• Rituxan® (rituximab)
Oral P13K Delta Inhibitor
1 Phase 2 study to support an accelerated approval marketing application with FDA
2 Study arm initiated under clinical collaboration with BeiGene, Ltd.
Zandelisib (ME-401) is an oral, once-daily, selective inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) in clinical development for the treatment of B-cell malignancies. In April 2020, we entered a global license, development and commercialization agreement to further develop and commercialize zandelisib with Kyowa Kirin Co., Ltd. (KKC). MEI and KKC will co-develop and co-promote zandelisib in the U.S., with MEI recording all revenue from U.S. sales. KKC has exclusive commercialization rights outside of the U.S.
We are conducting a global Phase 2 study of zandelisib as a monotherapy for the treatment of adults with relapsed or refractory (r/r) follicular lymphoma (FL). Upon completion of the Phase 2 clinical trial we are planning a submission with the Food and Drug Administration (FDA) to support an accelerated approval of a marketing application. Also ongoing is a multi-arm, open-label, Phase 1b dose escalation and expansion trial evaluating zandelisib as a monotherapy and in combination with other therapies or investigational agents in patients with r/r B-cell malignancies.
PI3Kδ inhibitors are validated for the treatment of B-cell malignancies, but first-generation drugs are challenged by dose-limiting toxicities that restrict clinical utility. This presents an opportunity for the development of a next-generation candidate with pharmaceutical properties that can maintain clinical utility while potentially minimizing the immune-related adverse events which have limited their use.
To that end, the pharmaceutical properties of zandelisib allow exploration of flexible dosing regimens such as an intermittent dosing schedule, which has the potential to maintain clinical benefit while minimizing immune-related toxicities common to other PI3Kδ agents, either as a monotherapy or in combination with other therapies or investigational agents.
MECHANISM OF ACTION
The PI3K/AKT/mTOR pathway is an important signaling pathway for many cellular functions such as cell survival, cell cycle progression and cellular growth. The PI3K family of enzymes within this pathway have been shown to play a critical role in the proliferation and survival of certain cancer cells. There are several isoforms of PI3K that are expressed in different types of cells; the delta isoform is often overexpressed in cancer cells of the B-lymphocyte lineage, such as B-cell leukemias and lymphomas, and is understood to be important for survival of these cells.
Zandelisib displays high selectivity for the PI3K delta isoform and functions to inhibit its activity.
ABOUT B-CELL MALIGNANCIES
B-cell malignancies are those starting in B lymphocytes, a type of white blood cell. They include both slow growing (indolent) diseases as well as aggressive diseases and represent a collection of different blood cancers. Examples include chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.
Phase 1b Study
An ongoing Phase 1b study in patients with r/r FL and other B-cell malignances is evaluating zandelisib as a monotherapy whereby patients are administered zandelisib once daily at 60 mg for two 28-day cycles and then on an intermittent schedule of once daily dosing for the first 7 days of each subsequent 28-day cycle (i.e. the intermittent schedule or IS). A previous cohort of monotherapy patients in the study was treated with zandelisib administered continuously once daily or were switched to IS after Cycle 2 was completed.
In addition, the Phase 1b study is also evaluating zandelisib in combination with rituximab or zanubrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor developed by BeiGene, Ltd. Evaluation of the zandelisib and zanubrutinib combination is being conducted under a clinical collaboration agreement with BeiGene.
Data from a total of 57 patients treated with zandelisib on the intermittent schedule, including 36 patients with r/r FL, 10 patients with r/r chronic lymphocytic leukemia (CLL), and 11 patients with other B-cell malignancies, was featured in a poster discussion at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program.
The overall response rate in 36 patients with r/r FL was 83%, with 22% achieving a complete response. The overall response rate was 76% in 17 patients administered zandelisib as a monotherapy and 89% in 19 patients administered zandelisib in combination with rituximab. The overall response rate in 9 evaluable patients with CLL was 89%.
Median duration of response in patients with FL was not yet been reached and median follow-up was 13.2 months (range: 3.0-27.6). Responses appeared durable across patient subsets analyzed (prior lines of therapy (1 vs ≥ 2), treatment group (i.e. monotherapy or in combination with rituximab) or tumor bulk (< 5 cm vs ≥5 cm)).
Zandelisib was generally well-tolerated. The rate of drug related grade 3 AESI was: diarrhea 3.5% (2 57); colitis 3.5% (2/57); rash 1.8% (1/57); ALT/AST elevation 1.8% (1/57); non-infectious pneumonitis 1.8% (1/57). No grade ≥3 AESI has been reported after Cycle 3, when patients are treated with the IS, and the discontinuation rate due to adverse events was 7% (4/57). There were no isolated grade 3 elevations in ALT and AST: such elevations were transient and in each case were associated with grade 3 diarrhea or rash.
Phase 2 Study to Support Accelerated Approval with U.S. FDA
We are conducting the TIDAL study (Trials of PI3K DeltA in Non-Hodgkin's Lymphoma), a global Phase 2 study evaluating zandelisib as a monotherapy for the treatment of adults with r/r FL after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. Subject to the results, upon completion of the Phase 2 clinical trial, we are planning a submission with FDA to support an accelerated approval of a marketing application under 21 CFR Part 314.500, Subpart H.
The study is evaluating zandelisib administered once daily at 60 mg for two 28-day cycles and then on an intermittent schedule of once daily dosing for the first seven days of each subsequent 28-day cycle (i.e. IS). Approximately 120 patients will be enrolled and treated with the IS regimen; the primary efficacy endpoint will be the rate of objective responses to therapy and other endpoints will include duration of response and tolerability of zandelisib.