Early Activity of Novel BTK Degrader Shown in Chronic Lymphocytic Leukemia

In a phase 1 dose-escalation study, an investigational BTK degrader showed clinically meaningful results in patients with chronic lymphocytic leukemia and elicited a response.

NX-2127, a novel orally bioavailable degrader of the Bruton tyrosine kinase (BTK), demonstrated clinically meaning degradation of the BTK in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and other B-cell malignancies, according to initial findings from a phase 1 dose-escalation study announced in a press release by Nurix Therapeutics, Inc.1

NX-2127 carries the normal cellular protein degradation mechanism which allows it to catalyze degradation of BTK. This mechanism is important in B-cell malignancies because the BTK enzyme is present in the B-cell development, differentiation, and signaling that helps lymphoma and leukemia cells survive.

“The initial data from our study are the first proof-of-mechanism of targeted protein degradation in patients with hematologic malignancies,” said Arthur T. Sands, MD, PhD, president and chief executive officer of Nurix, in a press release. "The concept of degrading BTK as a new therapeutic strategy in hematologic cancer has taken an important step forward, and the NX-2127 program has hit an exciting milestone in its clinical development.”

The phase 1 clinical trial was designed to investigate the safety and tolerability of NX-2127 in patients with B-cell malignancies, including CLL, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone lymphoma, Waldenstrom macroglobulinemia (WM), follicular lymphoma, and diffuse large B-cell lymphoma. The coprimary end points of the study included determining the number of patients who experience dose-limiting toxicities (DLTs), establishing the maximum tolerated dose of the agent, objective response rate, and observing the number of patients with adverse events (AEs) or laboratory abnormalities.2

Secondary end points in the study included pharmacokinetics, duration of response, progression-free survival, overall survival, further evaluation of safety and tolerability, and the complete response rate.

In the first 2 cohorts, which were comprised of patients with CLL or SLL with no BTK C481 mutation and those who were BTK C481 mutation-positive, patients were treated with either 100 mg or 200 mg of NX-2127.1,2 The agent led to a significant decrease in BTK levels in peripheral blood in all patients who started therapy on day 1. Further, the BTK level continued to be suppressed throughout the dosing period. In the first dose cohort, BTK degradation exceeded 80% at a steady state and in the second dose cohort, it exceeded 90%. In preclinical models, BTK degradation of this magnitude led to anti-tumor responses, signally efficacy promise for NX-2127.1

It was also noted that one 78-year-old patient with CLL who was previously treated with 2 lines of therapy including ibrutinib (Imbruvica) had a partial response to NX-2127.

In terms of safety, no DLTs have been observed with NX-2127 given orally once daily at either 100 mg or 200 mg. The drug appears well-tolerated so far in all cohorts. Currently, 5 of the 6 patients continued to receive the agent for a duration of 4 to 19 weeks. The sixth patient, who was diagnosed with WM, discontinued treatment due to disease progression.

Following this positive data, the phase 1a/1b portion of the study is ongoing and actively recruiting patients with relapsed or refractory B-cell malignancies. To be eligible for the study, patients are required to be 18 years of age or older with measurable disease, a- ECOG performance status of 0 or 1, adequate organ and bone marrow function, previously treated with 2 prior lines of therapy, and must require systemic therapy.1,2

“Patients with relapsed and refractory B cell malignancies continue to require new drugs and new modalities to address their unmet medical need, and we believe that NX-2127 may offer a novel mechanism to block uncontrolled B cell signaling and tumor growth with the further potential to overcome acquired resistance to current treatments,” said Robert J. Brown, MD, senior vice president of clinical development at Nurix Therapeutics, Inc, in the press release.1 "The safety profile of NX-2127 to date is encouraging and we look forward to completing the dose-escalation portion of the study and moving into the expansion phase in selected cancers in the first half of 2022."

References:

1. Nurix Therapeutics announces initial data from the first phase 1a dose escalation trial of nx-2127 in patients with relapsed or refractory b cell malignancies. News release. October 27, 2021. Accessed October 28, 2021.https://bit.ly/3Gvg4U4

2. A Study of NX-2127 in adults with relapsed/refractory b-cell malignancies. Clinicaltrials.gov. Accessed October 28, 2021. https://bit.ly/3w6Ukcp