On December 11, 2023 Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with hematologic malignancies and solid tumors, reported positive clinical data from its orally available degraders of BTK, NX-5948 and NX-2127, which are being evaluated in separate Phase 1a/1b clinical trials in patients with relapsed or refractory (r/r) B-cell malignancies, including CLL, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), primary CNS lymphoma (PCNS), and Waldenström’s macroglobulinemia (WM) (Press release, Nurix Therapeutics, DEC 11, 2023, View Source [SID1234638433]). These data were presented in two posters at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, which is being held in San Diego, California.

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"Targeting BTK is an established treatment paradigm for patients with CLL and other B-cell malignancies. BTK degraders represent a novel next generation therapy for these patients," said Alexey Danilov, M.D., Ph.D. Professor and Co-Director, Toni Stephenson Lymphoma Center, City of Hope National Medical Center and an investigator on both studies. "CLL patients whose disease progresses on or after treatment with BTK inhibitors, most often due to the development of resistance, have no effective treatment options. The oral availability of BTK degraders, their ability to target BTK mutations, and their acceptable tolerability highlight the potential for these agents in the refractory CLL treatment landscape and potentially in earlier lines of therapy."

"The emerging efficacy and safety finding from our differentiated BTK degraders, NX-5948 and NX-2127, highlight the potential of degraders to become the next dominant class of agents in the valuable BTK-targeted therapy market," said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. "This first clinical disclosure for NX-5948 supports our strategy to broadly develop NX-5948 in CLL and other non-Hodgkin lymphoma conditions."

Nurix reported data from the dose escalation stage of its Phase 1a/1b clinical trial evaluating daily oral dosing of BTK degrader NX-5948 in patients with r/r B-cell malignancies. These data were from 26 patients enrolled in cohorts 1-5 (50-450 mg) who had received a median of four prior therapies (range 2-10, including BTKi, BCL2i, bispecific antibody or CAR-T therapy) and included patients with acquired mutations associated with drug resistance. Dose-dependent pharmacokinetics (PK) were observed, resulting in rapid, robust, and sustained BTK degradation in all patients treated once daily with oral NX-5948. In the CLL population that received doses ranging from 50 to 200 mg, six of seven patients demonstrated clinical benefit with three partial responses (PR) that were all ongoing as of the October 17, 2023 data cut, including one over nine months and three showing stable disease (SD), with treatment ongoing in two patients. In NHL patients (n= 19) who were treated with doses from 50 to 450 mg, durable responses were seen across indications, with almost half the patients continuing to receive treatment as of the cut-off date. NX-5948 was well-tolerated across all doses tested (50-450 mg) with no dose limiting toxicities (DLTs) or treatment-related serious adverse events (SAEs) and no treatment emergent adverse events (TEAEs) that resulted in drug discontinuation. Importantly, there were no incidences of atrial fibrillation or hypertension. Dose escalation continues across all indications and the study is actively enrolling patients in the United States, the United Kingdom, and the Netherlands. Additional data with higher dose levels and longer treatment duration are expected in 2024.

Data from the Phase 1a dose escalation and Phase 1b dose expansion cohorts (CLL, MCL and DLBCL) of Nurix’s clinical trial of NX-2127, an orally available degrader of both BTK and cereblon neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3) were reported in a second poster presentation. The presentation included data from 54 patients with r/r B-cell malignancies treated once daily with NX-2127 at doses that ranged from 100 to 300 mg. The patient population had a median age of 72.5 years (range 50-92 years) and had received a median of four prior lines of therapy (range 2-11, including BTKi, BCL2i, IMiDs, bispecific antibodies, or CAR-T therapy). Among the patients with CLL, 36% had acquired BTK mutations associated with BTK inhibitor drug resistance prior to entry in the study. NX-2127 exhibited dose-dependent PK, leading to robust and sustained degradation of BTK and biologically-relevant degradation of Ikaros. Treatment with NX-2127 resulted in encouraging rapid and durable responses in this heavily pre-treated patient population with complete responses (CR) reported in two (MCL and DLBCL) of the 17 evaluable NHL patients. These responses were durable for over one year. Two PRs in other NHL patients (MZL and FL) were also reported. Among the 27 evaluable patients with CLL, 11 experienced a PR for an overall response rate (ORR) of 40.7%. This compares favorably to earlier results presented at ASH (Free ASH Whitepaper) 2022 showing a preliminary 33% ORR.

NX-2127 had a manageable safety profile that was consistent with previous reports for BTK-targeted and immunomodulatory therapies. The most common grade ≥3 TEAEs were neutropenia, which showed evidence of dose response, hypertension and anemia. Atrial fibrillation was observed in six patients (11.1%, down from 17% reported previously), with three patients (5.6%) having grade ≥3 events. Twenty-one patients (38.9%) had serious TEAEs, of which eight (14.8%) had serious adverse events considered related to NX-2127 treatment. Two patients experienced DLTs (cognitive disturbance; neutropenia), and 13 patients developed TEAEs that resulted in discontinuation of NX-2127. As of the September 15, 2023 cutoff date, treatment was ongoing in 13 patients.

Webcast details
The live webcast KOL event, which will begin at 8:30 p.m. PT (11:30 p.m. ET) on Monday, December 11, 2023, and the subsequent replay, will be available in the Investors section of the Nurix website under Events and Presentations.

About NX-5948
NX-5948 is an investigational, orally bioavailable, small molecule degrader of BTK. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022).

About NX-2127
NX-2127 is a novel bifunctional molecule that degrades BTK and cereblon neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). NX-2127 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Additional information on the ongoing clinical trial can be accessed at www.clinicaltrials.gov (NCT04830137).