ZANUBRUTINIB, A SECOND GENERATION BTK INHIBITOR, IN ANTI-MAG ANTIBODY NEUROPATHY: A PHASE II ITALIAN MULTICENTER CLINICAL TRIAL (MAZINGA)

The primary objective is to investigate whether 12 months of zanubrutinib treatment leads to an improvement of at least 1 point in at least 2 neurological scales, including Overall Neuropathy Limitations Scale (ONLS), INCAT disability, INCAT sensory sum scores (ISS), MRC sum score, and I-RODS functional score. This objective addresses the clinical need to assess neurological improvement in patients with anti-MAG antibody polyneuropathy, a condition characterized by progressive sensory and motor deficits associated with underlying lymphoproliferative disorders such as Waldenstrom macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia, or monoclonal gammopathy of unknown significance.

The secondary objectives include: • To evaluate electroneurography/electromyography (ENG/EMG) improvement, specifically reduction of distal motor latency, increase of terminal latency index, or increase of sensory nerve action potential amplitude after zanubrutinib treatment at 12, 24, and 48 months; • To evaluate efficacy by hematological overall response rates, event-free survival, time to progression (defined as worsening of at least 1 point in two neurological scales), and overall survival; • To study the safety profile of zanubrutinib in patients with anti-MAG antibody polyneuropathy.

Exploratory objectives aim to evaluate quality of life using the FACT-GOG-NTX-13 questionnaire, identify correlations between neurologic response and hematologic overall response (complete response, very good partial response, partial response) at 24 and 48 months with demographic, clinical, and molecular features, evaluate reduction of MYD88 mutational burden by cell-free DNA (cf-DNA) during treatment, and assess emergence of BTK and PLCG2 mutational status in relapsing patients.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **adult** and **elderly** participants aged **18 years and older** of **both male and female genders**. Participants are individuals diagnosed with **peripheral anti-MAG neuropathy** associated with underlying hematologic conditions including **Waldenström macroglobulinemia**, **marginal zone lymphoma**, **chronic lymphocytic leukemia**, or **monoclonal gammopathy of unknown significance**. The trial population was selected based on confirmed presence of **anti-MAG antibodies** with a titer of at least 7,000 BTU and the presence of **IgM monoclonal protein**. Participants with Waldenström macroglobulinemia were required to have clonal lympho-plasmocytes of 10% or greater according to WHO criteria. No vulnerable populations were included in this study. The sponsor did not provide specific information regarding lifestyle considerations such as diet, physical activity, or habits for the study participants.

This is a Phase II, multicenter clinical trial investigating zanubrutinib, a second-generation BTK inhibitor, in patients with anti-MAG antibody neuropathy. The study will evaluate the efficacy of zanubrutinib in improving neurological function in patients with peripheral anti-MAG neuropathy associated with underlying conditions including Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia, or monoclonal gammopathy of unknown significance. The investigational medicinal products include zanubrutinib capsules and BRUKINSA 80 mg hard capsules, both administered via the oral route. The maximum daily dose is 320 mg, with a maximum total dose of 480 mg. The active substance, zanubrutinib, is of chemical origin.

The main objective of this trial is to investigate whether 12 months of zanubrutinib treatment leads to an improvement of at least 1 point in at least 2 neurological scales, including the Overall Neuropathy Limitations Scale (ONLS), INCAT disability score, INCAT sensory sum scores (ISS), MRC sum score, and I-RODS functional score. The primary endpoint is defined as the proportion of patients with neurological improvement, characterized by an improvement of at least 1 point in at least 2 neurological scales at 12 months of zanubrutinib treatment. Secondary endpoints include the proportion of patients with neurological improvement after 24 and 48 months of treatment, the proportion of patients with electrophysiological improvement assessed by electroneurography and electromyography (ENG/EMG) parameters at 12, 24, and 48 months, and changes in levels of monoclonal protein, IgM, and anti-MAG antibody titers at these time points.

Principal inclusion criteria require participants to be aged 18 years or older with a diagnosis of anti-MAG antibody polyneuropathy and presence of anti-MAG antibodies with a titer of at least 7,000 BTU. Participants must have an IgM monoclonal protein underlying MGUS, Waldenström macroglobulinemia (defined by WHO criteria as clonal lympho-plasmocytes ≥10%), marginal zone lymphoma, chronic lymphocytic leukemia, or low-grade lymphoma not otherwise specified. The maximum treatment period for each participant is 48 months.

The estimated recruitment start date is December 29, 2025, with an estimated study completion date of March 31, 2031. Participant involvement extends up to 48 months, during which neurological assessments, electrophysiological evaluations, and laboratory measurements will be performed at baseline and at 12, 24, and 48 months. The study visits include a screening visit to confirm eligibility, baseline assessments, and follow-up visits at specified intervals throughout the treatment period to evaluate neurological improvement, electrophysiological parameters, and immunological markers. The end-of-study visit will occur at 48 months or upon early termination. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, disease progression, or investigator decision based on safety or efficacy concerns.

The experimental medication utilized in this clinical trial is **zanubrutinib**, a second-generation **BTK inhibitor** administered as the active treatment. Two formulations of zanubrutinib are employed in the study: zanubrutinib capsules (sponsor product code BGB-3111) and **BRUKINSA** 80 mg hard capsules, both containing zanubrutinib as the **active substance** of chemical origin. The pharmaceutical forms consist of capsules and hard capsules, respectively. The route of administration for both formulations is **oral**. The maximum daily dose is **320 mg**, with a maximum total dose of **480 mg**. The maximum treatment period extends to **48 months**. The dosing regimen and administration schedule are designed to evaluate the therapeutic efficacy of zanubrutinib in the treatment of **anti-MAG antibody neuropathy** over a 12-month treatment duration, with assessment of neurological improvement based on multiple validated scales including the **Overall Neuropathy Limitations Scale (ONLS)**, **INCAT disability score**, **INCAT sensory sum scores (ISS)**, **MRC sum score**, and **I-RODS functional score**.

Participant compliance monitoring throughout the treatment period will be essential to ensure adherence to the prescribed dosing schedule and to accurately assess treatment outcomes. The investigational medicinal products are manufactured and supplied by BEIGENE and BEONE MEDICINES IRELAND LIMITED, with BRUKINSA holding marketing authorization in the European Union (EU/1/21/1576/001). Both formulations are classified as non-paediatric formulations and are designated with the test product role in the trial protocol.

Efficacy will be assessed through multiple neurological scales and biomarker measurements. The primary endpoint is the proportion of patients demonstrating neurological improvement, defined as an improvement of at least 1 point in at least 2 neurological scales at 12 months of **zanubrutinib** treatment. The neurological scales utilized include the Overall Neuropathy Limitations Scale (ONLS), INCAT disability score, INCAT sensory sum scores (ISS), MRC sum score, and I-RODS functional score.

Secondary efficacy assessments will evaluate the proportion of patients with neurological improvement at 24 and 48 months of treatment. Additionally, electroneurography and electromyography (ENG/EMG) parameters will be measured to assess improvement from baseline, including decrease of distal motor latency, increase of terminal latency index, and increase of sensory nerve action potential amplitude at upper limbs. These ENG/EMG assessments will be conducted at 12, 24, and 48 months. Further secondary endpoints include the measurement of monoclonal protein levels, **IgM** levels, and anti-MAG antibody titers at 12, 24, and 48 months.