On March 24, 2022 MEI Pharma, Inc. (NASDAQ: MEIP) and Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), reported 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 (Press release, Kyowa Hakko Kirin, MAR 24, 2022, View Source [SID1234610893]). 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.
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"The FDA’s current position on the assessment of benefit and risk of PI3K inhibitors solely based on single arm studies appears to have evolved, as evidenced by the position the FDA communicated at the recent meeting on zandelisib, and the upcoming ODAC meeting scheduled for April 21, 2022 to discuss whether randomized data should be required for the class of PI3K inhibitors to demonstrate appropriate evidence of efficacy and safety," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "Clearly, the outcome of our recent FDA meeting is a disappointing development. Nonetheless we will continue to focus on the ongoing Phase 3 COASTAL study as we consider options that provide the most expeditious approval pathway utilizing randomized data, and which we believe will demonstrate the potential of zandelisib to help patients. Today’s announcement in no way diminishes our conviction to the development of zandelisib and the promise of its emerging clinical profile. Based on current projections, MEI believes we have sufficient cash for operations to complete the COASTAL study enrollment in 2024."
Dr. Gold continued: "In partnership with Kyowa Kirin, we remain committed to the ultimate potential of zandelisib to address important medical needs as a single agent or in combination with other therapies providing physicians, and their patients, important new treatment options. We plan on completing evaluation of the Phase 2 TIDAL study, and look forward to sharing final data later this year to further advance an understanding of zandelisib’s clinical utility."
"Our dialogue with the FDA has updated our understanding of the evolving regulatory view of the PI3K inhibitor drug class. With this knowledge, we can focus our efforts to advance the COASTAL program," said Yoshifumi Torii, Ph.D., Executive Officer, Vice President, Head of R&D of Kyowa Kirin. "Our teams around the world have made steady progress to enroll patients and give us important momentum. Together with MEI Pharma, we will continue to work with the investigators, patients, and advocacy organizations to drive continued progress."
About 21 CFR Part 314.500, Subpart H
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.
About Zandelisib
Zandelisib, a selective PI3Kδ 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.
In April 2020, MEI and Kyowa Kirin entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin will co-develop and co-promote zandelisib in the U.S., with MEI booking all revenue from the U.S. sales. Kyowa Kirin has exclusive commercialization rights outside of the U.S.
Conference Call and Webcast
MEI Pharma will host a conference call and webcast on March 24, 2022 at 4:30pm Eastern Time. To access the live call, please dial 1-833-974-2378 (United States) or 1-412-317-5771 (International). Please ask to join the MEI Pharma call. The event is also available via a live audio webcast at this link, and on the Investors section of MEI’s website at View Source A replay of the webcast will be archived on MEI’s website for at least 30 days following the event.