BTK Protein Degrader Shows Strong Clinical Performance--Kyinno's BTK Degrader and Inhibitor Screening Cell Models

Targeted therapy focusing on two key pathways (BTK/BCL2) has become the standard treatment for chronic lymphocytic leukemia (CLL), revolutionizing the treatment landscape for both frontline and relapsed/refractory CLL. Emerging resistance patterns limit the efficacy of currently available therapies: BTK mutations confer resistance to both covalent and non-covalent BTK inhibitors (cBTKi and ncBTKi) [1]. Some mutations lead to 'kinase-inactive' or 'kinase hyperactive' BTK mutants that maintain B-cell receptor signaling through the scaffolding function of BTK. There is an urgent need for new therapeutic approaches that target both the emerging resistant mutations and the scaffolding activity of BTK.

Nurix's novel BTK degrader NX-5948 is currently in Phase I clinical trials. Positive results from the Phase Ia trial were reported at the EHA meeting on June 17. This study included 31 patients with relapsed or refractory CLL and 48 patients with NHL/WM. Doses ranged from 50, 100, 200, 300, 450, to 600 mg, taken orally once daily. NX-5948 was well-tolerated in both NHL and CLL patients, with no increased signal of adverse effects at higher doses. The most common adverse events were purpura/bruising, thrombocytopenia, neutropenia, and fatigue. NX-5948 demonstrated strong clinical activity, with an objective response rate (ORR) of 69.2%. Deep and durable clinical responses were observed in the refractory CLL patient cohort, including patients previously treated with other therapies and those with adverse genetic mutations associated with poor prognosis and BTK inhibitor resistance. As of April 17, 2024, all responses have persisted. Rapid pharmacodynamic responses were observed: 15 out of 18 patients showed efficacy at the first scan (8 weeks post-treatment). Currently, 27 out of 31 patients remain on treatment. No intrinsic resistance to NX-5948 was observed. These data support the continued development of NX-5948 for CLL treatment. Nurix plans to conduct a Phase Ib dose expansion study. Data on NHL/WM will be released in the second half of 2024.

Good tolerability shown by NX-5948

Clinical Efficacy of NX-5948

Mechanism of NX-5948 [2]

Currently, besides Nurix, other companies are also developing BTK degraders. For example, Abbvie (ABBV-101) and BeiGene (BGB16673) BTK degraders are in Phase I clinical trials for the treatment of relapsed and refractory B-cell malignancies.

Kyinno Biotechnology Inc. has constructed multiple cell lines expressing common BTK mutations associated with drug resistance, as well as in vivo animal models. We have also conducted related functional validations. The validation results are as follows. Please contact us for more information.

Kyinno Biotechnology Inc. BTK Cell Lines and In-Vivo Animal Models

Tumor Growth Curves of Partial BTK Cell Models:

In-Vitro Efficacy Data of Some BTK Cell Models:

KC-1695 Ba/F3-ETV6-BTK

KC-1853 Ba/F3-ETV6-BTK-F517L

KC-2647 Ba/F3-ETV6-BTK-C481S-K558T

KC-2776 Ba/F3-ETV6-BTK-T474I

KC-2892?Ba/F3-ETV6-BTK-C481S

In-Vitro BTK Protein Degradation Testing:

KC-2776 Ba/F3-ETV6-BTK-T474I:

Reference

[1] Liton et al. Latest Results from an Ongoing First-in-Human Phase 1a/b Study of NX-5948, a Selective Bruton’s Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory CLL and Other B-cell Malignancies. EHA Hybrid Congress – June 16, 2024.

[2] Searle et al. Initial Findings From a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton’s Tyrosine Kinase Degrader, in Patients with Relapsed/Refractory B-Cell Malignancies. The 21st Annual International Ultmann Chicago Lymphoma Symposium, 19–20 April 2024, Chicago, IL, USA.