Zanubrutinib for anti‑MAG IgM‑associated demyelinating neuropathy

Zanubrutinib, a Second Generation BTK Inhibitor, in Anti-MAG Antibody Neuropathy: a Phase II Italian Multicenter Clinical Trial (MAZINGA)

This trial will try zanubrutinib, an oral BTK inhibitor, in adults with anti‑MAG IgM‑associated demyelinating neuropathy to see if 12 months of treatment improves nerve function and symptoms.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Azienda Ospedaliera di Padova (Academic / other)
• Drugs / interventions: zanubrutinib
• Locations: 1 site (Padova, PD)
• Trial ID: NCT07392229 on ClinicalTrials.gov

What this trial studies

The MAZINGA trial is a multicenter, open‑label, single‑arm Phase IIA study testing oral zanubrutinib given for 12 months in adults with IgM anti‑myelin‑associated glycoprotein (anti‑MAG) demyelinating polyneuropathy. The primary outcome is clinical neurological improvement, defined as at least a one‑point improvement in two or more validated scales such as the Overall Neuropathy Limitations Scale (ONLS), INCAT Disability Score, and INCAT Sensory Sum Score. Participants must have neurophysiological evidence of demyelination and an underlying IgM monoclonal gammopathy with anti‑MAG titers ≥7,000 BTU, and patients with prior BTK inhibitor use or significant axonal damage are excluded. Safety, tolerability, and secondary clinical and electrophysiological measures will be monitored throughout the treatment period.

Who should consider this trial

Good fit: Adults (≥18) with confirmed anti‑MAG IgM‑associated demyelinating polyneuropathy, neurophysiological evidence of demyelination, anti‑MAG titers ≥7,000 BTU, and an underlying IgM monoclonal gammopathy who have not previously received BTK inhibitors are ideal candidates.

Not a fit: Patients with prior BTK inhibitor exposure, aggressive non‑Hodgkin lymphoma or IgM multiple myeloma, or moderate-to-severe axonal nerve damage are unlikely to benefit from this treatment.

Why it matters

Potential benefit: If successful, zanubrutinib could reduce disability and sensory symptoms and offer a targeted oral treatment option for patients with anti‑MAG neuropathy associated with IgM monoclonal gammopathies.

How similar studies have performed: BTK inhibitors have shown promise in related IgM‑mediated disorders and small case series suggest potential benefit for anti‑MAG neuropathy, but randomized controlled evidence in this specific condition is still lacking.

Eligibility criteria

Inclusion Criteria (MAIN):

* age ≥18 years;
* diagnosis of anti-MAG antibody polyneuropathy;
* neurophysiological (ENG/EMG) evidence of a demyelinating polyneuropathy with evidence of disproportionately prolonged distal motor latency in one or more nerves -excluding the median nerve if related to carpal tunnel syndrome
* IgM monoclonal protein underlying MGUS (based on the WHO definition of clonal lympho- plasmocytes \<10%), Waldenstrom macroglobulinemia (based on the WHO definition of clonal lympho-plasmocytes ≥10%), marginal zone lymphoma, chronic lymphocytic leukemia or low- grade lymphoma not otherwise specified;
* presence of anti MAG antibodies (titer ≥ 7.000 BTU);
* neurophysiological (ENG/EMG) evidence of demyelinating polyneuropathy.

Exclusion Criteria (MAIN):

* Previous treatment with BTK inhibitors
* Aggressive non-Hodgkin lymphoma or IgM multiple myeloma
* Evidence of moderate or severe motor nerve axonal damage, defined when occurring diffuse polyneuropathic denervation or a recruitment pattern lower than intermediate in ≥50% of muscles examined, and/or INCAT at lower limbs ≥4.
* ECOG \>3
* Use of strong CYP3A inducers within 14 days prior to the first dose of zanubrutinib

Where this trial is running

Padova, PD

• UOC Ematologia, Azienda Ospedale Università Padova — Padova, Pd, Italy (Recruiting)

Study contacts

• Study coordinator: Andrea Visentin, Dr, Medical Doctor

Conditions Anti-MAG IgM-associated Demyelinating Polyneuropathy