Umbralisib

Overview

Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.[1] WP

Umbralisib is a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon.[1][2][3] WP

The most common side effects include increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash.[1] WP

Umbralisib was granted accelerated approval for medical use in the United States in February 2021. However, due to concerns for increased long term side effects leading to inferior overall survival which led to increased FDA scrutiny in the form of an ODAC review, it has been withdrawn from the US market.[1][4–7] WP

Uses, dosage and effects

Medical uses

In April 2022, TG Therapeutics announced the voluntary withdrawal of Ukoniq (umbralisib) from sale for its approved use in the treatment of marginal zone lymphoma and follicular lymphoma. Furthermore, the company withdrew the pending Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) which utilized umbralisib in tandem with ublituximab, known as the "U2" regimen. The decision was based on the overall survival (OS) data from the phase III trial, Unity-CLL, that illustrated and increasing imbalance in OS.[8] WP

Umbralisib is indicated for adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen; and adults with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.[1][8][9][10] WP

Risks and side effects

Adverse effects

The prescribing information provides warnings and precautions for adverse reactions including infections, neutropenia, diarrhea and non-infectious colitis, hepatotoxicity, and severe cutaneous reactions.[1] WP

History

History

It has undergone clinical studies for chronic lymphocytic leukemia (CLL). Three year data (including follicular lymphoma and DLBCL) was announced June 2016. It is in combination trials for various leukemias and lymphomas, such as mantle cell lymphoma (MCL) and other lymphomas.[11–16] WP

Umbralisib was granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for use in people with marginal zone lymphoma (MZL), a type of cancer with no specifically approved therapies.[17] WP

FDA approval was based on two single-arm cohorts of an open-label, multi-center, multi-cohort trial, UTX-TGR-205 (NCT02793583), in 69 participants with marginal zone lymphoma (MZL) who received at least one prior therapy, including an anti-CD20 containing regimen, and in 117 participants with follicular lymphoma (FL) after at least two prior systemic therapies. The application for umbralisib was granted priority review for the marginal zone lymphoma (MZL) indication and orphan drug designation for the treatment of MZL and follicular lymphoma (FL).[1][18–22] WP

Legal status

Legal status

In June 2022, due to safety concerns, the US Food and Drug Administration (FDA) withdrew its approval for Ukoniq (umbralisib).[10] WP

Updated findings from the UNITY-CLL clinical trial show a possible increased risk of death in people receiving Ukoniq. As a result, the FDA determined the risks of treatment with Ukoniq outweigh its benefits. Based upon this determination, the drug's manufacturer, TG Therapeutics, announced it was voluntarily withdrawing Ukoniq from the market for the approved uses in MZL and FL.[8][10] WP

Chemistry

Formula

C31H24F3N5O3 PC

CAS number

1532533-67-7 PC

Molar mass (g/mol)

571.5 PC

IUPAC name (computed by PubChem)

2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one PC

SMILES

C[C@@H](C1=C(C(=O)C2=C(O1)C=CC(=C2)F)C3=CC(=CC=C3)F)N4C5=NC=NC(=C5C(=N4)C6=CC(=C(C=C6)OC(C)C)F)N PC

InChIKey

IUVCFHHAEHNCFT-INIZCTEOSA-N PC

PubChem CID

72950888

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. 5 February 2021
2. Journal / agency Lunning M, Vose J, Nastoupil L, Fowler N, Burger JA, Wierda WG, Schreeder MT, Siddiqi T, Flowers CR, Cohen JB, Sportelli P, Miskin HP, Weiss MS, O'Brien S. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. November 2019. doi:10.1182/blood.2019002118 · PMID 31558467 · PMC7042665
3. Journal / agency Burris HA, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncology. April 2018. doi:10.1016/S1470-2045(18)30082-2 · PMID 29475723
4. Other TG Therapeutics Announces FDA Accelerated Approval of Ukoniq (umbralisib). 5 February 2021
5. Journal / agency Drug Approval Package: Ukoniq (umbralisib). 5 March 2020
6. Journal / agency FDA Briefing Document - Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies
7. Other TG Therapeutics, Inc.; Withdrawal of Approval of New Drug Application for UKONIQ (Umbralisib Tosylate) Tablets, Equivalent to 200 Milligrams Base. 31 May 2022
8. Other TG Therapeutics Announces Voluntary Withdrawal of the BLA/sNDA for U2 to Treat Patients with CLL and SLL. 15 April 2022
9. Journal / agency Ukoniq- umbralisib tablet, film coated
10. Journal / agency FDA withdrawing cancer drug Ukoniq (umbralisib). 1 June 2022
11. Other Inman, Silas. Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. 19 March 2016
12. Other Vantage, EP. Therapy Focus –- TG Could Benefit From Zydelig Setback. 29 March 2016
13. Other TG Therapeutics, Inc. Announces First Patient Enrolled in the Registration-Directed UNITY-DLBCL Phase 2b Trial. June 2016
14. Other ClinicalTrialsGov NCT02268851 A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL
15. Other Follow-Up Data for Combination of TGR-1202 (umbralisib) plus Ibrutinib in Patients with Relapsed or Refractory CLL and MCL. 14 June 2017
16. Other ClinicalTrialsGov NCT02793583 Study to Assess the Efficacy and Safety of Ublituximab + TGR-1202 With or Without Bendamustine and TGR-1202 Alone in Patients With Previously Treated Non-Hodgkin's Lymphoma (UNITY-NHL)
17. Other Columbus, Gina. FDA Grants Umbralisib Breakthrough Designation for Marginal Zone Lymphoma. 22 January 2019
18. Journal / agency Orphan Treatment of extranodal marginal zone lymphoma. 11 April 2019
19. Journal / agency Orphan Treatment of splenic marginal zone lymphoma. 11 April 2019
20. Journal / agency Orphan Treatment of Follicular Lymphoma. 11 April 2019
21. Journal / agency Orphan Treatment of nodal marginal zone lymphoma. 11 April 2019
22. Journal / agency Advancing Health Through Innovation: New Drug Therapy Approvals 2021. 13 May 2022

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