As of the October 10, 2024 data cut, sixty (60) patients with relapsed or refractory CLL/SLL were enrolled. This cohort of CLL/SLL patients was a heavily pretreated population that had received a median of four prior lines of therapy (range = 1-12) including prior covalent BTK inhibitors (98.3%), prior BCL2 inhibitors (83.3%), and prior non-covalent BTK inhibitors (28.3%). At baseline, a large number of patients had mutations associated with BTK inhibitor resistance, including mutations in BTK (38.6%) and PLC2G (12.3%). Poor prognostic features were common, including TP53 mutations (40.4%), and five patients (8.3%) had central nervous system (CNS) involvement.

The data presented at the ASH Annual Meeting include safety findings for all patients in the NX-5948 Phase 1a/1b dose escalation and expansion cohorts (n=125), including those with CLL/SLL and those with non-Hodgin’s lymphoma (NHL). Patients were treated with NX-5948 at starting doses ranging from 50 mg to 600 mg once daily by oral administration, and intra-patient dose escalation was permitted per protocol. NX-5948 was well tolerated across all doses evaluated, and safety findings in the CLL/SLL cohort were consistent with the overall population as well as previous safety analyses. Among the CLL/SLL patients, the most common treatment emergent adverse events were purpura/contusion (36.7%, all grade 1 or 2), fatigue (26.7%, all grade 1 or 2), petechiae (26.7%, all grade 1 or 2), neutropenia (23.3%, 18.3% grade 3 or higher), and rash (23.3%, 1.7% grade 3 or higher). Importantly, across the entire population, there was only one case of grade 1 atrial fibrillation in a patient with pre-existing atrial fibrillation.

Among the efficacy evaluable patients with CLL/SLL (n=49), NX-5948 treatment resulted in a robust objective response rate (ORR) of 75.5% across all doses tested, with the majority of responses occurring at the first assessment (Week 8). With longer time on treatment, the ORR increased to 84.2% based on an exploratory efficacy analysis of patients who had at least two response assessments (Week 16). Responses were observed across all populations regardless of prior treatment, baseline mutations, high-risk molecular features, or CNS involvement. This includes patients with baseline BTK mutations associated with treatment resistance to both covalent and non-covalent BTK inhibitors. Robust BTK degradation was observed in all patients, including those with baseline BTK mutations.

Responses were durable with the median duration of response not reached. Thirteen patients had duration of response greater than six months, and five patients remain on treatment and in response beyond one year of treatment.