Bexobrutideg (NX-5948): A Novel BTK-Degrading Agent for Hematologic Malignancies and Beyond

1. Introduction to Bexobrutideg (NX-5948)

Bexobrutideg, formerly known as NX-5948, is an orally bioavailable, brain-penetrant, small molecule that functions as a specific degrader of Bruton's Tyrosine Kinase (BTK).[1] This investigational agent is at the forefront of targeted protein degradation, a novel therapeutic modality with the potential to overcome limitations of existing kinase inhibitors.[1] The development of bexobrutideg is primarily focused on addressing significant unmet medical needs in various B-cell hematologic malignancies, with emerging potential in the treatment of inflammatory and autoimmune diseases.[1]

The development of bexobrutideg is being led by Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company. Nurix specializes in the discovery, development, and commercialization of targeted protein modulation medicines, particularly protein degraders.[1] A cornerstone of Nurix's innovative approach is its proprietary DELigase™ platform. This integrated discovery engine utilizes DNA-encoded libraries (DEL) combined with artificial intelligence tools, termed DEL-AI, to identify and advance novel drug candidates that specifically target E3 ubiquitin ligases.[2] The company's strategy involves either harnessing or inhibiting the natural function of these E3 ligases to selectively decrease or increase the levels of disease-causing proteins within cells.[3] Beyond bexobrutideg, Nurix's pipeline includes other clinical-stage assets such as NX-2127, another BTK degrader which also degrades Ikaros (IKZF1) and Aiolos (IKZF3), and NX-1607, an inhibitor of the E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B), alongside several partnered programs.[3] This commitment to protein degradation technology underscores Nurix's strategic focus on pioneering distinct therapeutic modalities rather than incremental improvements on existing drug classes.

The rationale for developing bexobrutideg stems from the critical role of BTK in B-cell biology and the limitations of current BTK inhibitor (BTKi) therapies. BTK is a non-receptor tyrosine kinase essential for B-cell receptor (BCR) signaling, which in turn governs B-cell development, differentiation, proliferation, and survival.[9] Dysregulation of BTK activity is a well-established driver in many B-cell malignancies, including chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), and various non-Hodgkin lymphomas (NHLs). While covalent and non-covalent BTK inhibitors have revolutionized the treatment landscape for these diseases, their efficacy can be compromised by the emergence of resistance mutations (e.g., BTK C481S) that prevent drug binding, or by kinase-independent scaffolding functions of the BTK protein that are not addressed by simple kinase inhibition.[4] Furthermore, off-target effects of some BTKis can lead to undesirable toxicities, such as cardiovascular complications. Bexobrutideg, by inducing the degradation of the entire BTK protein, offers a mechanism to potentially overcome these resistance mechanisms and potentially provide a more complete and durable response.[9] This focus on addressing BTKi resistance positions bexobrutideg for initial utility in patient populations with high unmet needs who have progressed on or are intolerant to existing BTKi therapies.

A key differentiating feature of bexobrutideg, highlighted consistently since its early development, is its ability to penetrate the central nervous system (CNS).[1] This property was likely a deliberate design objective, aiming to address the challenge of CNS involvement in certain B-cell malignancies, such as primary CNS lymphoma or CNS relapse of systemic lymphomas, which are notoriously difficult to treat due to the blood-brain barrier limiting the efficacy of many systemic therapies.

Beyond oncology, the role of BTK in signaling pathways of both B-cells and myeloid cells (e.g., Toll-like receptor and Fc receptor signaling) implicates it in the pathogenesis of various autoimmune and inflammatory conditions.[1] The potential for bexobrutideg to achieve deep and sustained suppression of these pathways forms the basis for its exploration in diseases such as rheumatoid arthritis and autoimmune cytopenias.[2]

2. Chemical Properties and Formulation

The unique identity and characteristics of bexobrutideg are fundamental to its novel mechanism and therapeutic potential.

Nomenclature:

The nonproprietary name assigned to the compound formerly known as NX-5948 is bexobrutideg.1 This name was officially adopted in March 2025 following collaboration with the United States Adopted Name (USAN) Council.1 Of particular note is the assignment of the novel suffix "-deg." This suffix was specifically designated to classify bexobrutideg and similar future agents as members of a new pharmacological class: targeted protein degraders. This nomenclature recognizes the distinct mode of action, differentiating these molecules from traditional inhibitors (e.g., "-tinibs" for kinase inhibitors).1 The formal establishment of this suffix is a landmark event, signifying regulatory acknowledgment of protein degradation as a unique therapeutic strategy and potentially influencing the classification and regulatory pathways for this emerging field of medicines.

Chemical Identity and Characteristics:

Bexobrutideg is identified by the chemical name 3-\amino]carbonyl]-3-pyridinyl]-4-piperidinyl]methyl]-4-piperidinyl]phenyl]amino]-5--2-pyrazinecarboxamide.12 Its molecular formula is C42​H54​N12​O5​, corresponding to a molecular weight of 806.97 g/mol.12 The CAS Registry Number for bexobrutideg is 2649400-34-8.12

The complex chemical name strongly suggests a bifunctional molecular architecture, characteristic of PROTAC® (Proteolysis-Targeting Chimera) molecules. The presence of the "(3S)-2,6-Dioxo-3-piperidinyl" moiety is indicative of a thalidomide-like ligand that binds to the E3 ubiquitin ligase cereblon (CRBN). The remaining extensive structure would encompass the BTK-binding "warhead" and the linker connecting these two functional ends, consistent with its described mechanism of action.[12]

For research purposes, bexobrutideg exhibits solubility up to 50 mM in dimethyl sulfoxide (DMSO) and is typically supplied at a purity of ≥98%.[12] Recommended storage for the research-grade compound is at -20°C.[12]

Interestingly, bexobrutideg possesses physicochemical properties that deviate from those typically associated with CNS-penetrant drugs. For instance, it has a molecular weight significantly exceeding the commonly cited guideline of ≤360 Da for CNS agents, and also surpasses typical thresholds for polar surface area (TPSA) and hydrogen bond donor (HBD) count.[13] Its calculated CNS Multi-Parameter Optimization (MPO) score is 2.2 (or 2.7 when accounting for solvent-exposed HBDs), which is generally lower than that of established CNS drugs and would conventionally predict reduced CNS exposure.[13] Despite these "unfavorable" properties, bexobrutideg demonstrates effective CNS penetration and activity, a phenomenon attributed to its catalytic mechanism of action, which allows for efficacy at very low unbound drug concentrations within the CNS.[13] This challenges traditional drug design paradigms for CNS therapeutics and suggests that catalytic mechanisms may offer a way to overcome certain pharmacokinetic barriers.

