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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by TG Therapeutics Inc, umbralisib (TGR 1202) is different from other PI3Kδ inhibitors in having Casein Kinase-1ε (CK1ε) inhibitory activity, a major regulatory pathway of protein translation. Given orally, umbralisib was granted breakthrough Therapy status by the FDA for use in Marginal Zone Lymphoma (MZL) which has no specifically approved therapies. The results of a Phase 2 trial (UNITY-NHL) released in 2019 showed that it was well tolerated with a safety profile distinct from other PI3Kδ inhibitors with fewer occurrences of autoimmune-like toxicities such as colitis. On the basis of these results, TG Therapeutics Inc have requested FDA accelerated approval in MZL and FL. Dactolisib (VP-BEZ235), developed by Novartis and licensed by ResTORbio, is an imidazoquinoline PI3K inhibitor, also known to inhibit the mTOR pathway. Orally administered, it was the first PI3K inhibitor to enter clinical trials in 2006. However, in some clinical trials, including some in HER2-negative breast cancer and pancreatic neuroendocrine tumors, patients experienced significant side effects, and so further progression was not warranted.
The evidence to date on umbralisib for the treatment of refractory marginal zone lymphoma and follicular lymphoma
Published in Expert Opinion on Pharmacotherapy, 2022
Janelle Schweitzer, Meghan Hoffman, Solomon A. Graf
As the fourth PI3-K inhibitor to gain regulatory approvals for refractory iB-NHLs, umbralisib could potentially be overlooked for its contribution to the evolving landscape of managing iB-NHL. It is quite possible, however, that umbralisib ultimately establishes a favored status from among its PI3K inhibitor competitors – particularly the oral agents idelalisib and duvelisib – for its apparently improved tolerability. Indeed, the National Comprehensive Cancer Network has listed umbralisib not only as a treatment consideration besides alternatives according to its FDA label but, in recognition of its apparently favorable toxicity profile, also as a single consideration for 3rd-line and subsequent therapy in patients who are elderly or infirm[18]. Of note, copanlisib, with its intravenous administration and distinct toxicity profile, should maintain a niche with patients treated with a PI3K-inihibitor for R/R iB-NHL and at risk for poor compliance with oral oncolytics, for example. All that said, we cannot emphasize enough that selection among PI3K inhibitor options is not, to date, based on head-to-head evidence and that such analyses are needed, particularly as each of the pivotal, phase 2 trials defined distinct inclusion criteria and enrolled heterogeneous populations.
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
Umbralisib (TGR-1202, Rhizen Pharmaceuticals) (26) is a second-generation selective PI3Kδ inhibitor with less potency than 24 and 25 (IC50s for PI3Kα, β, γ, and δ were greater than10 µM, 1116 nM, 1065 nM, and 22 nM, respectively) [49]. There are currently six clinical trials of 26 underway, one of which is UNITY-CLL [49]. Umbralisib was just approved by the USFDA on February 5, 2021 to treat patients with relapsed or refractory marginal zone lymphoma (MZL) or with relapsed or refractory follicular lymphoma (FL). Parsaclisib (INCB050465, Incyte) (27) is a highly selective PI3Kδ inhibitor with IC50s of greater than 20 µM for PI3Kα, β, and γ; yet the IC50 for PI3Kδ was 1 nM [49,95]. 27 has been evaluated in patients with advanced B cells malignancies as a single treatment or in combination with itacitinib and with the chemotherapy combination for non-Hodgkin’s lymphoma [49]. Parsaclisib (27) and its derivatives have been covered by a patent for the treatment of lymphoma and leukemia [96].
Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2020
Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
Similar to BTK inhibitors, the next generation of PI3K inhibitors like duvelisib, umbralisib, copanlisib, buparlisib and other agents may be better tolerated than idelalisib. Of these, duvelisib and umbralisib are the most advanced in their clinical development. Clinical trials of these agents are ongoing and early results indicate that they are highly active in CLL and may have different toxicity profiles [130,131]. Duvelisibis a potent inhibitor of PI3Kδ, but in contrast to idelalisib, it is also a potent inhibitor of PI3Kγ [132–135]. Phase 1 and phase 3 clinical trials indicate that duvelisib has high clinical efficacy in relapsed/refractory CLL; however, it has demonstrated similar toxicities to those observed with idelalisib. Neutropenia, diarrhea and infection were the most frequent AEs reported during treatment. In 2018, duvelisib was approved by the Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory CLL [134]. Umbralisib is a next-generation PI3Kδ, and casein kinase-1ε (CK1ε) inhibitor.It is relatively well tolerated and displays reduced inhibitory activity on T regulatory cell. In addition, the drug is less hepatotoxic than idelalisib [135]. In a phase 1 study performed in relapsed or refractory CLL and B-cell lymphoma, umbralisib had a favorable safety profile and good clinical activity. In contrast to idelalisib, there were no observed cases of grade 3 hepatotoxicity or colitis, and the only grade 3 or higher adverse event was neutropenia. This agent can replace idelalisib in the treatment of CLL if it is found to display better tolerability in ongoing clinical trials.