HZ-a-018 Is a Highly Selective and Potent BTK Inhibitor with CNS-Penetrating Profile for Central Nervous System Lymphoma

Central nervous system lymphoma (CNS lymphoma) is an aggressive and rare type of extranodal non-Hodgkin lymphoma associated with CNS invasion, that arises most often in the brain and sometimes affects the eyes and cerebrospinal fluid (CSF). Combination chemotherapy with high-dose methotrexate is currently the first-line regimen for CNS lymphoma, but there is no uniform standard of care for the treatment of R/R (refractory or relapsed) CNS lymphoma. Bruton's tyrosine kinase (BTK) plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in CNS lymphoma, and represents an excellent therapeutic target. Recently, several BTK inhibitors are approved for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and waldenstrom's macroglobulinemia (WM), but with limited central nervous system (CNS) penetrance and activity for CNS lymphoma.

HZ-A-018 is a potent and selective novel covalent BTK inhibitor with excellent pharmacokinetics and pharmacology properties in preclinical study. HZ-A-018 exhibits strong BTK inhibition potency at biochemical and cellular level. In addition, HZ-A-018 penetrates CNS and demonstrates activity in two animal models of brain malignancies. Oral administration of HZ-A-018 can significantly improve survival relative to treatment with vehicle and ibrutinib. The potent BTK inhibition activity of HZ-A-018 and the ability to penetrate the CNS supports its development for the treatment of B-cell malignancies, including CNS lymphoma.

HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of oral HZ-A-018 in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who have received ≥1 prior therapy. The dose escalation part was initiated with a 3 + 3 design in 28-day cycles. The primary objective for phase 1 was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included complete response (CR) rate, duration of response (DOR), progression free survival (PFS), overall survival (OS), and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed at the beginning of cycle 2 and cycle 3 and then every 8 weeks and was measured according to International PCNSL Collaborative Group (IPCG). Safety was assessed in all pts. The preliminary results showed that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The results provide preliminarily evidence that HZ-A-018 offers a new treatment strategy for R/R CNS lymphoma. The efficacy, safety, and tolerability of HZ-A-018 at the RP2D established in the phase I dose escalation and expansion part will be investigated in phase 2.

No relevant conflicts of interest to declare.