Formulation:

Bexobrutideg has been developed as an orally bioavailable small molecule.1 In clinical trials, it is administered as an oral dose once daily.4

The following table summarizes the key chemical and formulation properties of bexobrutideg:

Table 1: Summary of Bexobrutideg (NX-5948) Chemical and Formulation Properties

Property	Description	Source Snippet(s)
Nonproprietary Name	Bexobrutideg	1
Previous Identifier	NX-5948	1
Significance of "-deg" Suffix	Designates a new class of targeted protein degraders, recognizing novel degradation MoA	1
Developer	Nurix Therapeutics, Inc.	1
Chemical Name	3-\amino]carbonyl]-3-pyridinyl]-4-piperidinyl]methyl]-4-piperidinyl]phenyl]amino]-5--2-pyrazinecarboxamide	12
Molecular Formula	C42​H54​N12​O5​	12
Molecular Weight	806.97 g/mol	12
CAS Number	2649400-34-8	12
Solubility (DMSO)	Soluble to 50 mM	12
Purity (research grade)	≥98%	12
Formulation Type	Oral small molecule	1
Route of Administration	Oral, once daily (in clinical trials)	4
CNS MPO Score	2.2 (2.7 accounting for solvent-exposed HBDs)	13

3. Mechanism of Action and Pharmacology

Bexobrutideg represents a distinct pharmacological approach as a Bruton's Tyrosine Kinase (BTK) degrader, belonging to the class of targeted protein degraders, specifically engineered as a PROTAC® (Proteolysis-Targeting Chimera).[1]

Detailed Mechanism of Action:

The mechanism of bexobrutideg involves hijacking the cell's natural protein disposal system. As a bifunctional molecule, it possesses two key binding domains connected by a linker: one domain selectively binds to BTK, and the other binds to cereblon (CRBN), a substrate receptor component of the Cullin-RING E3 ubiquitin ligase complex.10 This dual binding facilitates the formation of a ternary complex, bringing BTK into close proximity with the CRBN E3 ligase machinery. Once this complex is formed, the E3 ligase catalyzes the polyubiquitination of the BTK protein. This polyubiquitin chain acts as a molecular tag, marking BTK for recognition and subsequent degradation by the 26S proteasome.10

The critical distinction of this mechanism is that it leads to the selective elimination and removal of the entire BTK protein from the cell, encompassing both wild-type and mutant forms of BTK.[9] This is fundamentally different from traditional BTK inhibitors, which merely block the kinase activity of the protein. By removing the entire protein, bexobrutideg can abrogate not only the kinase-dependent signaling functions of BTK but also any potential kinase-independent scaffolding roles the protein might play, which can contribute to cell survival and resistance.[9] This comprehensive targeting of BTK offers a potential advantage in overcoming multiple mechanisms of resistance observed with conventional BTK inhibitors.

Catalytic Nature and Efficiency:

A hallmark of PROTAC degraders like bexobrutideg is their catalytic mode of action. Unlike inhibitors that typically require a 1:1 stoichiometric relationship with their target for sustained inhibition, a single molecule of bexobrutideg can orchestrate the degradation of multiple BTK protein molecules.13 After facilitating the ubiquitination of one BTK molecule, the degrader is released and can engage another BTK molecule, repeating the cycle. Preclinical studies have quantified this efficiency, demonstrating that a single molecule of bexobrutideg can induce the degradation of approximately 10,000 copies of BTK protein per hour at clinically relevant concentrations.3

This catalytic efficiency, often referred to as "event-driven pharmacology," implies that potent and sustained pharmacodynamic effects (i.e., BTK protein knockdown) can be achieved and maintained even at relatively low intracellular drug concentrations and systemic exposures compared to what would be required for stoichiometric inhibitors.[1] This characteristic may contribute to an improved therapeutic index, potentially minimizing off-target effects and allowing for efficacy even if high trough concentrations are not continuously maintained. It also underpins its ability to exert effects in challenging pharmacokinetic environments like the CNS.

Pharmacodynamics:

Bexobrutideg exhibits potent and selective BTK degradation. In vitro, it induces BTK degradation with a DC50 (concentration required for 50% degradation) of less than 1 nM and achieves a maximum degradation (Dmax) of over 98%.12 Specifically in primary human B cells, the DC50 for BTK degradation is exceptionally low at 0.034 nM.12 This degradation is rapid and complete.10 Importantly, bexobrutideg demonstrates activity against various mutant forms of BTK, including those conferring resistance to covalent BTK inhibitors (e.g., C481S), and clinical responses have been observed in patients irrespective of BTK mutation status.4 The compound is described as a "highly selective" degrader of BTK, suggesting minimal impact on other cellular proteins.4

Pharmacokinetics (PK):

Bexobrutideg is designed for oral administration and is orally bioavailable.1 A significant PK attribute is its ability to penetrate the blood-brain barrier (BBB). Preclinical studies in rodents have confirmed CNS exposure, with an unbound brain-to-plasma partition coefficient (Kp,uu) consistent with CNS penetration.11 Clinically, bexobrutideg has been detected in the cerebrospinal fluid (CSF) of patients with CNS-involved B-cell malignancies at concentrations that exceed the minimum free plasma levels associated with BTK degradation in vitro.13 This CNS penetration is achieved despite bexobrutideg possessing physicochemical properties (e.g., high molecular weight, high hydrogen bond donor count, high polar surface area) that would traditionally predict poor BBB permeability.13 This apparent paradox is likely resolved by its catalytic mechanism, allowing for pharmacodynamic effects at the low unbound drug concentrations achievable in the CNS. This capability to effectively target BTK within the CNS, despite not adhering to conventional CNS drug design rules, suggests that catalytic mechanisms like protein degradation could broaden the scope of "druggable" targets within the CNS.

