The New-generation PI3Kδ Inhibitor / New CD20 Monoclonal Antibody Combination (umbralisib + Ublituximab) Phase III Clinical Success!

- May 07, 2020-

TG Therapeutics is a biopharmaceutical company dedicated to developing innovative therapies for patients with B cell-mediated diseases. Recently, the company announced the positive top-line results of the global Phase III UNITY-CLL test. The trial was conducted in patients who had not previously received treatment (primary treatment) and relapsed / refractory (treated) chronic lymphocytic leukemia (CLL), and evaluated the efficacy and safety of the combined regimen of umbralisib and ublituximab (U2), and Compared with the obinutuzumab + chlorambucil solution.


The trial was conducted under the Special Program Evaluation (SPA) agreement with FDA. The results showed that the trial had reached the primary endpoint in the pre-specified interim analysis: According to the independent review committee (IRC) assessment, compared with the obinutuzumab + chlorambucil treatment group, the U2 treatment group had no progression of survival (PFS) A statistically significant improvement (p <0.0001) was achieved, and treatment benefits were observed in both the previously untreated (initial treatment) and relapsed / refractory (treated) CLL patient populations.


Due to its excellent efficacy, the trial will be terminated early on the recommendation of the Independent Data Safety Monitoring Board (DSMB). According to the data from the trial, TG plans to submit a U2 regimen for regulatory applications for CLL patients who have not previously received treatment (initial treatment) and relapsed / refractory (treated) CLL patients by the end of 2020.


Umbralisib is an oral, once-daily, new-generation PI3Kδ inhibitor that uniquely inhibits CK1-ε, which may allow it to overcome some of the tolerance issues associated with the first-generation PI3Kδ inhibitor. ublituximab is a novel glycoengineered anti-CD20 monoclonal antibody that targets a unique epitope of CD20 antigen on mature B lymphocytes.


If approved, U2 will provide a new, non-chemotherapy regimen for CLL patients who have not previously received treatment (initial treatment) and CLL patients who have failed or relapsed to previous treatments.


Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. It is estimated that in 2020, more than 20,000 new cases of CLL will be diagnosed in the United States. Although the symptoms of CLL may disappear for some time after the initial treatment, the disease is considered incurable, and many people will require additional treatment due to the recurrence of malignant cells.


John Gribben, MD, Professor of Medical Oncology, Barts Cancer Institute, London, UK, said: “We are very pleased to see that this important trial is in first-line and relapsed / refractory CLL patients The combination of umbralisib and ublituximab has achieved positive results. Today ’s results mark the first successful phase III clinical trial based on the PI3Kδ therapy regimen in the CLL patient population, including patients who have not previously received treatment. At present, CLL is still There is no cure and there is still an urgent need for new treatment options, especially those that provide different mechanisms and safe treatment options. "

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ublituximab is a new type of glycoengineered anti-CD20 monoclonal antibody that targets the unique epitope of CD20 antigen on mature B lymphocytes. This epitope is different from many CD20 monoclonal antibodies currently on the market, including ofatumumab, ocrelizumab / rituximab, obinutuzumab (GA101).


Currently, ublituximab is in phase III clinical development for the treatment of multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL).

ublituximab

Umbralisib is a dual-acting inhibitor of phosphoinositide-3-kinase δ (PI3Kδ) and casein kinase 1ε (CK-1ε), which may allow it to overcome some of the tolerance issues associated with the first-generation PI3Kδ inhibitors. Phosphatidylinositol-3 kinase (PI3K) is a class of enzymes involved in various cellular functions such as cell proliferation and survival, cell differentiation, intracellular transport, and immunity. PI3K has four subtypes (α, β, δ, and γ), of which δ subtype is strongly expressed in cells of hematopoietic origin, often associated with B-cell-associated lymphoma.


Umbrasib has nanomolar potency against the δ subtype of PI3K, and has high selectivity to the α, β, and γ subtypes. Umbralisib also uniquely inhibits casein kinase 1-ε (CK1-ε), which may have a direct anti-cancer effect, and may also modulate T cell activity associated with immune-mediated adverse events previously observed in PI3K inhibitors.


The currently approved PI3Kδ inhibitors are associated with autoimmunity-mediated toxicity, such as hepatotoxicity, pulmonary toxicity, and colitis. Compared with the approved PI3K inhibitors, umbralisib's specific differences, its unique inhibitory effect on CK1-ε, and its unique and patented chemical structure may have differentiated characteristics in the PI3K inhibitor class.

ublituximab

In January of this year, TG started to submit a new drug application (NDA) to the US FDA, seeking accelerated approval of umbralisib for patients with previously treated marginal zone lymphoma (MZL) and follicular lymphoma (FL).


Previously, the FDA has granted four orphan drug qualifications (ODD) for umbralisib, including FL and all three MZLs (lymph nodes, extralymph nodes, and spleen MZL). In addition, the FDA granted umbralisib a breakthrough drug qualification (BTD) for the treatment of adult patients with relapsed or refractory MZL who had previously received at least one anti-CD20 therapy.