Nurix Therapeutics Launches Expansion Cohort Evaluating NX-2127 in CLL

Robert J. Brown, MD

Nurix Therapeutics has initiated an ongoing phase 1 trial (NCT04830137) to examine NX-2127, an immunomodulatory oral BTK inhibitor. This trial, the first of several planned phase 1b expansion cohorts evaluating NX-2121, will focus on patients with chronic lymphocytic leukemia (CLL).

“Our decision to advance NX-2127 in patients with CLL is based on the promising efficacy, safety, pharmacokinetic, and pharmacodynamic data from the ongoing phase 1a dose-escalation trial. There is a significant unmet need for a therapeutic approach with the potential to address the growing problem of relapse due to the development of BTK inhibitor resistance. We aim to meet that need and are encouraged by the emerging data demonstrating the potential of BTK degradation to treat acquired resistance mutations for both standard of care and newly developed BTK inhibitors,” Robert J. Brown, MD, executive vice president of clinical development at Nurix, said in a press release.

NX-2127 is an orally-bioavailable degrader of BTK with immunomodulatory activity and is designed to treat patients with relapsed or refractory B-cell malignancies. NX-2127 exploits the normal cellular protein degradation mechanism, the E3 ligase-mediated ubiquitin-proteasome pathway, to elicit BTK degradation.

BTK is an enzyme involved in B-cell development, differentiation, and signaling that is critical for the growth and survival of lymphoma and leukemia cells in many B-cell malignancies. BTK inhibitors including ibrutinib (Imbruvica) are approved for the treatment of patients with B-cell malignancies. However, certain patients cannot tolerate these agents, and some develop specific mutations in the BTK protein that can lead to drug resistance.

BTK degradation may overcome resistance in patients with BTK mutations. In addition, NX-2127 causes degradation of transcription factors including Ikaros and Aiolos that are involved in regulating T-cell function, leading to immunomodulatory activity.

This multicenter phase 1 study is designed to evaluate the safety, pharmacokinetic, pharmacodynamic, and preliminary clinical activity of NX-2127 in adults with relapsed or refractory B-cell malignancies.

Investigators are conducting the study in 2 parts. The phase 1a portion is a dose-escalation study in which cohorts of patients will receive increasing oral doses of NX-2127 once daily to determine the maximum tolerated dose and/or the optimal phase 1b dose based on safety and tolerability. The phase 1b portion is a dose-expansion phase in which cohorts of patients with specific cancers will receive NX-2127 to further evaluate the safety and clinical activity of the recommended dose.

The phase 1b expansion cohorts will enroll as many as 40 patients with CLL across clinical sites in the United States. Investigators plan to enroll eligible patients with pretreated CLL or small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.

All patients will receive NX-2127 at a dose of 100 mg orally once daily. To be eligible for enrollment, patients must have received at least 2 prior regimens including a BTK inhibitor.

The phase 1a dose-escalation phase of the trial will continue to enroll patients without CLL at doses ranging from 50 mg to 300 mg orally once daily.

The expansion into CLL is based on recent positive data from Nurix’s ongoing phase 1a dose-escalation study of NX-2127. Findings from the study demonstrated a clinically meaningful benefit as defined by confirmed responses by International Workshop on CLL criteria in heavily pretreated patients with relapsed/refractory CLL who had received a median of 6 prior lines of therapy. Notably, clinical responses occurred in patients with BTK mutations that confer resistance to current covalent and noncovalent BTK inhibitors alike.

Moreover, all patients experienced robust and durable BTK degradation, and all patients demonstrated evidence of immunomodulatory activity mediated through the E3 ligase cereblon. All patients also displayed biologic activity at the 100 mg dose, which also conveyed a favorable safety profile.

“We. . .will provide a full clinical update at a future medical conference in the second half of 2022,” Brown concluded.

Reference

Nurix Therapeutics announces positive dose finding data in chronic lymphocytic leukemia and advances NX-2127 to next phase of clinical development. News release. Nurix Therapeutics. May 26, 2022. Accessed May 31, 2022. https://yhoo.it/3NPmvUN