Table 2: Pharmacological Profile of Bexobrutideg (NX-5948)

Pharmacological Aspect	Details	Significance	Source Snippet(s)
Drug Class	BTK Degrader, Targeted Protein Degrader (PROTAC®)	Novel therapeutic modality targeting BTK for elimination.	1
Specific MoA	Bifunctional molecule; recruits BTK to CRBN E3 ligase complex, leading to ubiquitination and proteasomal degradation of BTK.	Eliminates entire BTK protein, addressing kinase and scaffolding functions; overcomes certain inhibitor resistance mechanisms.	10
Catalytic Efficiency	One bexobrutideg molecule degrades ~10,000 BTK copies/hour. Event-driven pharmacology.	Allows for efficacy at low drug concentrations, potentially improving safety and enabling sustained effect.	1
Potency (BTK Degradation)	DC50 <1 nM (in vitro general); DC50 = 0.034 nM (primary human B cells); Dmax >98%. Sub-nanomolar potency for wild-type and mutant BTK.	Highly potent degradation of the target protein.	11
Selectivity	Described as "highly selective" for BTK.	Minimizes potential off-target effects.	4
Activity vs. Mutants	Effective against BTKi-resistant cell lines and degrades mutant BTK forms (e.g., C481S). Clinical responses independent of BTK mutation status.	Potential to treat patients who have developed resistance to conventional BTK inhibitors.	4
Oral Bioavailability	Orally bioavailable.	Convenient route of administration.	1
Brain/CSF Penetration	Crosses BBB; detected in patient CSF at active concentrations. Kp,uu consistent with CNS penetration. Achieved despite "unfavorable" physicochemical properties.	Potential for treating primary CNS lymphomas and CNS involvement of systemic B-cell malignancies. Redefines CNS drug design parameters.	12

4. Preclinical Development

The preclinical evaluation of bexobrutideg has provided a robust foundation for its clinical development, demonstrating its potent mechanism of action, efficacy in relevant disease models, and unique pharmacokinetic properties.

In Vitro Studies:

Laboratory studies have consistently highlighted bexobrutideg's potent and rapid activity. It induces comprehensive degradation of BTK in primary human B cells with a DC50 of 0.034 nM.12 This high potency extends to various tumor cell lines, critically including those that have developed resistance to existing BTK inhibitor therapies, which underscores its potential utility in relapsed or refractory disease settings.4 The compound effectively degrades both wild-type BTK and clinically relevant mutant forms, such as the C481S mutation often responsible for covalent BTKi resistance.10 A key mechanistic finding from in vitro experiments is the calculation of its catalytic efficiency: a single molecule of bexobrutideg is capable of promoting the degradation of approximately 10,000 copies of BTK protein per hour when present at clinically relevant concentrations.3 This catalytic turnover is a fundamental differentiator from traditional inhibitors.

In Vivo Animal Models:

The promising in vitro activity of bexobrutideg has translated into significant efficacy in various animal models of disease.

In B-cell malignancy models, bexobrutideg has demonstrated the ability to inhibit tumor growth and improve survival in TMD8 xenograft mouse models, which represent a type of diffuse large B-cell lymphoma.[12] Crucially, reflecting its designed brain-penetrant properties, bexobrutideg was shown to cross the blood-brain barrier and effectively degrade BTK within the intracranial environment. This translated to preclinical efficacy in mouse models of brain lymphoma, providing strong early validation for its potential in treating CNS lymphomas or CNS involvement of other B-cell cancers.[11] This early demonstration of CNS activity was a significant step, de-risking a challenging therapeutic area and likely influencing the inclusion of CNS lymphoma patients in early clinical trials.

In inflammatory condition models, bexobrutideg has also shown notable effects. In a mouse model of collagen-induced arthritis, administration of bexobrutideg led to a reduction in inflammation and overall symptom severity.[12] Further mechanistic work, presented at the American College of Rheumatology (ACR) Convergence 2024, detailed its capacity to achieve profound suppression of B-cell receptor (BCR), Toll-like receptor (TLR), and Fc receptor (FcR) signaling pathways in immune cells. These findings were accompanied by demonstrations of efficacy in preclinical models of arthritis and other inflammatory diseases.[14] This broad immunomodulatory activity, extending beyond simple B-cell effects due to BTK's role in myeloid cells as well, supports the exploration of bexobrutideg in a range of autoimmune conditions.

Regarding CNS exposure and activity, preclinical studies in rodents confirmed dose-dependent brain exposure of bexobrutideg, with an unbound brain-to-plasma partition coefficient (Kp,uu) indicative of significant CNS penetration.[13] Data presented at AACR 2025 further emphasized the unique physicochemical properties of bexobrutideg that enable this CNS exposure, despite it not conforming to traditional predictive metrics for CNS drug candidates.[18]

The collective preclinical evidence, spanning in vitro potency, in vivo efficacy in cancer and inflammation models, and particularly the CNS activity, directly informed the strategic design of the first-in-human clinical trial program for bexobrutideg. The selection of diverse B-cell malignancies, including those with CNS involvement, for the initial clinical studies (NCT05131022) is a clear reflection of the strengths and unique attributes identified in these foundational preclinical investigations.[11]

Table 3: Overview of Key Preclinical Findings for Bexobrutideg (NX-5948)

