In short
ME-401, also known as zandelisib, is an investigational medicine that blocks a protein called PI3Kδ, which plays a role in the growth of certain blood cancers. It is being studied in follicular lymphoma and other indolent non-Hodgkin lymphomas. One completed phase 2 trial in the EU Clinical Trials Information System tested ME-401 as a first-line treatment for follicular lymphoma in 60 participants.
Key points
- ME-401 (zandelisib) is a selective PI3Kδ inhibitor under investigation for B-cell blood cancers.
- One phase 2 trial studied ME-401 combined with rituximab-bendamustine in 60 participants with untreated follicular lymphoma.
- The phase 2 trial is completed and measured event-free survival at 24 months (EFS24).
- A phase 1 dose-escalation study in 9 Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma reported an objective response rate of 100%.
- In the phase 1 study, the most common severe side effect was decreased neutrophil count, seen in 55.6% of patients.
- ME-401 is given as capsules by mouth; the recommended phase 2 dose in Japanese patients was 60 mg daily.
What is ME-401?
ME-401, also known by its international nonproprietary name zandelisib, is an investigational medicine being developed for the treatment of certain cancers that begin in blood-forming tissue, such as non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). It belongs to a class of drugs called phosphatidylinositol 3-kinase (PI3K) inhibitors, specifically targeting the delta isoform of the enzyme. ME-401 has not been granted a marketing authorisation in the records reviewed here, meaning it remains an experimental therapy under clinical investigation.
The EU Clinical Trials Information System lists ME-401 in the therapeutic area of hemic and lymphatic diseases, which covers disorders of the blood and lymph system. The substance is supplied by MEI Pharma, Inc., the sponsor of early development studies.
How does ME-401 work?
ME-401 is a selective inhibitor of the phosphatidylinositol 3-kinase δ (PI3Kδ) enzyme. PI3Kδ is a signalling protein found mainly in white blood cells called B cells. In B-cell malignancies such as follicular lymphoma and chronic lymphocytic leukaemia, overactive PI3Kδ signalling contributes to the survival and growth of the cancer cells. By blocking this enzyme, ME-401 aims to interrupt the signals that keep these malignant B cells alive, which can lead to their death and a reduction in the cancer burden.
Which conditions is ME-401 studied for?
- Follicular lymphoma — a slow-growing (indolent) form of non-Hodgkin lymphoma that affects B cells. The completed phase 2 trial tested ME-401 as part of first-line treatment for this condition.
- Indolent non-Hodgkin lymphoma — a broader group of slow-growing B-cell lymphomas. A phase 1 study evaluated ME-401 in Japanese patients with relapsed or refractory indolent non-Hodgkin lymphoma.
- Chronic lymphocytic leukaemia (CLL) — a cancer of the blood and bone marrow. The sponsor's early research summary names CLL as one of the conditions the medicine is being developed for.
How is ME-401 given?
ME-401 is given as capsules by mouth. In the phase 2 follicular lymphoma trial, participants received ME-401 60 mg micronised capsules orally. In the phase 1 dose-escalation study in Japanese patients, ME-401 was administered on a continuous daily schedule at doses of 45 mg or 60 mg until disease progression or unacceptable toxicity. An early healthy-volunteer study also used oral capsules, and an intravenous formulation of radiolabelled ME-401 was administered to trace how the body absorbs, processes and removes the drug.
What do the clinical trials show?
One clinical trial of ME-401 is registered in the EU Clinical Trials Information System. It is a phase 2 interventional study that enrolled 60 participants with follicular lymphoma and is now completed. The trial, known as NLG-FL5 or FLAME, evaluated whether adding ME-401 to standard first-line treatment could improve outcomes. Participants received ME-401 combined with rituximab and bendamustine, while a comparator arm received rituximab alone for low-risk disease; high-risk patients were randomised 1:1 to receive ME-401 in addition to rituximab-bendamustine.
The primary measure in this trial was event-free survival at 24 months (EFS24) — the proportion of patients alive and free of disease events such as progression, relapse or the need for new treatment within two years of starting the trial.
Separately, a phase 1 dose-escalation study conducted in Japan evaluated ME-401 in nine patients with relapsed or refractory indolent non-Hodgkin lymphoma. In that study, the investigator-assessed objective response rate, based on modified Lugano criteria, was 100%, including two complete responses (22.2%) in patients with follicular lymphoma who received 60 mg daily. The median duration of response was 7.9 months, median progression-free survival was 11.1 months, and median time to response was 1.9 months. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The recommended phase 2 dose in Japanese patients was established as 60 mg daily.
What side effects are known?
In the phase 1 study of ME-401 in Japanese patients, the most common severe (grade 3 or higher) treatment-emergent adverse events were decreased neutrophil count, which occurred in 55.6% of patients (5 of 9), and diarrhoea, which occurred in 33.3% (3 of 9). Immune-related toxicities led to discontinuation of ME-401 in four patients; these included hepatobiliary disorder, increased aspartate and alanine aminotransferase (liver enzymes), diarrhoea or colitis, organising pneumonia, stomatitis (inflammation of the mouth), and rash. The authors of the study described the safety profile of ME-401 at 60 mg daily as manageable. No safety data from the phase 2 follicular lymphoma trial have been published in the sources reviewed here.