zandelisib (ME-401)

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.

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).

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.

P2, N=61, Active, not recruiting, Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 --> May 2028 | Trial primary completion date: Sep 2024 --> May 2028

P1, N=14, Active, not recruiting, Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 --> May 2028 | Trial primary completion date: Sep 2024 --> May 2028

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.

P1/2, N=13, Active, not recruiting, Deepa Jagadeesh | Recruiting --> Active, not recruiting | N=54 --> 13

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.

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.

P1/2, N=0, Withdrawn, Jacob Soumerai, MD | N=34 --> 0 | Not yet recruiting --> Withdrawn

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

P2, N=169, Terminated, 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