Model Type	Specific Model/Cell Line	Key Findings	Significance	Source Snippet(s)
In Vitro	Primary human B cells	Potent BTK degradation (DC50 = 0.034 nM).	Confirms high potency in target human cells.	12
In Vitro	BTKi-resistant tumor cell lines	Effective against resistant lines.	Potential to overcome acquired resistance to current therapies.	4
In Vitro	Wild-type and mutant BTK (e.g., C481S)	Degrades both forms.	Broad activity irrespective of common resistance mutations.	10
In Vitro	Cellular assays	Catalytic efficiency: 1 molecule degrades ~10,000 BTK copies/hour.	Explains potency at low concentrations.	3
In Vivo	TMD8 DLBCL xenograft mouse model	Inhibits tumor growth, increases survival.	Demonstrates anti-cancer efficacy in vivo.	12
In Vivo	Mouse brain lymphoma models	Crosses BBB, degrades BTK intracranially, shows efficacy.	Strong rationale for treating CNS malignancies.	11
In Vivo	Mouse model of collagen-induced arthritis	Reduces inflammation and symptom severity.	Supports potential in autoimmune/inflammatory diseases.	12
In Vivo	Rodent models (PK studies)	Dose-dependent brain exposure; Kp,uu consistent with CNS penetration.	Confirms BBB permeability.	13
Ex Vivo	Immune cells (preclinical inflammation models)	Deep suppression of BCR, TLR, and FcR signaling.	Broad immunomodulatory effects beyond B-cells.	14

5. Clinical Development Program: NCT05131022 and Other Studies

The clinical development of bexobrutideg is centered around the ongoing Phase 1a/1b trial, NCT05131022, which is systematically evaluating its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy across a range of B-cell malignancies.

Overview of the Phase 1a/1b Clinical Trial (NCT05131022):

The full title of this first-in-human study is "A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies".19 It is registered under ClinicalTrials.gov identifier NCT05131022 and EudraCT number 2021-003125-29.1

The study employs an open-label design and is structured in two main parts:

• Phase 1a (Dose Escalation): This part aimed to evaluate the safety and tolerability of bexobrutideg across increasing dose levels in patients with various relapsed/refractory B-cell malignancies. It followed a standard 3+3 dose-escalation design to identify dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD), and/or select the recommended Phase 2 dose(s) (RP2D) for further investigation.[11]
• Phase 1b (Cohort Expansion): Following the determination of suitable dose(s) from Phase 1a, this part involves enrolling distinct cohorts of patients with specific B-cell malignancies. The objectives are to further characterize the longer-term safety profile and to obtain more robust preliminary data on the anti-tumor activity of bexobrutideg in these defined populations.[1]

The trial is actively enrolling patients in the United States, the United Kingdom, and the Netherlands.[4] As of early 2025, the Phase 1a dose-escalation cohort for Chronic Lymphocytic Leukemia (CLL) was reported as fully enrolled.[10] Phase 1b dose expansion cohorts, including those for CLL (at 200 mg and 600 mg daily doses) and Waldenström Macroglobulinemia (WM), are ongoing.[1]

Patient Populations and Studied Indications in NCT05131022:

The trial enrolls adult patients with relapsed or refractory B-cell malignancies who have received at least two prior lines of therapy and have measurable disease according to indication-specific criteria.11 Patients are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.11

Specific indications being studied include:

• Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL): This population is heavily pre-treated, with many patients having received prior BTK inhibitors (both covalent and non-covalent) and BCL2 inhibitors. A significant proportion are considered "double refractory," representing a population with very limited effective treatment options.[2]
• Waldenström Macroglobulinemia (WM): Patients with relapsed or refractory WM are included.[1]
• Other B-cell Non-Hodgkin Lymphomas (NHL): The protocol allows for enrollment of patients with non-Germinal Center B-cell (non-GCB) Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and Marginal Zone Lymphoma (MZL).[11]
• Primary/Secondary Central Nervous System (CNS) Lymphoma: Leveraging bexobrutideg's brain penetrance, patients with CNS lymphoma are specifically included.[11]

Key exclusion criteria for the study include prior treatment with any BTK degrader, recent (within specified timeframes) radiotherapy, systemic chemotherapy, monoclonal antibody therapy, or other small molecule therapies. Limits are also placed on recent stem cell transplantation, CAR-T cell therapy, and use of systemic corticosteroids or other immunosuppressive drugs. Patients with active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia, or active graft-versus-host disease (GVHD) are also excluded.[11]

Expansion into Autoimmune Indications:

Nurix Therapeutics has outlined plans to extend the clinical investigation of bexobrutideg into autoimmune and inflammatory diseases. This includes initiating clinical testing in autoimmune cytopenias, such as warm autoimmune hemolytic anemia (wAIHA), anticipated in 2025. This will initially be explored by adding a cohort for CLL patients with secondary autoimmune hemolytic anemia to the ongoing NCT05131022 trial.2 Furthermore, the company is considering filing a separate Investigational New Drug (IND) application for non-malignant hematology indications, specifically autoimmune cytopenias, in 2025.7 This strategic expansion into autoimmunity is a logical step, given the drug's mechanism and preclinical data, and the study in CLL patients with secondary AIHA offers an efficient way to obtain early human proof-of-concept within an existing trial framework.

Dosing Regimens Explored in NCT05131022:

Bexobrutideg is administered orally, once daily.4 In the Phase 1a dose-escalation portion for CLL/SLL, daily doses explored were 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, and 600 mg.2 The Phase 1b dose expansion cohorts for CLL are proceeding with 200 mg and 600 mg daily doses.10 Similar dose ranges, up to 600 mg daily, have been tested in patients with WM.2

Clinical Efficacy (from NCT05131022):

Emerging data from the NCT05131022 trial have been presented at major hematology conferences, demonstrating promising anti-tumor activity.

• Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL):
• Data presented at the American Society of Hematology (ASH) Annual Meeting in 2024 (cutoff October 17, 2023, for an earlier dataset, and later updates for the 49-patient cohort) indicated an Overall Response Rate (ORR) of 75.5% among 49 efficacy-evaluable relapsed/refractory (r/r) CLL/SLL patients across all tested dose levels (50 mg to 600 mg). The majority of these responses were observed at the first disease assessment, typically at Week 8.[2]
• More mature data from the fully enrolled Phase 1a CLL/SLL cohort (n=48 patients) were detailed in an abstract for the European Hematology Association (EHA) 2025 Congress (presenting author: Zulfa Omer; data cutoff: January 2, 2025).[10]
• Patients in this cohort had a median of 4 prior lines of therapy (range 2-12). Prior treatments included covalent BTK inhibitors (97.9%), non-covalent BTK inhibitors (27.1%), BCL2 inhibitors (83.3%), and combined BTKi+BCL2i (81.3%).
• Among 47 response-evaluable patients, the ORR was 80.9%, with all responses being Partial Responses (PRs).
• Responses were noted to be rapid, with a median time to first response of 1.9 months (range 1.6-11.1 months).
• The responses appeared durable, with the median Duration of Response (DoR) not yet reached. Thirteen patients had been on study for over 12 months, and five patients for over 18 months.
• Importantly, efficacy was observed irrespective of prior treatment history, the presence of high-risk genetic mutations (in TP53, PLCG2, BCL2, and BTK – including both kinase active and kinase dead mutations), or CNS involvement. The high ORR and durability in such a heavily pre-treated and often double-refractory CLL population, where therapeutic options are scarce and prognoses poor, are clinically very significant and suggest that bexobrutideg's mechanism is effectively overcoming multiple layers of resistance.
• Waldenström Macroglobulinemia (WM):
• Data presented at the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) in October 2024 and at ASH 2024 showed an ORR of 77.8% in nine efficacy-evaluable patients with r/r WM. Responses showed increasing depth over time, with a steady decrease in serum IgM levels observed from week 8 of treatment. One patient achieved a greater than 90% reduction in IgM levels.[2]
• Further updates on the clinical activity and safety in WM are anticipated at the EHA 2025 Congress (presentations by Dima El-Sharkawi / David Lewis).[6]
• CNS Clinical Activity:
• Consistent with its preclinical profile, bexobrutideg has been shown to be detectable in the cerebrospinal fluid (CSF) of patients with CNS-involved B-cell malignancies.[13]
• Clinically meaningful responses have been reported in patients with primary CNS lymphoma or CLL with CNS involvement.[13] One notable case described a patient with CLL and CNS involvement who demonstrated a deepening response over time, approaching criteria for a complete response.[13] The demonstration of clinical responses in CNS lymphoma and CLL with CNS involvement represents a potentially significant advancement, as the CNS is a sanctuary site where many existing therapies have limited efficacy.

Safety and Tolerability Profile (from NCT05131022):

Across the various patient populations and dose levels tested (50 mg to 600 mg daily), bexobrutideg has been generally well-tolerated.2

• CLL Cohort (EHA 2025 Abstract; n=48) [10]:
• No Dose-Limiting Toxicities (DLTs) were observed during the Phase 1a dose-escalation portion.
• Only one patient discontinued treatment due to a Treatment-Emergent Adverse Event (TEAE).
• The most frequently reported TEAEs (any grade) included: purpura/contusion (41.7%, no Grade ≥3 events), fatigue (31.3%, no Grade ≥3 events), neutropenia (29.2% overall; 22.9% Grade ≥3), rash (29.2% overall; 2.1% Grade ≥3, 2.1% reported as a Serious Adverse Event - SAE), diarrhea (29.2% overall; 4.2% Grade ≥3), and petechiae (25.0%, no Grade ≥3 events).
• One Grade 5 event (pulmonary embolism) occurred in a patient with a pre-existing history of atrial fibrillation; this event was considered unrelated to bexobrutideg by the investigators.[10]
• WM Cohort [22]: The safety profile in patients with WM was reported to be consistent with that observed in the overall study population. The most common adverse events included purpura/contusion, neutropenia, and thrombocytopenia, which were mostly low-grade.

A key aspect of the safety profile, noted in earlier updates, was the apparent absence of atrial fibrillation or significant hypertension, which are known class-effects for some other BTK inhibitors.[4] The lack of DLTs in the CLL Phase 1a and the manageable nature of common TEAEs are crucial. If this favorable safety profile, particularly concerning cardiovascular events, is maintained in larger, longer-term studies, it could significantly broaden bexobrutideg's applicability, especially in elderly CLL patients with comorbidities.

Table 4: Clinical Trial NCT05131022 - Key Design Features

Feature	Details	Source Snippet(s)
Full Title	A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies	19
ClinicalTrials.gov ID	NCT05131022	1
EudraCT ID	2021-003125-29	19
Phase	Phase 1a (Dose Escalation) / Phase 1b (Cohort Expansion)	11
Design	Open-label, first-in-human, 3+3 dose escalation (Phase 1a) followed by cohort expansions (Phase 1b)	11
Key Objectives (Phase 1a)	Evaluate safety and tolerability, identify DLTs, determine MTD and/or RP2D.	11 (inferred)
Key Objectives (Phase 1b)	Further evaluate longer-term safety, preliminary anti-tumor activity (ORR, DoR), PK, PD.	1 (inferred)
Main Patient Populations	Adults with r/r B-cell malignancies: CLL/SLL, WM, non-GCB DLBCL, FL, MCL, MZL, Primary/Secondary CNS Lymphoma.	11
Investigated Dose Ranges	Oral, once daily. Phase 1a (CLL): 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg. Phase 1b (CLL): 200 mg and 600 mg.	2
Key General Inclusion Criteria	Adults, ≥2 prior lines of therapy, measurable disease, ECOG PS 0-2.	11
Key General Exclusion Criteria	Prior BTK degrader, recent specified anti-cancer therapies, certain corticosteroid use, active uncontrolled autoimmune cytopenias, active GVHD.	11

Table 5: Summary of Clinical Efficacy of Bexobrutideg (NX-5948) in Relapsed/Refractory CLL/SLL (NCT05131022 - Phase 1a)

Efficacy Endpoint	Result (Data Cutoff: Jan 2, 2025)	Patient Details (n=47 evaluable)	Notes	Source
Overall Response Rate (ORR)	80.9%	Median 4 prior lines (range 2-12); 97.9% prior cBTKi, 83.3% prior BCL2i, 81.3% prior BTKi+BCL2i.	All responses were Partial Responses (PRs).	10
Median Time to First Response	1.9 months	(Range 1.6-11.1 months)	Responses were rapid.	10
Median Duration of Response (DoR)	Not Reached	13 patients >12 months on study; 5 patients >18 months on study.	Responses appear durable.	10
Activity vs. High-Risk Features	Efficacy observed regardless of prior treatments, mutations in TP53, PLCG2, BCL2, BTK (kinase active/dead), or CNS involvement.		Broad activity in difficult-to-treat subgroups.	10

