zandelisib (ME-401) / MEI - LARVOL DELTA

A long-lasting PI3Kδ inhibitor zandelisib forms a water-shielded hydrogen bond with p110δ and demonstrates sustained inhibitory effects. (PubMed, Am J Cancer Res) - "The binding kinetics of zandelisib, parsaclisib, idelalisib, and duvelisib to PI3Kδ were evaluated using surface plasmon resonance (SPR) analysis with the BiacoreTM system, and their binding in living cells was confirmed using the NanoBRETTM TE Intracellular Kinase Assay system. The crystal structure of PI3Kδ in complex with zandelisib was determined at 2.5 Å resolution, revealing the benzimidazole group in zandelisib formed a hydrogen bond to the side chain of Lys779 in p110δ, the catalytic subunit of PI3Kδ. These studies demonstrated a longer duration of action of zandelisib compared to the other compounds, which was attributable to the hydrogen bond between zandelisib and Lys779 in p110δ."

Journal • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PIK3CD

ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=13 | Terminated | Sponsor: Deepa Jagadeesh | Active, not recruiting ➔ Terminated; Funding unavailable

Trial termination • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology

A phase II study of zandelisib in patients with relapsed or refractory indolent non-Hodgkin lymphoma: ME-401-K02 study. (PubMed, Br J Haematol) - P2 | "Zandelisib showed favourable efficacy and tolerability in Japanese patients with relapsed or refractory indolent non-Hodgkin B-cell lymphoma. This unique dosing schedule may maintain efficacy while mitigating the safety issues observed with other PI3Kδ inhibitors (ClinicalTrials.gov number, NCT04533581)."

Journal • P2 data • B Cell Lymphoma • Follicular Lymphoma • Gastrointestinal Disorder • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • PIK3CD

PI3 Kinase Pathway Regulates CAR T Cell Trogocytosis (ASH 2024) - "Moreover, ME401 treated CAR T cells exhibited a lower expression of PD1 (MFI 778 vs 1930) (p=0.002, N=3) and & LAG3 (10414 vs 20180) (p=0.1, N=3) compared to control CAR T cells. We have shown that PI3K p110δ pathway is an important regulator of CAR mediated trogocytosis and targeting this pathway could be of potential clinical benefit."

CAR T-Cell Therapy • IO biomarker • Oncology • CD19 • LAG3 • PD-1 • RAC1

The PI3Kδ inhibitor zandelisib on intermittent dosing in relapsed/refractory follicular lymphoma: Results from a global phase 2 study. (PubMed, Hemasphere) - "Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies."

Journal • P2 data • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Indolent Lymphoma • Infectious Disease • Lymphoma • Oncology • Pneumonia • Respiratory Diseases • PIK3CD

Study of ME-401 in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 ➔ May 2028 | Trial primary completion date: Sep 2024 ➔ May 2028

Trial completion date • Trial primary completion date • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study of ME-401 in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma (NHL) (clinicaltrials.gov) - P2 | N=61 | Active, not recruiting | Sponsor: Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 ➔ May 2028 | Trial primary completion date: Sep 2024 ➔ May 2028

Trial completion date • Trial primary completion date • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

MEI Pharma Reports Third Quarter Fiscal Year 2024 Results and Operational Highlights (Businesswire) - "Recent Highlights...While the threshold was met to proceed to Cohort 2, following a strategic review the Company decided to continue to advance ME-344 via its ongoing development of a new formulation rather than through the addition of a new cohort of patients. The Company has already initiated research and development activity of the new formulation...The Company expects to provide an update on our formulation efforts in the first half of calendar 2025...Research and development expenses decreased by $9.9 million to $5.2 million for the quarter...The decrease was primarily related to a reduction in zandelisib program costs, as well as reduced personnel and related costs from our reductions in headcount. These decreases were partially offset by increases related to clinical trials, reformulation and manufacturing costs associated with ME-344 and increased clinical costs for the ongoing clinical study with voruciclib."

