First Trial of BTK Inhibition in Anti-MAG Polyneuropathy Reports Baseline Data at PNS 2026

Baseline characteristics from the phase 2 MAGNAZ trial evaluating the combination of zanubrutinib (Brukinsa; BeiGene) and rituximab in IgM monoclonal gammopathy of undetermined significance (MGUS)-associated anti-myelin-associated glycoprotein polyneuropathy (anti-MAG PNP) were featured among the abstracts at the 2026 Peripheral Nerve Society (PNS) Annual Meeting in Maastricht, Netherlands.¹

The investigator-initiated trial, conducted across two Dutch academic centers, represents the first prospective study to formally evaluate BTK inhibition added to standard rituximab therapy in this rare and often disabling neuropathy.

Background and Rationale

Anti-MAG PNP is a chronic, progressive demyelinating neuropathy caused by pathogenic IgM antibodies targeting the myelin-associated glycoprotein. It presents predominantly with sensory dysfunction, ataxia, tremor, and distal limb weakness, and is driven by an IgM M-protein produced by a MGUS B-cell clone.

Rituximab, a CD20-targeting monoclonal antibody, has been the standard treatment for more than two decades, but response rates in controlled trials have been modest. The pivotal RIMAG trial, the largest placebo-controlled study to date, found that only 20% of rituximab-treated patients achieved a 2-point improvement on the INCAT disability scale versus 0% on placebo (P = .027), and open-label cohort data suggest clinical response rates of approximately 30 to 50%.^2,3

Zanubrutinib is a next-generation, highly selective Bruton's tyrosine kinase (BTK) inhibitor approved for B-cell malignancies including Waldenstrom macroglobulinemia, a condition that shares the same IgM-secreting B-cell clone biology as anti-MAG PNP. BTK inhibition suppresses B-cell receptor signaling and IgM production upstream of CD20, providing a mechanistically complementary approach to rituximab. The rationale for combining both agents is to achieve more complete and durable suppression of the pathogenic IgM clone than either drug alone.¹

Study Design

MAGNAZ (NCT05939037) is a multicenter, single-arm, open-label phase 2 trial with a 3-year follow-up.¹ All patients received rituximab 375 mg/m² given 4 times weekly in combination with continuous zanubrutinib 320 mg daily. Hematological response was evaluated at 6 months; patients achieving at least a partial response continued for an additional 6 months. Those achieving at least a very good partial response continued on treatment, while non-responders were followed for clinical outcomes only.

Led by Monique Minnema, MC, a professor at UMC Utrecht, in The Netherlands, the neurological primary endpoint was the proportion of patients with at least a 2-point improvement on the INCATds after 12 months. Secondary endpoints included I-RODS, IgM-RODS, distal MRC sum score, and ataxia MICARS score.

Enrolled Population

Between March 2024 and December 2025, 49 patients were screened and 32 (72% men) were enrolled. Mean age was 66 years (SD 8.1). Twenty-one patients (66%) had an anti-MAG titer above 70,000 BTU. Neurological symptoms at study entry were mostly symmetrical (78.1%) and predominantly sensorimotor (87.5%); 4 patients (12.5%) had purely sensory involvement.

Median INCATds at baseline was 4 (IQR 3 to 4), median I-RODS was c60 (IQR c52 to c65), and median IgM-RODS was 55.5 (IQR 46 to 64.5). Median distal MRC sum score was 60.5 (IQR 49.3 to 64.3) and mean ataxia MICARS score was 27.4 (SD 13.2).¹ The investigators noted that further baseline characteristics and initial efficacy results will be presented at the conference.

Clinical Context

The interest in BTK inhibition for anti-MAG PNP draws from experience in Waldenstrom macroglobulinemia, where BTK inhibitors including ibrutinib and zanubrutinib have shown substantial activity against IgM-secreting clones. A peripheral neuropathy substudy of the phase 3 ASPEN trial, which evaluated zanubrutinib versus ibrutinib in Waldenstrom macroglobulinemia, reported resolution of peripheral neuropathy symptoms in 71.4% of patients at a median of 10.1 months, suggesting meaningful neurological benefit from BTK inhibition in IgM-driven neuropathy.⁴ The MAGNAZ trial extends this rationale to the MGUS-associated anti-MAG PNP population, where no approved therapy currently exists.

Limitations and Disclosures

As a single-arm trial without a comparator group, MAGNAZ will not be able to directly isolate the contribution of zanubrutinib from that of rituximab. The trial is partially funded by BeiGene Switzerland GmbH, the manufacturer of zanubrutinib, alongside academic and charitable sources. Full efficacy results are anticipated following 12-month follow-up of enrolled patients.

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REFERENCES
1. MAGNAZ trial investigators. Multicenter, phase II study in patients with anti-MAG polyneuropathy and zanubrutinib treatment: MAGNAZ trial. Abstract submitted to: Peripheral Nerve Society Annual Meeting; June 13-16, 2026; Maastricht, Netherlands. Abstract P 361.
2. Leger JM, Viala K, Nicolas G, et al. Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. Neurology. 2013;80(24):2217-2225. doi:10.1212/WNL.0b013e318296e92b. https://doi.org/10.1212/WNL.0b013e318296e92b
3. Parisi M, Dogliotti I, Clerico M, et al. Efficacy of rituximab in anti-myelin-associated glycoprotein demyelinating polyneuropathy: clinical, hematological and neurophysiological correlations during 2 years of follow-up. J Peripher Nerv Syst. 2022;27(4):293-302. doi:10.1111/jns.12514. https://doi.org/10.1111/jns.12514
4. Castillo JJ, Branagan AR, Sarosiek S, et al. Peripheral neuropathy in the phase 3 ASPEN study of Bruton tyrosine kinase inhibitors for Waldenstrom macroglobulinemia. Blood Adv. 2022;6(3):769-778. doi:10.1182/bloodadvances.2021005788. https://doi.org/10.1182/bloodadvances.2021005788