Table 6: Summary of Clinical Efficacy of Bexobrutideg (NX-5948) in Relapsed/Refractory Waldenström Macroglobulinemia (NCT05131022)

Efficacy Endpoint	Result (Data from IWWM-12/ASH 2024)	Patient Details (n=9 evaluable)	Notes	Source
Overall Response Rate (ORR)	77.8%	Relapsed/refractory WM patients.		2
IgM Level Reduction	Steady decrease from week 8; 1 patient >90% reduction.		Increasing depth of response over time.	22

Table 7: Summary of Common Treatment-Emergent Adverse Events (TEAEs) with Bexobrutideg (NX-5948) in CLL Patients (NCT05131022 - Phase 1a, n=48)

Adverse Event	Any Grade (%)	Grade ≥3 (%)	SAEs (%)	Notes	Source
Purpura/Contusion	41.7%	0%	0%	No DLTs. 1 patient discontinued due to a TEAE (not specified). One Grade 5 pulmonary embolism (unrelated).	10
Fatigue	31.3%	0%	0%		10
Neutropenia	29.2%	22.9%	Not specified		10
Rash	29.2%	2.1%	2.1%		10
Diarrhea	29.2%	4.2%	Not specified		10
Petechiae	25.0%	0%	0%		10

6. Regulatory Status and Milestones

Bexobrutideg has achieved several important regulatory milestones that underscore its potential clinical significance and aim to facilitate its development and review process. These designations from key health authorities highlight the recognized unmet medical need in the targeted patient populations.

Nonproprietary Name Assignment:

In March 2025, the investigational compound NX-5948 was assigned the nonproprietary name bexobrutideg by the United States Adopted Name (USAN) Council.1 A particularly notable aspect of this assignment was the designation of the new suffix "-deg". This suffix was specifically created to identify bexobrutideg and future similar agents as belonging to the novel pharmacological class of targeted protein degraders, thereby formally acknowledging their distinct mechanism of action compared to traditional inhibitors or other therapeutic modalities.1 This action by a national naming authority is a significant step in establishing targeted protein degradation as a recognized and distinct therapeutic strategy, which can aid in clear communication among healthcare professionals and standardize the field.

U.S. Food and Drug Administration (FDA) Designations:

Bexobrutideg has received multiple special designations from the U.S. FDA:

• Orphan Drug Designation (ODD): In March 2025, the FDA granted ODD to bexobrutideg for the treatment of Waldenström Macroglobulinemia (WM).[1] WM is a rare, indolent type of non-Hodgkin lymphoma. ODD is granted to drugs intended for rare diseases or conditions affecting fewer than 200,000 people in the U.S. This designation provides several incentives to the sponsor, including potential tax credits for qualified clinical testing, waiver or partial payment of FDA application fees, and, if the drug is eventually approved for the designated indication, seven years of market exclusivity for that indication.[1] The granting of ODD for WM acknowledges the significant unmet medical need for improved treatments for this patient population.
• Fast Track Designation: Bexobrutideg has received two separate Fast Track designations from the FDA:

1. For the treatment of adult patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.[2]
2. For the treatment of Waldenström Macroglobulinemia (WM).[2] Fast Track designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. Benefits include more frequent meetings with the FDA to discuss the drug's development plan, eligibility for Accelerated Approval and Priority Review if relevant criteria are met, and the possibility of a rolling review of the New Drug Application (NDA).[4]

European Medicines Agency (EMA) Designations:

• PRIME (PRIority MEdicines) Designation: The EMA granted PRIME designation to bexobrutideg for the treatment of patients with relapsed or refractory CLL/SLL who have been previously treated with at least a BTK inhibitor and a BCL2 inhibitor.[2] The PRIME scheme is designed to provide early and enhanced scientific and regulatory support to medicines that have the potential to address significant unmet medical needs. This enhanced interaction aims to optimize development plans and facilitate the generation of robust data for accelerated assessment, potentially leading to earlier patient access.

The combination of these regulatory designations (Orphan Drug, multiple Fast Tracks, and PRIME) from both U.S. and European authorities provides strong validation for bexobrutideg's development program. It signals a recognition by regulatory bodies of the drug's promising early clinical data and its potential to offer a significant therapeutic advancement for patients with serious, life-threatening conditions where current treatment options are limited or insufficient. Nurix's regulatory strategy appears well-aligned with targeting these areas of high unmet need, thereby maximizing the potential impact of bexobrutideg and leveraging pathways designed to expedite the availability of promising new medicines.

Table 8: Timeline of Key Regulatory Designations for Bexobrutideg (NX-5948)

Date (Approx.)	Regulatory Body/Authority	Designation/Milestone	Indication(s)	Key Implications	Source Snippet(s)
2024	U.S. FDA	Fast Track Designation	Relapsed/Refractory CLL/SLL (adults, after ≥2 lines including BTKi & BCL2i)	Facilitated development, potential for Accelerated Approval/Priority Review.	2
2024	U.S. FDA	Fast Track Designation	Waldenström Macroglobulinemia (WM)	Facilitated development, potential for Accelerated Approval/Priority Review.	2
2024	European Medicines Agency (EMA)	PRIME Designation	Relapsed/Refractory CLL/SLL (after BTKi & BCL2i)	Enhanced regulatory support, potential for accelerated assessment.	2
March 2025	United States Adopted Name (USAN) Council	Nonproprietary name "bexobrutideg" assigned; new "-deg" suffix created	N/A (General Classification)	Formal recognition as a new class of targeted protein degraders.	1
March 2025	U.S. FDA	Orphan Drug Designation (ODD)	Waldenström Macroglobulinemia (WM)	Market exclusivity (if approved), fee waivers, tax credits. Addresses unmet need in a rare disease.	1

7. Key Scientific Presentations and Publications

The evolving scientific understanding and clinical data for bexobrutideg (NX-5948) have been consistently disseminated through presentations at major international scientific conferences and are beginning to be reflected in the broader scientific literature. These communications trace the journey of bexobrutideg from a preclinical concept to a promising clinical-stage therapeutic.

