MEI Pharma, Inc. and Kyowa Kirin Co., Ltd. provided an update after a recent meeting with the U.S. Food Drug Administration (FDA) to discuss the pursuit of a marketing authorization for zandelisib, a phosphatidylinositol-3-kinase (“PI3K”) inhibitor drug candidate, via the accelerated approval pathway under 21 CFR Part 314.500, Subpart H, based on data generated by the single arm Phase 2 TIDAL study. In the meeting, the FDA informed the companies of its position that a randomized trial is now needed to adequately assess drug efficacy and safety of PI3K inhibitor drug candidates, including zandelisib. Based on this view, the agency discouraged a filing based on the Phase 2 TIDAL study data and emphasized that the companies continue efforts with the ongoing, randomized Phase 3 COASTAL study as planned.

Accordingly, in line with the FDA's recommendation, the companies do not plan to submit an FDA marketing application based on the single arm Phase 2 TIDAL study. In addition, while the FDA stated that safety on the 60 mg intermittent schedule appears reasonable, it recommended continued dose exploration to further support the current dose and regimen. Under 21 CFR Part 314.500, Subpart H, a drug candidate may be eligible for accelerated approval if it is intended to treat a serious or life-threatening disease or condition, and the product would provide meaningful therapeutic benefit over existing treatments.

Under accelerated approval, a product may be approved based on adequate and well-controlled clinical studies establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefits. As a condition of approval, the FDA may require that a sponsor receiving accelerated approval perform adequate and well-controlled post-marketing clinical studies to verify the predicted clinical benefit. The FDA historically granted accelerated approval to PI3K inhibitors under 21 CFR Part 314.500, Subpart H for relapsed or refractory follicular and marginal zone lymphomas.

Such approvals were granted with the expectation that confirmatory Phase 3 studies producing randomized data would follow the approval. Generally the FDA has expressed a preference for randomized trials, however, the recent meeting with the FDA was the first instance that the agency informed the companies that data from a single arm study, such as the Phase 2 TIDAL clinical study, would not be adequate to evaluate benefit and risk under 21 CFR Part 314.500, Subpart H and that a randomized study is required to support a potential accelerated approval. Zandelisib, a selective PI3Kd inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies.

Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen (IDT). The IDT leverages molecular and biologic properties specific to zandelisib. In November 2021, MEI Pharma announced data from ongoing Phase 2 TIDAL study (NCT03768505) evaluating zandelisib as a single agent for follicular lymphoma (FL) patients who received at least two prior systemic therapies.

Zandelisib demonstrated a 70.3% objective response rate (ORR) as determined by Independent Review Committee (IRC) assessment in the primary efficacy population (n=91). In addition, 35.2% of patients achieved a complete response. At the time of the data cutoff, the data were insufficiently mature to accurately estimate duration of response (DOR).

In line with previously reported data from the Phase 1B study, zandelisib was generally well tolerated. With 9.4 months (range: 0.8-24) median duration of follow-up in the total study population (n=121), interim data demonstrated a discontinuation rate due to any drug related adverse event of 9.9%. Patients enrolled in the study will continue to be followed for safety and DOR.

Ongoing zandelisib studies include the cohort in TIDAL evaluating patients with R/R marginal zone lymphoma (MZL) and continuing follow up in the cohort of the study evaluating patients with R/R FL. Also ongoing is the Phase 3 COASTAL study (NCT04745832) comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab, in patients with R/R FL or MZL who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL is intended to support marketing applications in the U.S. and globally.

Other ongoing studies include a Phase 2 pivotal study in Japan (NCT04533581) in patients with indolent B-cell non-Hodgkin's lymphoma (iNHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström's macroglobulinemia (WM) conducted by Kyowa Kirin. In March 2020, the FDA granted zandelisib Fast Track designation for the treatment of adult patients with R/R follicular lymphoma who have received at least two prior systemic therapies. In November 2021, the FDA granted zandelisib Orphan Drug designation for the treatment of patients with follicular lymphoma.