Advances and Challenges in MMN Treatment: The Role of IVIG and Novel Therapies

Intravenous immunoglobulin (IVIG) remains a cornerstone in treating Multifocal Motor Neuropathy (MMN). However, its use has drawbacks and limitations. 'Most patients with MMN require long-term maintenance therapy with IVig to avoid clinical deterioration,' said Hans Katzberg (an Associate Professor of Neurology) at the University of Toronto in his speech at the 2024 Peripheral Nerve Society (PNS) annual meeting in Montreal, Canada. Despite continuous treatment, a significant proportion of MMN patients still experience disease progression and a gradual loss of muscle strength. Moreover, the dosage required to maintain clinical response often increases over time. Some studies have observed persistent conduction block even when clinical improvements are noted, indicating an incomplete resolution of the underlying pathology. While IVIG is generally well-tolerated, it can cause inconvenience to patients. Nevertheless, the consequences of untreated MMN can be far more severe, highlighting the importance of early initiation of IVIG therapy for better outcomes.

In addition to IVIG, other agents such as immunosuppressants, immunomodulators, steroids, and plasmapheresis have been employed in MMN treatment. However, the benefits of these treatments need to be well-established, and in some cases, they may exacerbate symptoms rather than alleviate them.

Dr. Katzberg mentioned that recent research has shifted focus to targeting the complement system, specifically C2, in MMN treatment. C2 is less abundant in circulation than other complement components like C3 and C4, making it an attractive therapeutic target. Being at the crossroads of the classical and lectin pathways, C2 plays a crucial role in their activation. By targeting C2, downstream activation of both pathways can be blocked, potentially reducing inflammation and membrane damage. Empasiprubart, a novel investigational agent, is a C2-specific humanized monoclonal antibody designed to exploit this therapeutic strategy. Empasiprubart features mutations that extend its half-life by increasing its affinity for FcRn, allowing for prolonged action. Empasiprubart binds to C2 at neutral pH, internalizing and degrading it in an acidic environment, thereby reducing C2 levels in a targeted manner.

Dr. Katzberg presented the design of the ARDA trial, a phase II randomized, double-blinded, placebo-controlled study to evaluate the safety, tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of two empasiprubart dosing regimens in adults with MMN. The trial involved an initial IVIG dependency assessment period, followed by a monitoring phase to ensure stability before randomization.

Primary outcomes of the ARDA trial focus on the safety of empasiprubart, assessed through clinical laboratory tests. Secondary endpoints include time to IVIG rescue, muscle strength, motor function, quality of life, treatment satisfaction, and exploratory endpoints such as complement and cytokine levels.

'As MMN is a rare disease, it is critical for us to capture as much information as we can comprehensively. iMMersioN is an effort by ArgenX to do a natural history study.'  said  Dr. Katzberg. This study involves regular clinic visits every three months to monitor various outcomes, aiming to enhance our understanding of the disease's progression and inform future therapeutic strategies. This multi-faceted approach underscores the ongoing efforts to improve treatment options and outcomes for patients with MMN.