American Society of Hematology (ASH) Annual Meetings:

• ASH 2021: Initial preclinical findings were presented by Robbins et al., highlighting that NX-5948 could cross the blood-brain barrier and effectively degrade BTK within the CNS, leading to efficacy in mouse models of brain lymphoma.[11] This early work established the CNS-penetrant potential of the molecule.
• ASH 2023: Positive clinical data from the dose-escalation phase (Phase 1a) of the NCT05131022 trial in patients with relapsed/refractory (r/r) B-cell malignancies were shared. Notably, in the CLL population (doses 50-200 mg), six out of seven patients demonstrated clinical benefit, including three partial responses (PRs). The drug was reported as well-tolerated with no dose-limiting toxicities (DLTs) or treatment-related serious adverse events (SAEs) at these early dose levels.[4]
• ASH 2024: More extensive data from the r/r CLL/SLL cohort (49 efficacy-evaluable patients across all dose levels from 50 mg to 600 mg) were presented, showing a robust objective response rate (ORR) of 75.5%. Bexobrutideg continued to be well-tolerated across the tested dose range.[2]

European Hematology Association (EHA) Congress:

• EHA 2024: Clinical data supporting clinically meaningful responses in patients with primary CNS lymphoma or CLL with CNS involvement were presented by K. Linton, further substantiating the therapeutic potential of bexobrutideg in CNS malignancies.[13]
• EHA 2025 (Planned Presentations):
• An abstract by Zulfa Omer (for poster/oral presentation) detailed updated findings from the fully enrolled Phase 1a CLL/SLL cohort (n=48) of NCT05131022. Key results included an ORR of 80.9% (all PRs) in 47 evaluable patients, a median time to first response of 1.9 months, and a median duration of response not yet reached. Responses were observed irrespective of prior treatments or high-risk mutational status. The safety profile remained favorable with no DLTs.[6]
• Presentations by Dima El-Sharkawi and David Lewis were anticipated to provide updated clinical activity and safety data for bexobrutideg in patients with Waldenström Macroglobulinemia.[6]

American Association for Cancer Research (AACR) Annual Meeting:

• AACR 2024: The first clinical evidence demonstrating bexobrutideg's brain penetration and clinical activity within the CNS was presented.[2]
• AACR 2025: A poster presentation titled "NX-5948 is a CNS-penetrant catalytic Bruton's tyrosine kinase (BTK) degrader that breaks established design rules for CNS drugs" detailed the unique physicochemical properties of bexobrutideg that enable its CNS exposure despite not conforming to traditional CNS drug design metrics. Data confirmed its detection in patient CSF and its clinical efficacy in CNS lymphoma/CLL. The catalytic efficiency (one molecule degrading ~10,000 BTK copies/hour) was also highlighted.[3]

International Workshop on Waldenström's Macroglobulinemia (IWWM):

• IWWM-12 (October 2024): Data presented showed an ORR of 77.8% in nine efficacy-evaluable patients with WM, with responses deepening over time. The safety profile was consistent with the broader study population.[20]

American College of Rheumatology (ACR) Convergence:

• ACR Convergence 2024 (November 2024): A poster presentation titled "NX-5948, A Clinical-Stage BTK Degrader, Achieves Deep Suppression Of BCR,...source Of Arthritis And Other Inflammatory Diseases" provided key preclinical evidence supporting the rationale for expanding bexobrutideg's development into inflammatory and autoimmune diseases.[14] This marked an important public step in validating bexobrutideg for non-oncology indications.

TPD & Induced Proximity Summit:

• 7th Annual TPD & Induced Proximity Summit (October 2024): P. O'Connor delivered a presentation on the "Clinical Activity of NX-5948: A First-in-Class BTK Degrader," likely summarizing the clinical progress, including its CNS activity.[13]

Journal Publications:

While full peer-reviewed publications of the NCT05131022 clinical trial results are typically anticipated as cohorts mature and the trial progresses, the foundational science and trials-in-progress have been referenced in reviews and earlier preclinical disclosures. For example, a 2025 review in Cancers by Wang et al. discusses BTK protein degraders as an exciting drug class for CLL, highlighting the unmet need.9 Earlier preclinical work by Noviski et al. and Robbins et al. 11 laid the groundwork for the current clinical studies.

The consistent presentation of evolving data at these high-profile scientific meetings demonstrates a strategic approach by Nurix Therapeutics to build a comprehensive and cohesive scientific narrative around bexobrutideg. The focus on its differentiated efficacy in resistant populations, unique CNS activity, and the catalytic nature of its mechanism of action has been a common thread, educating the scientific community on its potential advantages.

8. Future Development and Potential Implications

Bexobrutideg (NX-5948) is poised for significant advancements in its clinical development program, with plans to move into later-stage trials for its lead indications and expand into new therapeutic areas. Its unique profile suggests considerable potential to address unmet medical needs in hematologic malignancies and inflammatory diseases.