Commercial • Pipeline update • Trial status • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Learnings from phosphatidylinositol 3-kinase inhibitors in lymphoma-Moving to a model where less can be more. (PubMed, Br J Haematol) - "of zandelisib with zanubrutinib in follicular and mantle cell lymphoma is an important addition to the data. Br J Haematol 2024 (Online ahead of print). https://doi.org/10.1111/bjh.19419."

Journal • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Oncology

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas. (PubMed, Br J Haematol) - P1 | "The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone."

Journal • Fatigue • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Oncology • Thrombocytopenia • PIK3CD

ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=13 | Active, not recruiting | Sponsor: Deepa Jagadeesh | Recruiting ➔ Active, not recruiting | N=54 ➔ 13

Enrollment change • Enrollment closed • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology

Safety Results of a Phase I Study of Zandelisib + R-CHOP in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) (ASH 2023) - P1/2 | "In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP."

Clinical • P1 data • Anemia • Constipation • Diffuse Large B Cell Lymphoma • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • Thrombocytopenia • BCL2 • BCL6 • MYC • PIK3CD

MEI Pharma Reports First Quarter Fiscal Year 2024 Results and Operational Highlights (Businesswire) - "For the quarter ended September 30, 2023, cash used in operations was $18.5 million, compared to $14.8 million during the quarter ended September 30, 2022. The increase in cash used in operations was primarily due to changes in working capital associated with the wind down of zandelisib activities with Kyowa Kirin and professional services primarily related to advisory and legal fees associated with various stockholder-related activities, including stockholder-initiated consent solicitations....Research and development expenses were $3.5 million for the quarter ended September 30, 2023, compared to $19.5 million for the quarter ended September 30, 2022. The decrease was primarily related to a reduction in zandelisib costs as we continued the wind down of development activities announced in December 2022, as well as reduced personnel and related costs from our fiscal year 2023 reduction in headcount."

Commercial • Hematological Malignancies • Oncology

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia. (PubMed, Expert Opin Drug Metab Toxicol) - "Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies...Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies."

Journal • Review • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases • PIK3CD

Genomic diversity and biogeographic distributions of a novel lineage of bacteriophages that infect marine OM43 bacteria. (PubMed, Microbiol Spectr) - "In this study, we isolated and sequenced two novel OM43 phages, MEP401 and MEP402...Metagenomic mapping analysis suggests that members in these two groups are globally ubiquitous with distinct distribution patterns. This study provides important insights into the genomic diversity and biogeography of the OM43 phages in the global ocean."

Journal

Zandelisib + Tazemetostat in R/R Follicular Lymphoma (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Jacob Soumerai, MD | N=34 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

EFFICACY AND SAFETY OF ZANDELISIB ADMINISTERED BY INTERMITTENT DOSING IN JAPANESE PATIENTS WITH RELAPSED/REFRACTORY INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA: PRIMARY ANALYSIS OF THE PHASE 2 STUDY MIRAGE (EHA 2023) - P2 | "This study demonstrates a favorable efficacy and safety profiles consistent with TIDAL study in a Japanese patient population with r/r indolent B-NHL. Zandelisib is being investigated as a potential new therapeutic option for these patients. Marginal zone, Indolent non-Hodgkin's lymphoma, Follicular lymphoma, PI3K"

Clinical • P2 data • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Indolent Lymphoma • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • PIK3CD

MEI Pharma Reports Third Quarter Fiscal Year 2023 Results and Operational Highlights (Businesswire) - "Kyowa Kirin has been evaluating whether to continue developing zandelisib in Japan and after meeting with the PMDA has concluded this month that conducting a randomized study consistent with agency guidance to support a marketing application would likely not be feasible to complete within a time period that would support further investment. As a result, Kyowa Kirin decided to discontinue development of zandelisib in Japan. The discontinuation of zandelisib in Japan was a business decision by Kyowa Kirin based on the most recent regulatory guidance from the PMDA and is not related to the zandelisib clinical data generated to date. In light of Kyowa Kirin’s decision to discontinue development of zandelisib in Japan, the parties intend to terminate the global license, development and commercialization agreement executed in April 2020."

