Dizal Pharma Initiated the phase 2 study of DZD8586 in patients with CLL/SLL

Dizal Pharma has initiated a phase 2 study (CTR20240120) of DZD8586, a fully blood-brain barrier (BBB) penetrable LYN/BTK dual inhibitor, for the treatment of CLL/SLL in China. The sponsor aims to enroll an estimated 155 patients with rr-CLL/SLL. The patients in the three groups will receive DZD8586 at doses of 25 mg, 75 mg, and 100 mg.

https://doi.org/10.1038/nchembio.502

Recently, Dizal highlighted various results from preclinical and clinical studies of DZD8586. As DZD8586 inhibits both LYN and BTK simultaneously, it demonstrated anti-proliferative effects in cell lines expressing C481X and pirtobrutinib resistance mutations. Additionally, DZD8586 exhibited potent cell growth inhibition and induced cell death in a variety of DLBCL cell lines. Moreover, it demonstrated profound tumor growth inhibition in both CNS tumor models, attributed to its specific blood-brain barrier (BBB) penetration.

DZD8586 demonstrated consistent results in the early human study. The dose escalation and expansion results of the phase 1 study provided a positive signal in patients with rr-B-NHL. A total of 17 patients with various diagnoses including CLL, SCNSL, DLBCL, MCL, FL, and MZL were evaluated for efficacy assessment, revealing an objective response rate (ORR) of 64.7% (11/17). mong 6 patients with DLBCL, 5 (83.3%) achieved tumor response, including one patient with GCB. Grade 3+ TEAEs were thrombocytopenia (5/25), neutropenia (4/25), and upper respiratory tract infection (1/25).

In 2020, Dizal filed a patent (US20230122807) claiming BTK inhibitors with blood-brain barrier (BBB) penetration, but without reported data on LYN inhibition. The potential of a compound to cross the blood-brain barrier in rats was evaluated by the total brain-to-plasma ratio (K p, brain) by measuring the AUC brain/AUC plasma. K p, brain of compound 2, 10, 14 were around 1.35, 0.38, and 0.32, respectively.

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