On December 9, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported the latest data from a pooled safety and efficacy analysis of DZD8586, a non-covalent blood-brain barrier (BBB) penetrant LYN/BTK dual inhibitor, in B-cell non-Hodgkin lymphoma (B-NHL) (Press release, Dizal Pharma, DEC 9, 2024, View Source [SID1234648943]). The data were presented at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The analysis pooled data from ongoing phase 1/2 clinical studies evaluating DZD8586 in patients with B-NHL who had progressed following, or were intolerant to, prior systemic therapies. As of October 20, 2024, 61 patients were included in the efficacy analysis and 84 patients were included in the safety set.

Anti-tumor efficacy:

In chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), the overall response rate (ORR) was 57.9% (≥ 50 mg) by data cutoff. Tumor response was observed in patients with prior treatment of covalent and non-covalent BTKi, and Bcl-2i. Tumor responses were observed in patients with classic BTK resistance mutations (C481X) as well as BTK "dead" mutations. Preliminary anti-tumor activity was observed in patients pre-treated by pirtobrutinib, with T474I mutation as well.
Significant tumor response was also observed in other B-NHL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), and central nervous system lymphoma (CNSL).
Safety:

Dose-dependent thrombocytopenia and neutropenia were the most common ≥grade 3 TEAEs, which could be well managed in the clinic.
PK and pharmacodynamic biomarker

Dose-proportional PK profile and dose-dependent modulation of pharmacodynamic biomarkers were observed.
In patients with CNSL, the Kpuu,CSF at steady state were 1.21 and 0.98, suggesting high CNS penetration of DZD8586 in human.
"A significant proportion of B-NHL patients treated with BTK inhibitors will eventually relapse and develop drug-resistant mutations. Two primary types of clinical resistance mutations have been identified: C481X mutation and BTK loss-of-activity mutations," said Xiaolin Zhang, PhD, CEO of Dizal. "DZD8586, as a non-covalent dual inhibitor targeting both BTK-dependent and -independent pathways, has demonstrated promising antitumor activity and safety profile in patients who did not respond to or develop resistance to both covalent and non-covalent BTK inhibitors, including those with CLL/SLL and other B-NHL. With multiple clinical development programs ongoing or under planning, DZD8586 is expected to bring significant clinical benefit to patients with relapsed or refractory B-NHL."

Bruton’s Tyrosine Kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. However, resistance can arise through multiple mechanisms, compromising the treatment outcome and posing an urgent clinical challenge. The C481X mutation disrupts covalent BTK inhibitors binding to BTK enzyme and leads to treatment failure. Additionally, BTK-independent resistance mechanism due to loss of or much diminished BTK enzyme activity was also identified in the clinic. Currently, there is no targeted therapy available to address both resistance mechanisms.

DZD8586 was designed as a LYN/BTK dual inhibitor with high selectivity against other TEC family kinases (TEC, ITK, TXK and BMX), as well as full BBB penetration. By targeting BTK and LYN, it blocks both BTK-dependent and -independent BCR-signaling pathways, which may potentially overcome resistance to approved covalent and non-covalent BTK inhibitors.