Discontinued • Licensing / partnership • Hematological Malignancies • Oncology

EFFICACY AND SAFETY OF ZANDELISIB ADMINISTERED BY INTERMITTENT DOSING (ID) IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) FOLLICULAR LYMPHOMA: PRIMARY ANALYSIS OF THE GLOBAL PHASE 2 STUDY TIDAL (EHA 2022) - P2, P3 | "This profile supports evaluation of zandelisib as a single agent and in combination regimens in various B-cell malignancies, both in R/R disease and in earlier lines of therapy. Zandelisib plus rituximab vs chemoimmunotherapy is being evaluated in the phase 3 study COASTAL in R/R FL and MZL (NCT04745832)."

Clinical • P2 data • Bone Marrow Transplantation • Dental Disorders • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Inflammation • Lymphoma • Marginal Zone Lymphoma • Oncology • Pneumonia • Stomatitis • Transplantation • PIK3CD

Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study (ASH 2022) - P2, P3 | "Single agent zandelisib on ID was associated with high rate of durable responses (72.5% ORR, 36.3% CR rate in PEP) in heavily pretreated R/R FL pts, including those with POD24 and refractory disease, and was associated with a relatively lower incidence of Gr ≥3 AESI and AE-related discontinuations, compared with CD. Based on the safety and efficacy profiles observed in this study, these results support further evaluation of zandelisib ID, alone or in combinations, in various B-cell malignancies. Zandelisib plus rituximab vs."

Clinical • P2 data • Bone Marrow Transplantation • Dental Disorders • Fatigue • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Inflammation • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Novel Coronavirus Disease • Oncology • Pain • Pneumonia • Respiratory Diseases • Stomatitis • Transplantation • PIK3CD

Safety and Efficacy of the PI3Kδ Inhibitor Zandelisib in Combination with the BTK Inhibitor Zanubrutinib in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) or Mantle Cell Lymphoma (MCL) (ASH 2022) - P1 | "Zandelisib plus zanubrutinib was well tolerated with no increase in the rate or severity of class-related AEs compared to either agent alone. Few pts (4%) have discontinued due to an AE. We observed high response rates in R/R FL (80%) and MCL (76%)."

Clinical • Combination therapy • Atrial Fibrillation • Cardiovascular • Febrile Neutropenia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Musculoskeletal Pain • Neutropenia • Novel Coronavirus Disease • Oncology • Pain • Pneumonia • Respiratory Diseases • Septic Shock • PIK3CD

ME-401-002: A Study of ME-401 in Subjects With CLL/SLL, FL, and B-cell Non Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=97 | Terminated | Sponsor: MEI Pharma, Inc. | N=177 ➔ 97 | Trial completion date: Dec 2023 ➔ Mar 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2023 ➔ Mar 2023; discontinuation of zandelisib program

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Zandelisib (ME-401) in Subjects With Follicular Lymphoma or Marginal Zone Lymphoma After Failure of Two or More Prior Therapies (TIDAL) (clinicaltrials.gov) - P2 | N=169 | Terminated | Sponsor: MEI Pharma, Inc. | Trial completion date: Apr 2025 ➔ Mar 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Mar 2023; discontinuation of zandelisib program

Trial completion date • Trial primary completion date • Trial termination • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Phase 3 Study of Zandelisib (ME-401) in Combination With Rituximab in Patients With iNHL - (COASTAL) (clinicaltrials.gov) - P3 | N=82 | Terminated | Sponsor: MEI Pharma, Inc. | N=534 ➔ 82 | Trial completion date: Sep 2031 ➔ Mar 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2026 ➔ Mar 2023; Discontinuation of zandelisib program

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

"Here are the 8 RCTs (sorry some Ph2 not Ph3): Loncastuximab NCT04974996 ME-401 NCT04517435 Acalabrutinib NCT04529772 Acalabrutinib NCT04546620 Tafasitamab+ len NCT04824092 Mosunetuzumab NCT03677141 Glofitamab NCT04914741 Epcoritamab NCT0557897" (@AshAlizadeh)