Pivotal Clinical Trials:

Nurix Therapeutics has announced plans to initiate a suite of pivotal clinical trials for bexobrutideg in 2025. These trials are intended to support global registration for the treatment of patients with Chronic Lymphocytic Leukemia (CLL).2 For Waldenström Macroglobulinemia (WM), the company expects to complete the ongoing Phase 1b clinical trial cohort, determine the appropriate Phase 2 dose(s), and continue to explore optimal regulatory pathways for this indication.2

Further Exploration in Other B-cell Malignancies:

Evaluation of bexobrutideg in other B-cell malignancies included in the NCT05131022 study—such as non-GCB Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and particularly Primary/Secondary Central Nervous System (CNS) Lymphoma—is expected to continue. Further clinical updates for these populations are anticipated in 2025.7

Expansion into Inflammatory and Autoimmune Diseases:

A key area for future development is the expansion of bexobrutideg into inflammatory and autoimmune diseases, leveraging its potent BTK degradation and broad immunomodulatory effects. Nurix plans a sequenced, multi-organ system approach for this expansion.2 A new Phase 1b cohort within the NCT05131022 trial is expected to open for patients with CLL who also have associated autoimmune hemolytic anemia (AIHA).2 Additionally, the company is exploring the filing of a new Investigational New Drug (IND) application in 2025 specifically for non-malignant hematology indications, such as autoimmune cytopenias (e.g., warm autoimmune hemolytic anemia - wAIHA).2 The strong preclinical data showing efficacy in arthritis models and suppression of key immune signaling pathways (BCR, TLR, FcR) provide a solid rationale for this strategic diversification.12

Potential Advantages Over Existing BTK Inhibitors:

Bexobrutideg's distinct mechanism and properties offer several potential advantages over currently available BTK inhibitors:

• Overcoming Resistance: Its ability to degrade the entire BTK protein, including both wild-type and mutant forms (such as those with the C481S mutation), provides a mechanism to overcome resistance that arises from mutations affecting inhibitor binding sites or from kinase-independent scaffolding functions of BTK.[4] This is particularly relevant for patients who have failed prior BTKi therapies.
• CNS Activity: The demonstrated brain penetration and clinical activity in patients with CNS-involved B-cell malignancies address a critical unmet need, as many existing BTKis have limited CNS efficacy.[13]
• Differentiated Safety Profile: Early clinical data suggest a generally well-tolerated profile. Notably, there has been an absence of signals for certain cardiovascular toxicities, such as atrial fibrillation and significant hypertension, which are concerns with some covalent BTK inhibitors.[4] Confirmation of this favorable cardiovascular safety in larger trials would be a significant differentiator, especially for older patients or those with cardiac comorbidities.
• Catalytic Mechanism: The "event-driven pharmacology" allows for potent target degradation at potentially lower systemic drug exposures compared to stoichiometric inhibitors. This could contribute to an improved therapeutic window, enhancing safety while maintaining or improving efficacy, and enabling sustained pharmacodynamic effects.[3]

Unmet Needs Addressed by Bexobrutideg:

The development of bexobrutideg is targeted at several patient populations with significant unmet medical needs:

• Patients with relapsed/refractory CLL/SLL, especially those who are "double refractory" to both BTK inhibitors and BCL2 inhibitors, who currently have very limited effective treatment options.[4]
• Patients with relapsed/refractory WM, particularly after failure of existing BTK inhibitors, where subsequent therapeutic options are needed.[1]
• Patients with B-cell malignancies involving the CNS, a sanctuary site where effective, well-tolerated oral therapies are lacking.[13]
• Potentially, patients with certain autoimmune and inflammatory diseases who could benefit from potent and sustained modulation of B-cell and myeloid cell pathways mediated by BTK.[2]

If the promising early clinical signals are borne out in pivotal trials, bexobrutideg has the potential to reshape treatment paradigms. For instance, in heavily pretreated r/r CLL or in cases of CNS lymphoma, an effective and well-tolerated oral degrader could become a new standard of care, potentially altering treatment sequencing and reducing reliance on more toxic or complex therapies. The success of bexobrutideg would also serve as a significant validation for Nurix Therapeutics' DELigase™ and DEL-AI drug discovery platforms, bolstering confidence in their ability to generate further novel protein degraders for various diseases. While current data focuses on monotherapy, the unique mechanism and potentially favorable safety profile of bexobrutideg could also position it as an attractive candidate for future combination therapies with other anti-cancer agents to achieve even deeper and more durable remissions.

9. Conclusion

Bexobrutideg (NX-5948) has emerged as a highly promising, orally bioavailable, brain-penetrant Bruton's Tyrosine Kinase (BTK) degrader with a distinct catalytic mechanism of action. Developed by Nurix Therapeutics, this investigational agent represents a significant advancement in the field of targeted protein degradation. Its ability to induce the complete elimination of both wild-type and mutant BTK protein offers a compelling strategy to overcome known resistance mechanisms that limit the efficacy of traditional BTK inhibitors, including those related to kinase domain mutations and scaffolding functions of the BTK protein.

Preclinical studies have robustly demonstrated its potent BTK degradation, efficacy in various B-cell malignancy models (including those with CNS involvement), and promising activity in models of inflammatory disease. These findings have been translated into a comprehensive clinical development program, primarily centered around the Phase 1a/1b trial (NCT05131022). Early clinical data from this trial have been encouraging, showing substantial objective response rates and durable responses in heavily pre-treated patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Waldenström Macroglobulinemia (WM). Notably, responses in CLL have been observed irrespective of prior therapies or high-risk genetic features.

A key differentiating characteristic of bexobrutideg is its demonstrated CNS penetration and clinical activity in patients with CNS-involved B-cell malignancies, addressing a critical unmet medical need. Furthermore, the safety profile observed to date appears manageable and potentially differentiated from some existing BTK inhibitors, particularly concerning cardiovascular adverse events, although this requires confirmation in larger and longer-term studies.

The achievement of multiple favorable regulatory designations from the FDA (Orphan Drug Designation, Fast Track) and EMA (PRIME) underscores the potential of bexobrutideg to provide a significant therapeutic benefit in indications with limited treatment options. The assignment of the "-deg" suffix by the USAN Council formally recognizes its novel mode of action and establishes targeted protein degraders as a distinct pharmacological class.

Looking ahead, pivotal trials for CLL are planned for 2025, and development in WM and other B-cell malignancies continues. The planned expansion into autoimmune and inflammatory diseases, supported by strong preclinical rationale, could further broaden its therapeutic utility. If the efficacy and safety demonstrated in early trials are confirmed in these later-stage studies, bexobrutideg has the potential to become a cornerstone therapy for a range of B-cell cancers, particularly in resistant or CNS-involved settings, and may offer a novel therapeutic option for certain inflammatory conditions. Its progress represents not only a significant step for this specific molecule but also a validation of the broader potential of targeted protein degradation as a transformative therapeutic strategy.

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