Umbralisib (Ukoniq) Form

Umbralisib (Ukoniq™) is a kinase inhibitor. FDA Approved Indication(s) Ukoniq is indicated for the treatment of adult patients with: • Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen • Relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy _ TG Therapeutics, Inc., the manufacturer of Ukoniq, voluntarily withdrew Ukoniq after a post-market safety trial found an increased risk of death in people who used Ukoniq and the FDA withdrew its approval for the product (see Appendix D). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Ukoniq is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Marginal Zone Lymphoma and Follicular Lymphoma:

1. Authorization is not permitted due to lack of FDA and NCCN support. Member may not initiate therapy with Ukoniq. If member is currently using Ukoniq proceed to section II. A. Marginal Zone Lymphoma and Follicular Lymphoma for continued therapy criteria (see Appendix D). Approval duration: Not applicable B. Other diagnoses/indications (must meet 1 or 2):

2. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 1 of 6

   CLINICAL POLICY Umbralisib b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

3. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Marginal Zone Lymphoma and Follicular Lymphoma (must meet all):
4. Provider attestation of acknowledgment of FDA’s request for withdrawal of product due to increased risk of death in members who have used Ukoniq;
5. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Ukoniq for a covered indication and has received this medication for at least 30 days;
6. Member is responding positively to therapy;
   4. For Ukoniq requests, member must use umbralisib, if available, unless contraindicated or clinically significant adverse effects are experienced;
   5. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed both of the following (i and ii): i. 800 mg per day; ii. 4 tablets per day;
      b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
      Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less
      B. Other diagnoses/indications (must meet 1 or 2):
7. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

8. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line Page 2 of 6

   CLINICAL POLICY Umbralisib of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   III. Diagnoses/Indications for which coverage is NOT authorized:
   A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration FL: follicular lymphoma MZL: marginal zone lymphoma
   Appendix B: Therapeutic Alternatives
   Not applicable Appendix C: Contraindications/Boxed Warnings None reported Appendix D: Withdrawal from Market • TG Therapeutics, Inc., the manufacturer of Ukoniq, voluntarily withdrew Ukoniq after a post-market safety trial found an increased risk of death in people who used Ukoniq and the FDA withdrew its approval for the product.
   • FDA believes that the risk of Ukoniq outweighs its benefits. o This is based on a review of results from the UNITY clinical trial. In February 2022, FDA announced they were reviewing clinical trial data and alerted the public about a possible increased risk of death associated with Ukoniq based on analysis of the data. The manufacturer’s decision to withdraw Ukoniq was based on the withdrawal of the BLA and sNDA for U2 in chronic lymphocytic leukemia (CLL).
   o In the first analysis of overall survival (OS) that used a cut-off date of September 2021, there was an imbalance in favor of the control arm (HR: 1.23). In February 2022, considering the ad-hoc nature of the analysis where approximately 15% of patients had missing or outdated survival data and excluding deaths related to COVID-19, the two arms were approximately balanced (HR: 1.04). Pursuant to recent information request made by FDA, updated OS data was collected and showed an increasing imbalance in favor of the control arm, differing from the improved results provided to FDA in February 2022. o Neither the original preliminary OS results nor the updated preliminary OS results were statistically significant.
   • Currently FDA recommends patients should stop taking Ukoniq. o FDA recommends patients should stop taking Ukoniq and talk to health care professionals about alternative treatments. • Currently FDA recommends health care professionals stop prescribing and dispensing Ukoniq to patients. Page 3 of 6

   CLINICAL POLICY Umbralisib o Inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.
   V. Dosage and Administration
   Indication MZL, FL Dosing Regimen 800 mg PO QD Maximum Dose 800 mg/day VI. Product Availability
   Tablet: 200 mg VII.