Preclinical and First-in-Human Phase I Study of Bruton Tyrosine Kinase Degrader HZ-Q1070 in Patients with Recurrent or Refractory B-Cell Malignancies
Authors: Song Yuqin , Lin Ningjing , Liu Xingguo , Zhou Yubo , Wu Yizhe , Luo Xiaomin , Xie Jiangfeng , Ma Xinna , Hu Miao , Zhang Yanping , Li Jia , Zhou Xinglu 
Published: December 2024

Bruton tyrosine kinase (BTK) plays a critical role in the B-cell antigen receptor signaling (BCR) pathway and the pathogenesis of multiple B-cell malignancies. Covalent or noncovalent BTK inhibitors (BTKi) have been applied in the management of B-cell malignancies, but mutations in BTK can lead to BTKi resistance and limit therapeutic effectiveness due to reduction binding capacity to BTK, scaffold function leading to downstream BCR signaling hyperactivation. Utilizing small molecule-induced protein degradation provides a novel approach to targeting BTK for the treatment of B-cell malignancies (BCM). An orally BTK degrader HZ-Q1070 based on our DaTProD® platform was developed with excellent BTK degradation activity in preclinical studies. It is under evaluation in a phase I clinical trial (CTR20240471).

Preclinical studies demonstrated that HZ-Q1070 catalyzes the degradation of 50% of cellular BTK (DC50) at concentrations below 0.1 nM in lymphoma cell lines and peripheral blood mononuclear cells (PBMCs). HZ-Q1070 reduces viability in BTK-dependent lymphoma cell lines such as Mino, OCI-ly10, and TMD8, with IC50 values less than 0.3 nM. Notably, HZ-Q1070 catalyzes the degradation of mutated BTK variants (C481S, C481Y, C481F, T474M, V416L, T474I, L528W) with DC50 values below 1 nM. HZ-Q1070 also showed high-selective degradation of BTK. In an unbiased proteomics study, treatment of Mino cells with HZ-Q1070 resulted in significant BTK degradation without notable downregulation of other off-target proteins. Pharmacokinetic/pharmacodynamic (PK/PD) studies have shown that HZ-Q1070 exhibits excellent pharmacokinetic properties and rapid BTK degradation in vivo. In xenograft mouse models, daily oral administration of HZ-Q1070 led to superior tumor growth inhibition (TGI) compared to BTK inhibitors (BTKi), including in a Rec1 model containing the BTK-C481S mutation. HZ-Q1070 has been engineered to avoid the degradation of Aiolos and Ikaros, and as a result, it does not exhibit IMiD activity. Additionally, HZ-Q1070 demonstrates excellent pharmacokinetic properties in both rodents and non-rodents, along with a favorable safety profile.

A phase I study of HZ-Q1070-101 in R/R BCM in ongoing, with dose escalation and expansion parts. The primary objectives were to determine the safety and tolerability, maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary objectives included preliminary antitumor activity and pharmacokinetics (PK) and pharmacodynamics (PD). HZ-Q1070 was orally given once daily in 28-day cycles until disease progression, intolerance, death, withdrawal of consent, no further benefits from the treatment as determined by the investigator, or at end of study, whichever occurred first. In the dose escalation part, a “3+3” design was adopted across 5 dose levels. Safety was assessed per CTCAE v5.0 in all patients. Responses were evaluated after 12 weeks according to IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other BCM.

Eligible patients were diagnosed pathologically as B-cell malignant, including CLL/SLL, WM, MCL, FL, MZL, DLBCL and PCNSL ( in the dose expansion part only), relapsed or refractory to at least 2 prior systematic therapies (≥1 for WM and PCNSL). Other inclusion criteria included an ECOG performance status of 0-2 and adequate end-organ functions.

As of 3 May, 2024, 2 patients were enrolled in the first 25mg dose group. All treatment-related adverse events (TRAEs) were Grade 1. No DLT was observed. Pharmacokinetic data showed satisfied results. Pharmacodynamic results showed a degradation rate of BTK protein levels in peripheral blood mononuclear cells of more than 95%.

Conclusion:

In summary, our preclinical and clinical data showed HZ-Q1070 is a unique and excellent BTK degrader. The preliminary data from the FIH phase I study of HZ-Q1070 in R/R BCM demonstrated a safety profile and response signal. This trial is currently ongoing.