Development of Zandelisib for B-cell Malignancies Discontinued Outside of Japan

The development of zandelisib (ME-401) for the treatment of B-cell malignancies has been discontinued outside of Japan, according to an announcement from MEI Pharma, Inc. and Kyowa Kirin Co., Ltd.¹

The decision to discontinue the development of the PI3K inhibitor stems from feedback received from the FDA at a late November meeting, where the regulatory agency provided further guidance regarding the design and statistical analysis for the phase 3 COASTAL trial (NCT04645832). The companies determined that it would not be feasible to modify the trial based on the recommendations within a period of time that would justify further investment.

In March 2022, the FDA discouraged the pursuit of a marketing authorization of zandelisib in patients with follicular lymphoma or marginal zone lymphoma (MZL).² At the meeting, the FDA stated that a randomized trial should be used to support a filing for zandelisib for the treatment patients with indolent non-Hodgkin lymphoma (NHL); based on data from the single-arm phase 2 TIDAL trial (NCT03768505), the regulatory agency discouraged a filing. At the time, the regulatory agency told the companies to continue efforts with the phase 3 trial, as planned.

“Based on the most recent guidance received from the FDA at a late November meeting, we have jointly decided with Kyowa Kirin to discontinue development of zandelisib outside of Japan. We are very disappointed to share this decision in light of our belief in the potential of zandelisib to benefit patients and meet the ongoing need for new options to treat relapsed or refractory indolent NHLs,” Daniel P. Gold, PhD, president and chief executive officer of MEI Pharma, stated in a press release. “However, in light of FDA’s guidance, we no longer believe clinical development can be completed within a time period that would support further investment, or with sufficient certainty of the regulatory requirements to justify continued global development efforts.”

“We share MEI’s disappointment in making this decision,” Yoshifumi Torii, PhD, executive officer, vice president, and head of the R&D Division of Kyowa Kirin, added in the press release. “However, given the phase 2 data we previously announced on zandelisib, we still see potential to continue the program in Japan to address unmet patient needs. We are continuing the Japanese clinical trials, including phase 2 MIRAGE trial, and will consult the PMDA to understand the potential it offers for a regulatory submission.”

The open-label, controlled, multicenter, COASTAL trial was evaluating zandelisib in combination with rituximab (Rituxan) vs standard treatment with chemoimmunotherapy in patients with relapsed or refractory indolent NHL.³

The trial enrolled patients with histologically confirmed CD20-positive NHL with histological subtype limited to grade 1, 2, or 3a follicular lymphoma, and splenic, nodal, or extranodal MZL. Patients needed to have relapsed/refractory disease and have received at least 1 prior line of therapy, including an anti-CD20 antibody plus chemotherapy or lenalidomide (Revlimid).

Exclusion criteria included having a histologically confirmed diagnosis of follicular grade 3b or transformed disease, prior treatment with PI3K inhibitors, ongoing or a history of drug-induced pneumonitis, or known lymphomatous involvement of the central nervous system.

Enrolled patients were randomly assigned 1:1 to receive zandelisib plus rituximab for 6 cycles, then zandelisib alone for 20 cycles, vs rituximab plus bendamustine or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for 6 cycles.

Progression-free survival per independent review committee (IRRC) served as the trial’s primary end point. Key secondary end points included overall response rate per IRRC assessment, overall survival, patient-reported outcomes, safety, and tolerability.

Data from the TIDAL trial presented during the 2021 ASH Annual Meeting showed that at a minimum follow-up of 6 months, zandelisib elicited an objective response rate (ORR) of 70.3% (95% CI, 59.8%-79.5%) per IRC assessment in the primary efficacy population, including a complete response rate of 35.2% (95% CI, 25.4%-45.9%).⁴

Regarding safety, grade 3 or higher adverse effects of special interest included increased alanine aminotransferase or aspartate aminotransferase (1.7%), colitis (1.7%), diarrhea (5%), mucositis (2.5%), pneumonitis (0.8%), and rash (3.3%).

TIDAL examined single-agent zandelisib in patients with relapsed/refractory follicular lymphoma and patients with relapsed/refractory MZL who needed to have progressed after at least 2 previous systemic therapies, including chemotherapy and an anti-CD20 antibody.

References

1. MEI Pharma and Kyowa Kirin announce discontinuation of zandelisib development outside of Japan following recent FDA meeting. News release. MEI Pharma, Inc. and Kyowa Kirin Co, Ltd. December 5, 2022. Accessed December 6, 2022. https://bit.ly/3urYb3w
2. MEI Pharma and Kyowa Kirin provide regulatory update on zandelisib following meeting with the FDA. News release. MEI Pharma, Inc. and Kyowa Kirin Co, Ltd. March 24, 2022. Accessed December 6, 2022. https://yhoo.it/3tOTmC5
3. Phase 3 study of zandelisib (ME-401) in combination with rituximab in patients with iNHL - (COASTAL). ClinicalTrials.gov. Updated November 16, 2022. Accessed December 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04745832
4. MEI Pharma and Kyowa Kirin announce data from the ongoing global phase 2 TIDAL study evaluating zandelisib as a single agent in patients with relapsed or refractory follicular lymphoma. News release. Mei Pharma. November 30, 2021. Accessed December 6, 2022. https://bit.ly/3E9hpOC