric IgG1 monoclonal antibody that targets CD20. It is currently in phase III clinical development and is evaluating the treatment of cancer. (Chronic lymphocytic leukemia [CLL], non-Hodgkin's lymphoma [NHL]) and non-cancer (multiple myeloma [MM]) indications. In addition, TG has a number of assets that have entered phase I clinical trials, including PD-L1 monoclonal antibody TG-1501, covalently bound Bruton tyrosine kinase (BTK) inhibitor TG-1701, and so on. (from Bioon.com,compile hsppharma.com)
original source: TG Therapeutics Initiates Rolling Submission of New Drug Application (NDA) to U.S. Food and Drug Administration for Umbralisib as a Treatment for Patients with Previously Treated Marginal Zone Lymphoma or Follicular Lymphoma